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Conformational Studies of R-(-f)-2-Alkylidene- and R-(—)-2-Benzylidene-5-methylcyclohexanones

Devinder K . Anand, Michael K . Hargreaves*, and Mohsin A. K h a n

Chemistry Department, North East London Polytechnic, Romford Road, Stratford, London E15 4LZ

Z. Naturforsch. 36b, 978-988 (1981); received December 1, 1980/April 8, 1981

2-Alkyl/arylidene-5-methylcyclohexanones, CD Spectra, ORD Spectra, NMR Spectra The eis and trans 2-alkylidene-5-methylcyclohexanones have been separated and

distinguished. 2-Benzylidene-5-methylcyclohexanone was also prepared in both forms. The CD, ORD, UV and IR spectra are recorded and discussed. The NMR data include solvent and temperature effects.

Following earlier work on pulegone oxide and related compounds [1] it was decided to examine the CD and O R D spectra of the eis and the trans (methyl-carbonyl) isomers of the t i t le compound. After some initial difficulties connected with the isomerisation, both the eis and trans isomers of 2 -ethylidene-5-methylcyclohexanone were prepared.

Preparative Methods

The reaction scheme shows the various methods which were tried for the preparat ion of the title compounds. Method 1 (ref. [2]) gave a 20% yield, bu t the product was contaminated with start ing material and self-condensation products [3]. Meth-od 2 (ref. [4]) gave a low overall yield, 7 - 9 % . Method 3 (ref. [5]) gave a low yield, 10% (apparently it is unsuitable for ketones subst i tuted a t C3); a mixture of compounds 6 and 7 was obtained as shown by NMR Method 4 (ref. [6-8]) gave a mixture of eis and trans isomers in the rat io 9 : 1 as deter-mined by NMR. When benzaldehyde was used with method 1 a dibenzylidene compound was obtained, bu t a good yield was obtained a t a higher tem-pera ture [9] (method 5). No yield was obtained by the glyoxalate method with benzaldehyde.

All the methods enumerated above yield a mixture of eis and trans 2-alkyl(aryl)idene isomers. Unlike the trans isomer, t he eis 2-ethylidene-5-methylcyclo-hexanone could not be separated from the isomeric mixture by simple vacuum fract ionation or by gas chromatography, probably owing to thermal iso-

merisation (c/. ref. [10]). However, in the presence of p-toluene-sulphonic acid the eis isomer of 2-ethyl-idene-5-methylcyclohexanone was obtained in yields of up to 50%. The pure eis isomer was obtained from this enriched mixture, by repeated rapid distillation under reduced pressure.

Thermal isomerism of R-(-\- )-2-ethylidene-5-methyl-cyclohexanone

The failure of the separation of the isomeric products obtained by method 1 was thought to be due to thermal isomerisation. The effect of tem-perature and t ime on a sample kep t under argon was therefore studied. The results show t h a t the proportion of trans isomer is favoured a t elevated temperatures and t h a t the conversion of eis to trans is faster a t higher tempeia tures .

Nuclear magnetic resonance spectra

Initially, when only a mixture of the eis and trans 2-ethylidene-5-methylcyclohexanone was available, i t was impossible to distinguish the protons for analytical purposes, b u t with the preparat ion of the pure species the following shifts were found. The protons bonded to sp2 carbon were located a t 6.71 and 5.71 ppm (CDCI3) in the trans and eis methyl compounds (16 and 17) respectively. These figures agree with the values of Dubois and Dubois [11], and also with the addi t iv i ty rule produced by Pascual, Meier, and Simon [12] (c/. J a c k m a n and Sternhell [13], and Reddy and Goldstein [14]):

REACTION SCHEME

Method 1 MeCHO etc.

<5C=C-H = 5 . 2 8 + Z.

