Ring enlargements—II

Tclnhedron.

1966. Vol. 22, pp. 20S9 IO 2067.

Ptr~~O~

Prra

Ltd.

Printed

in Northern

Ireland

RING ENLARGEMENTS-II’ THE SCHMIDT

REACTION

ON CIS-8-METHYLHYDRINDAN-l-ONE*

G. DI MAIO and V. PERMU-~TI Istituto di Chimica Organica dell’llniversiti,

Rome., Italy

(Received 30 Norember 1965) Al&act-The Schmidt reaction with cis-8-methylhydrindan-l-one yielded a mixture of enlargement products of quinoline and isoquinoline type namely, octahydro-9-methyl-ibostyril, cyanethylcyclohexan-lone, I-methylen~2cyclohexanepropionitrile, cir- and ~rorrs-4,5,5~6,7,8,9,9a-octahydroBa-methyl-[1,5a)-tetraxoloquinoline and 4,5,5a,6,7,8,9,9a-cctahydro-9a-hydroxy-[l,5a]-tetrazoloquinoline. The origin of the two product types can be accounted for in terms of simultaneous action according to the two possible mechanisms for the Schmidt reaction.

IN PREVIOUS publications,1-s

reactions involving ring enlargement, namely reactions of some cycloalkanones with benzenesulphonhydroxamic acid to give N-hydroxylactams and the Schmidt reaction with hydrindan-l-one were discussed. Besides these two types of ring enlargement, many other reactions in which the entering atom may be nitrogen, oxygen or carbon are known. An interesting problem, common to many of these reactions, arises in the case of bicyclic systems in which the carbon atom involved is in the a-position to the ring junction. In such cases, the direction of the ring enlargement is not only determined by the rules according to which the most substituted carbon atom migrates, and the products sometimes correspond to migration of a less substituted atom or mixtures of products are obtained.P It is generally assumed that steric as well as electronic factors are responsible for these results. Two cases have been reported in previous publications,‘*s but, the oxidation of camphors with Caro’s acid, yielding apparently only acampholide, the “wrong” product from the point of view of electronic rules, is well known. Murray et aI.’ tried to identify the steric factors which operate concurrently with the electronic factors in camphor oxidation and proposed an hypothesis which l

Research carried out with 8nancial support of the Consiglio Naxionale delle Ricerche.

1 Note I, G. Di Maio and P. A. Tardella, Guzz. Chim. Zfaf. 91, 1345 (1961). x L. Pan&i, G. Di Maio, P. A. Tardella and L. d’Abbiero, Z&. Sci. 31, (II-A), 312 (l%l). * G. Di Maio and P. A. Tardella, Guar. Chim. Ztul. 91,1124 (1961). ’ This situation also arises often in monocyclic and noncyclic systems. Many examples are cited by P. de Mayo in MoLmuZarRearr~ements pp. 474,514. Interscience, New York (1963). LA. Baeyer and V. Villiger, Ber. Dtsch. Chem. bes. 35 3625 (1899). * R. R. Saucn, J. Amer. Chem. Sot. 81,925 (1959), demonstrated that by performing the reaction in buffered solution only the lactone derived from migration of the methylated carbon atom cut be isolated. This substance, in contrast to a-campholide is unstable in acid solution and for this reason had not been isolated by Baeyer and Villiger. ’ M. F. Murray, B. A. Johnson, L. R Pederson and A. C. Ott, J. Amer. Chem. Sot. 78,981 (1956). An analogous hypothesis had been formulated for the acyloin rearrangement by I. ElphimoffFelkin. Bulk Sot. Chfm. Z+. 1845 (1956) and by N. L. Wendler, D. Taub and R. Firestone, Experientiu 15, 237 (1959). 2059

2060

G. DI MAIO and V. m

involves an expansion of a 5-membered to a 6-membered ring and rearrangement of the migrating group to produce a transition state with a chair conformation.* Recently, Sauers and Beisler proposed another explanation, namely, the influence of steric factors of a torsional type. e The situation, however, is such that it is often very difficult to predict, even with approximation, the products of a ring enlargement owing to the different factors involved. It is also diEcult to find a substrate in which some of these factors can be eliminated.