<5c=c-i :=C-HB

Chemical shift for ethylene gem methyl eis carbonyl trans alkyl

Z Z z

5.28 0.44 1.13

—0.29 6.56 ± 0 . 3 ppm

Chemical shift for ethylene gem methyl Z trans carbonyl Z eis alkyl Z

5.28 0.44 0.81

— 0.26

6.27

Thus in the case of trans methyl compound (16) t h e observed value is clearly within the expected range whilst in the case of the eis methyl compound (17) there is some discrepancy. Evidence for t h e confirmation of assignment of the eis and trans

± 0 . 3 ppm

configuration was obtained by the analysis of aromatic solvent induced shifts (ASIS). The spectra of both t h e isomers were recorded a t 100 MHz in deuteriochloroform and deuteriopyridine. The re-sults are given in Table I . According to the carbonyl

plane rule of Williams and Bhacca [15] and Connally and McCrindle [16], the methyl group in the trans methyl (16) and the proton in the eis methyl isomer (17) are shielded f rom the C = 0 group in the aromatic solvent, and hence shifted upheld compared with the position in the aliphatic solvents, whilst the p ro ton = C - H and the = C - C H 3 of 17 are deshielded and, therefore, subjected to downfield shift (c/. Cottee and Timmons [10] in the case of trans 2-ethylidenecyclohexanone). Thus, on going

Table II. 220 MHz spectra of trans R-( + )-2-ethylidene-5-methylcyclohexanone, trans R-(—)-2-benzylidene-5-methylcyclohexanone and R-( + )-pulegone.

ö ppm R-( + )-Pulegone trans 2-Ethylidene-5- trans 2-Benzylidene-5- Assignment methylcyclohexanone methylcyclohexanone

1.00 (d) 3H JH-CH3 6.0 -CH-CH 3

1.01 (d) 3H JH-CH3 6.3 -CH-CH 3

1.02 (d) 3H JH-CH3 6.0 -CH-CH 3

1.30 (m) 1H signal width (m) 1H signal width may be Hsa or H4a 40 Hz ca. 40 Hz

may be Hsa or H4a

1.32 (m) 1H may be HSA or H4A

1.52 (m) 1H 1.75 (s) 3H (d) 3H J 7 = CH-CH3

trans to C = 0 1.85 (m) 1H overlapping with

signals of = C(CH3)2

1.82-2.15 3H overlapping 3H overlapping HSA or HßA of sequence signals of sequence signals

1.98 (s) 3H =CH-CH3 (s) (eis to C = 0)

2.05 1H overlapping with signals of methyl

HßA

2.24 (m) 1H signal width under 31 Hz

H3A

2.25 (m) l H J s a e 15.2 J 3a4a 11-0 ^3a4e 5.0

H3A

2.47 (d,d) 1H J6ae 11.0 HßE J 5a6e 2.6

2.53 ( d , d ) l H J 6 a e 12.5 HßE J5a6e 2.5

2.55 1H signal overlapping with signal of HEE

H3A

2.65 (d ,d ) lHJ 6 ae 12.5 HÖE J5a6e 2.5

2.70 (d,t) 1H i73ae 15.5 (d,t) 1 H «73ae 16.0 H3e J3e4a 5.0 «̂ 3a4a 6.0 J3E4E 4.5 Jz&ie 5.0

3.02 (d,t) 1H «73ae 15.5 «̂3E4A 5.0 J3E4E 4.5

H3e

6.71 (q) 1H J 7, 7, 7 = CH-CH3

7.3-7.5 6H all protons of =CH-C6H5

Table I. Aromatic solvent-induced shifts of protons of R-( + )-2-ethylidene-5-methylcyclohexanone 100 MHz.

ö ppm 6 ppm <5CDC13-<5C5D5N (CDC13) (C5D5N)

trans methyl = C-CH3 1.73 1.57 0.16 = C-H 6.71 6.79 — 0.08

eis methyl =C-CH 3 1.86 1.88 —0.02 = C-H 5.71 5.57 0.14

from deuteriochloroform to deuteriopyridine there is a downfield shift of = C - H in the trans compound (16) and an upfield shift in the eis compound (17). These results are in agreement with those of Cottee and Timmons [10] for a,/9-unsaturated ketones including trans 2-ethylidenecyclohexanone.