I

cam-8-Methylhydrindan-l-one possesses the conformation I with two equatorial and only one axial C-C bond on the cyclohexane ring.lO A molecule of this type should be hindered from attack at the concave side and, therefore, attack of the carbonyl group will occur predo~nantly from the convex side of the molecule.11 A study of the common ring enlargements (the Schmidt reaction, the BaeyerVilliger reaction and the reaction with diazomethane, etc.) on this substrate should result in a better understanding of the reactions involved. It is generally assumed that the SchmidP reaction can proceed via two different mechanisms (A and B)D and this possibility introduces a new variable factor for consideration. It is relatively certain that if the reaction takes path B, the only products are of the quinoline type for the following reasons: + OH R-C

/ \

NH-R

+ R*==C===N + R-C==N-R-=+ \ Nt+ +N, * Cases have been found in which the migration occurs vin transition states undoubtedly in the boat conformation: N. L. Wendler and D. Taub, J. Amer. C’hetn. Sot. 82,2836 (1960); D. Taub, R. D. Hoffsommer, H. C. Kuo, H. L. Slates and N. L. Wendler, Zbid.82,4012 (1960); R. S. Rosenfeld, ibid. 79,554O (1957). In addition an anaIogous case will be described in a forthcoming note on the Baeyer-Villiger reaction with c~~8-~~y~y~rn~-l~ne. l R. R. Sauen and J. A. Beiier,J. Org. Chem. 29,210 (1964). lo C. Djerasi, D. Marshall and T. Nakano, J. Amer. C/rem. Sot. 80,4853 (1958). l1 For an analogous case see R. B. Woodward, I?. E. Bader, H. Bickel, A. J. Frey and R. W. Kierstead, Terrahedron 2, 1 (1958). I* In the following Note the pinacolinic deamination of cis-&methyl-l-exo_~omethyI-hydrindan14 will be described and later the oxidation, by means of peracids of ketone I. la P. de Mayo, Molecular Rearrangements pp. 509410. Interscience, New York (1963) and Refs. cited therein.

Ring enlargement64I

2061

(a) cis-8-Methylhydrindan-l-one possesses only one oxime derivative (II) which has the hydroxyl group in unri position with respect to the methyl group, as is clearly shown by a steric model. This fact was confirmed since the Beckmann reaction on this oxime gives only the amide (III) with a quinoline structure according to NMR spectrum (in CHCl$: singlet at l-26 8 (3H); sharp band at l-50 8 (9-IOH); series of small bands from 2.20 6 to 2.40 6 (2H) which can be attributed to a -CO-CH, function. (b) It is probable that the oxime II and the diazoimino derivative (IV) are isosteric, since the -Na+ group is much more bulky than the -OH group. (c) It is knowrP that diazoimine intermediates rearrange according to the rule on anti-migration, which operates also in the Beckmann rearrangements.

n

III

l!z

Y

If, however, the reaction takes, even in part, the course A, some isoquinoline products should be produced (formation of which would be favoured by the chair transition state obtained by methylene migration, see arrows in V). If molar proportions of ketone and hydrazoic acid are used, a large amount of the starting ketone does not react as shown by GLC analysis. With a 3 : 1 ratio of hydrazoic acid to ketone the GLC of the neutral fraction indicates that more of the starting ketone reacts and no new products are formed, since some of the peaks present in the first GLC disappear. This situation is clearly depicted in Figs. 1 and 2.‘” With a hydrazoic acid: ketone ratio of 3: 1, the reaction products were separated into neutral and basicfractions. The neutral fraction partitioned by chromatography on silica gel, gave as major product, 10-l 5 y0 of cis-ocrahydro-9-merhylisocarbostyril (VI) based on the starting ketone and identified by elemental analysis, IR spectrum [bands at 3450, 3180, 3050 and 1667 cm-l (KBr)] and NMR spectrum (in CHCl,) singlet at 1.22 6 (3H); sharp band at 1.60 8 (8H); triplet very deformed at 3.38 6 (3H) attributed to a -CO-NH-CH,function. Further, this compound is different from the amide (III) obtained by Beckmann rearrangement of II to which must be attributed a quinoline structure.16 I4 P. A. S. Smith and J. P. Horwitz, J. Amer. Ckem. Sot. 72,3718 (1950). U Figs. 1 and 2 also reveal the complexityof the reaction. It can be assumed that all the peaks present in the first chromatogram but not in the second are due to intermediates which react with excess of reagent. This excess of reagent also enhances the size of the basic fraction of the reaction. I* Data reported in this work confirm the results of I. L. Knunyants and P. B. Fabrichnyi, Dokl. Akad. Nauk S.S.S.R. 68,523 (1949) for tetralone and of R. C. ElderEeld and E. T. L&n, J. Org. Chem. 26,1703 (1961) for norcamphor and cyclopentanonorcamphor. The different behaviour of the Schmidt and of the Beckmann reactions on the same ketone, in our opinion, are caused by the fact that the Beckmann reaction is controlled by the stereochemistry of the starting oxime, whereas in the Schmidt reaction a new control is introduced with the direction of the attack of the reagent on the substrate and with the duplicity of the mechanism.