Another technique for distinguishing between compounds with eis and trans protons has been employed by Ronayne, Sargeant, and Wilhams [17]. They observed tha t with decrease in t empera tu re the signals of trans methyl in 2-ethylidenecyclo-hexanone moved upfield in toluene-dg, b u t t h a t of the eis proton moved downfield. Table I I I shows t h a t in the case of trans isomer (16) t h e = C - H moved downfield whilst the = C - C H 3 moved upfield. I n the eis isomer (17), on the other hand, the = C - H moved upfield and the = C - C H 3 downfield as would be expected.

Chemical shift of ring protons

Owing to the overlapping of signals not all the protons associated with the ring could be assigned. However, all four compounds show similarity in their components. Those which could be assigned are indicated in Table I I .

Table III. Temperature variation of chemical shift of protons of R-( -f- )-2-ethylidene-5-methylcyclohexanone in toluene dg 100 MHz (Hz x 102).

Temperature eis trans [°K] <5=C-H <5 = C-CH3 <5=C-H <5 = C-CH3

213 526 190 686 132 223 528 189 685 133 233 529 189 682 133 243 531 188.5 681.5 134 253 532 188 680 135 263 534 187.5 679 135 273 534 187.5 677 137 283 536 187 676 137 293 538 187 675.5 138 303 539 187 675.5 139 313 540 187 675 140 323 541 187 673 141 333 542 187 673 141

Infrared spectra

Most discussions of the spectra of eis and trans compounds have centred on the stretching fre-quencies. I n the case of the trans ethylidene com-pound, these come a t 1680 cm-1 ( C = 0 ) and 1612 cm"1 (C=C), whilst in the eis ethylidene com-

pound the corresponding values are 1685 and 1621 cm - 1 . The differences between C = C and 0 = 0 — 0 = O are thus 68 and 64 cm - 1 respectively. These differences are very similar, as may be expected, since both have s-eis conformations. Timmons [18] found 65 cm - 1 for the s-eis pulegone and 35 cm - 1 for the s-trans carvone. Similarly, Erskine, and Waight [19] found 69-74 c m - 1 for s-eis and 38-45 cm - 1 for s-trans compounds, and Noack [20] also found 66-68 c m - 1 in the case of trans 2-ethylidenecyclohexanones in chloroform solutions; bo th have s-eis conformations of C = C - C = 0 . The I R frequencies of 2-benzylidenecyclohexanone show t h e same frequency differences.

On the other hand, the spectrum of 2-benzyl-6-methylcyclohexanone shows the differences a t 66 c m - 1 despite its supposedly s-trans conformation [21]. Thus, where an aromatic ring is a t tached a t carbon ß to the ketonic group, this criterion would appear to fail. Erskine and Waight [22] showed t h a t in a,/S-unsaturated ketones where there are alkyl or phenyl substi tuents a t the double bond, the rat io of the intensities is between 0.6 and 3.5, whereas for transoid compounds it is greater t han 6.

I n the present compounds the ratio of peak heights, which can be regarded as a rough measure of the intensity, were 0.94 and 1.51 for the trans and eis 2-ethylidene compounds (16 and 17) respec-tively, and 1.06 and 4.0 in the trans and eis benzyl -idene compounds (18 and 19) respectively. Dubois and Dubois [11] claimed tha t the eis and trans isomers of 2-ethylidenecyclohexanones have similar I R spectra, bu t i t can be seen t h a t there are differ-ences in our compounds a t 1600-1700 c m - 1 and again a t around 1500 and 1250 cm - 1 . Erskine and Waight [22] suggested tha t the main factor which influences the intensity of the C = C stretching on the a ,^-unsaturated ketone is the direct field effect of the C = 0 group. They believed tha t the resultant dipole in the C = C will be greater in the planar cisoid t h an in the planar transoid form, the mutua l effect of the two dipoles being to reduce the intensity of t he 0 = 0 band and increase the intensity of the C = C band in the cisoid as compared with the transoid form.