Cr. DI MAIO and V. PERMurn

2062

CH,

O C”z

clJL_A

NH +

CN

ti

!zlI

H H%

N-N

N-N

+

+ IX

s?n

CIS-a- METHYL HYDRINDANONE

-1

\

_

START

FIO. 1

Ring enlargements-~

2063

-_

START FIQ.

2

nitrile VII (3% of the starting ketone) identified by comparison of the parent acid with an authentic sample, and a mixture of two tetrazoles which could not be separated and presumably are VIII and IX. The NMR spectrum of the mixture (CC13 shows two singlets at 1.35 8 and 1.58 6, with about the same intensity, attributed to the angular methyl group, and a complex multiplet centered at 2.95 8 which can be attributed to the tetrazole system N The neutral fraction

also gave the unsaturated

-cH*-cy. The lack of absorption \

near 45 d, the position corresponding to the

N \ C=N

absorption of group -CH,-N

/ ,17 excludes the presence of tetrazoles of the \

N=N isoquinoline type. la These two compounds were produced in 8-10 % based on starting ketone and the GLC showed them to be present, in about equal proportions. As the basic fraction was extremely unstable, the neutral mixture derived by mild acid I7The tetmzole obtained from cyclohexanone poweses the following bands: 1.95 &4H) broad, mukiplet centered at 3.02 42I-I); multiplet centered at 448 &2H) (spectrum in ccl,). IDLater, a possible explanation for the formation of the rnurrisomer will be given.

G. DI htuo and V. PERMurn

2064

hydrolysis was investigated and found to consist mainly of cyanoethyl-cyclohexanone (X) and another compound (XI). Cyanoethyl-cyclohexanone (X) was formed in 20% yield (based on the starting ketone) and was identified by comparison with an authentic sample. After hydrolysis, X gave cyclohexane-1-propionic acid le also identified by comparison with a known sample. Compound XI gave a satisfactory elemental analysis for the formula ~H,,N,O. It was formed in 15 % yield with respect to the starting ketone. The IR spectrum of this compound does not show absorptions typical of amides, but shows hydroxyl absorption at 3 130 cm- l. The NMR spectrum (Ccl,) does not possess bands which could be assigned to methyl groups, but possesses a triplet at 3.02 6 which can be N / assigned to a -CH,-C group and an extended peak at 568 6 which disappears \ N after exchange with D,O. All these characteristics point to the structure XI and the compound is evidently closely related to cyanoethyl-cyclohexanone from which it could be derived by reaction with hydrazoic acid, although all attempts to transform X into XI under normal conditions of the Schmidt reaction were unsuccessful. N-N

cc/N

aY

X

Xl

The total yield of isolated compounds was approximately 60% based on starting material, but the reaction mixture contained gummy products as well as other minor constituents. DISCUSSION The above results show that although carbostyril (VI) is one of the major products of the reaction, compounds (VII, VIII, IX, X and XI) produced by migration of the more substituted carbon atom are prevalently formed and are derived from a common intermediate (XII).8o A careful examination of the data indicates that A and B mechanisms result in two different types of ring enlargement. In fact, it must be assumed that no quinoline compound can be formed via A mechanism for the following reasons: (a) As tetrazoles cannot be obtained by action of hydrazoic acid on the corresponding lactams, compounds VIII and IX should be formed via intermediates IV -+ XII following the B mechanism. (b) The unsaturated nitrile (VII) and, therefore, cyanoethyl-cyclohexanone, cannot be formed via amide III which could be formed by the A mechanism, because

1’ The scheme VII + XV + X, accounts for the loss of the methyl group and, therefore. formation of methylamine. However, attempts to isolate methylamine from the acid hydrolysis products were unsuccessful. I0 Fragmentation of XII is in keeping with the quaternary nature of the methylated carbon atom.

2065

Ring cnlargement.+II

the latter is stable towards sulphuric acid under the conditions of the Schmidt reaction.” (Experimental.) On the other hand, since no tetraxoles of the isoquinoline type were isolated, the amide VI does not result from rearrangement of XIII. In fact, of the two possible diaxoimino stereoisomeric derivatives (IV and XIII) the second, which should give enlargement in the direction of isoquinoline compounds, has little chance to exist. This is confirmed by the fact that cis-8-methylhydrindan-l-one forms only one oxime (II; corresponding to diaxoimino derivative, IV) and that the diazo group is sterically more bulky than the hydroxyl group. Hence, VI is probably formed from the intermediate V via the A mechanism only. In intermediate V the migration of the less substituted carbon atom (see arrows in V) is favoured in accordance with the hypothesis proposed by Murray et aL7 assuming a more energetically favoured transition state with a chair conformation. Mechanism A is, therefore, less favourable for the formation of III because of a boat transition state. An alternative route for the formation of III is via intermediate XII, which, will react with excess hydrazoic acid present yielding the tetrazole VIII rather than react with the water produced.

CN

X

The origin of compounds VII, IX and X can be easily rationalized as shown in Table 1.lOsss In conclusion it is suggested that the products of ring enlargement do not depend *I On the

contrary, by action of PC& in pet. ether at O’, amide III cao be easily converted into mmpound VII. *’ The step XIV + XVI is analogous to the Ritter reaction: J. J. Ritter and J. Kalish, J. Amer. Chem. Sot. 70,4048 (1948).

G. DI MNO and V. PEIUUITI

2066

on steric and electronic factors, but result from two parallel reactions, each governed by steric factors leading in different directions to ring enlargement. Thus, the formation of compounds of the quinoline type is probably due to the necessity of the truns transposition of the diazoimino intermediate (IV) than to the preferable migration of the methylated carbon atom. It should be of interest to determine the distribution of products resulting from a ring enlargement reaction proceeding by one mechanism only, and migration of the methylated carbon atom via sterically unfavourable boat conformations. EXPERIMENTAL M.ps were taken on the Kofler block and are uncorrected. IR spectra were taken as liquid films or KBr disks on a Perk&Elmer Model 137 Infracord spectrophotometer. The NMR spectra were taken in CHCl, or in Ccl,, as specified, on a Varian A 60 spectrometer; all chemical shifts (6 in ppm) were measured downfield from tetramethylsilane serving as internal standard. GLC were carried out on a Perk&Elmer 800 instrument, using as stationary phase fluorourate silicon FS 1265 and employing N, as carrier gas. The Schmidt reucrfon wirh cis-8-methy@&hr&nhycirindan-l-one (I). A solution of 2.29 g IU in 120 ml benzene was treated during ice cooling, with 7 ml cont. H,SO, and then dropwise (1 hr) with 25 cc of a 7% solution of hydrazoic acid in benzene. The stirring was continued until the gas evolution ceased (20 min). The reaction mixture was poured onto ice and extracted with CHCI,. The extract was washed with 2N NaOH and water, dried over Na$lO, and then evaporated to dryness under red. press. The yellow oily residue (580 mg) was chromatographed on silica gel (30 g). The elution with CHClt provided a number of 15 ml fractions which were examined by TLC and, according to properties, combined as follows: Fractions 3 4 5-6 7-18 19-34 35-41 42-82 83-end

Wt (mg_) 47 40 12 126 22 220 15

Physical appearance yellow oil yellow oil yellow oil yellow oil yellow oil + crystals yellow oil + crystals brown oil

The IR spectrum of fraction 4 (VII) showed a strong absorption located at 2250 cm-i due to the -CN group. This fraction was hydrolysed by boiling under reflux with 30% NaOHaq (3 ml) for 24 hr. After dilution with water and extraction with ether, the resulting aqueous solution was aciditied with HCl (Congo Red) and extracted with ether. Evaporation to dryness of the last dried ethereal extract gave a residue of 42 mg. This residue was transformed into benxylisothiouronium salt of I-methylenecyclohexans2-propionic acid according to Bruderlein et al.‘. After two crystallimtions from MeOH it had m.p. 148-149” and showed no depression upon mixture with an authentic sample. The IR spectra of the two substances were identical. (Found: C, 64.80; H, 8.05. Calc. for CI~HIOOINIS: C, 64.65; H, 7.84 %.) Fractions 19-34 were crystallixed from pet. ether until the m.p. was 97.5-99” and could not be raised by further crystallization. GLC showed that this product consisted of a mixture of two compounds approximately present in the same proportion (VIII and Ix). (Found: C, 6206; H, 8.39; N, 28.49. C,,H,,N, requires: C, 62.47; H, 8.39; N, 29.14%) Fractions 42-82 were sublimed at lw/O*S mm to give a material (VI) m.p. 107-108”. After crystallization from ether-pet. ether, the m.p. reached 112-113”. (Found: C, 71.73; H, lo38; N, 8.41. ClOH1,NO requires: C, 71.81; H, 10.25; N, 8.38%) The spectral data of all these compounds are reported in the theoretical section. U W. S. Johnson, J. Amer. Chem. Sot. 66,215 (1944). u F. Bruderlein, H. Bruderlein, H. Favre, R. Lapiem and Y. Lefebvre, Cumd. J. Chem. 38, 2085 (1960).

Ring enlargements--II

2067

After 7 days after completion of the reaction, the diluted acid solution was extracted with CHCl, The extract was washed with 10% Na,CO, and water, dried over Na,SO, and then evaporated to dryness. The residue (1.25 g) was chromatographed on silica gel (64 g) and fractions of 30 ml each were collected. The tirst 30 fractions were eluted with CHCl, and then AcOEt was used. The fractions were examined by means of TLC and, according to properties, combined as follows: Fractions l-7 8-26 32-50

Wt (mg) 50 400 300

Physical appearana oil yellow oil crystals

Fractions 8-26 were distilled in a Hickman apparatus at 175”/25 mm to give a colourless liquid whose IR spectrum was identical with that of the cyanoethyl-cyclohexanone (X). (Found: C, 71-28; H, 8.53. Calc. for GH,,NO: C, 71.49; H, 8.67%) Acidic hydrolysis of this compound yielded cyclohexan+l-propionic acid m.p. 615-63” and on admixture with an authentic sample. The IR spectra of these two substances were identical. Fractions 32-50 were decoloured with activated charcoal and crystallimd from ether-pet. ether. The crystalline compound (XI) obtained had m.p. 118-119”. (Found: C. 56.10; H, 7.76; N, 28.65. C,H1,N,O requires: C, 55.65; H, 7.27; N, 28.85x.) The spectral data of this compound are reported in the theoretical section. 7’7reBeckmann reaction on cis-8-methylhydrindan-1 -one oxime (II). A solution of II” (340 mg) in dry ether (7 ml) was gradually treated with 500 mg PC],, with ice cooling. The reaction mixture was left to stand overnight at room temp. and then poured onto 10 g ice. The resulting suspension was extracted with CHCl*. The extract was washed with 10 % NaCO, and water, dried over Na,SO, and evaporated to dryness. The oily residue was distilled in uacuo (at 150-160”/24 mm) to give a colourless liquid (l-methylene-cyclohexane-2-propionitrile) and a residue which, after de-coloration with activated charcoal, was distilled at 115”/0*2 mm to give a colourless viscous liquid, which slowlycrystallixed (III). After recrystallization from pet, ether it melted at 48-49”. The spearal data of this compound are reported in the theoretical section. (Found: C, 71.86; H, 1@19; N, 8.36. CiOHH,,NOrequires: C, 71.81; H, 10.25; N, 8*39x.) Action of cont. surphuric acid on carbostyril (III). Carbostyril (ID; 50 mg) was added to a mixture of 35 ml benzene and O-2 ml cont. H,!lO,, with ice cooling. The resulting mixture was stirred in an ia bath for 1 hr and then pouted on to 25 g ia. The suspension was extracted with CHCl,. The extract was washed with 10% Na&O, and water, dried over Na,SO, and evaporated to dryness. The residue (50 mg) had an IR spectrum identical with that of the starting material. Acknowledgment-We

thank Dr. C. Iavarone for NMR measurements.