Thus, in the present series of s-cisoid compounds the chromophoric system may be planar or nearly planar in the trans isomers (16 and 18), whereas in the eis isomers (17 and 19), coplanarity can only be achieved with difficulty, due to the interaction of

the C = 0 group with the alkyl (aryl) group. Braude and Timmons [23] showed tha t the position of vc=o with the degree of co-planarity in the enones:

CH3 CH3

c c / \ • \

Ph H H Ph

18 19

a C 0 C H 3 ^ C O C H j Q^COCHj

1663 cm"1 1686 cm"1 1693 cm"1

I t is apparent tha t , as it becomes difficult for the carbonyl side chain in the preceding enones to mainta in coplanarity with the cyclohexane ring, the VC—O values approach tha t of the sa tura ted com-pounds. I n the present s tudy the vc=o values of the eis and trans methyl compounds (16 and 17) are quite close bu t considerably lower t han t h a t for sa tura ted carbonyl group. This indicates t h a t the conformation of the conjugated chromophore is only slightly different in the two compounds, bu t in the case of benzylidene compounds (18 and 19) it may be seen t h a t the position of vc=o of the eis isomer being 1695 cm - 1 , t he chromophoric system is not planar in this isomer. The vc=o value of the trans isomer is 1675 cm - 1 , which indicates a high degree of coplanarity of the chromophoric system as compared with the eis isomer.

UV spectra

The UV spectra of the eis and trans isomers of bo th the ethylidene and the benzylidene compounds were recorded in polar and non-polar solvents and are shown in Figs. 1-8. For the sake of comparison, t he spectra of pulegone were also recorded. I n the case of the trans ethylidene compound n-+ji* as well as n7i* bands appear a t only slightly longer wavelength t h a n the position of these bands in the spectrum of the eis isomer in the same solvent. However, the intensity of the absorption of the 71-+71* band of the trans isomer is much greater t h a n t h a t of the eis isomer but the intensities of n->7t* do not differ noticeably.

I t is known t h a t the effects of non-planari ty on the position of the characteristic absorption band

of conjugated systems are not reliable but the effect on the intensity of the band is a simple criterion [24], Owing to depar ture of the enone chromophore from planari ty, t he interaction between the Tz-orbitals decreases and, therefore, the intensity of absorption is usually decreased. Thus, comparison of positions and intensities of n -*• n* bands in the eis and trans ethylidene compounds indicates t h a t the conforma-t ion of the enone chromophore is different in the two isomers and also the n ti* transition of trans has a quite large intensity compared with the eis isomer in the same solvent. The chromophoric system may be non-planar in the eis isomer but in t h e trans isomer it may be nearly planar.

Both the isomers of the benzylidene compound show two bands in the 220-290 nm region; the trans isomer also shows a band around 340 nm in non-polar solvents which is absent in polar solvents. This band should be due to n -> TI* transition of the conjugated carbonyl group and its absence in polar solvents is perhaps due to a blue shift so tha t it lies underneath the strong absorption band a t 298 nm. The absence of this band in the eis isomer probably results f rom the steric hindrance of the phenyl group by the oxygen of the carbonyl group, which prevents the planar i ty of the chromophoric par t of t he molecule. The non-planarity of the olefinic C = C and the carbonyl group is likely to shift the ab-sorption of the C — 0 group towards tha t of the unconjugated carbonyl group and hence the n - > n * transi t ion should be at a shorter wavelength com-pared with similar transition in the trans isomer. Thus the appearance of this band in the trans isomer in non-polar solvents and its absence in the eis isomer in all solvents probably reflects the con-formation of the enone chromophore in the two cases. The chromophoric system of the trans isomer (18) may be compared with t h a t of benzylidene acetone (20) [25] and the aldehyde (22) [26] which have the same position and equal molecular extinc-t ion coefficient of the long wavelength band, indicating similar conformations of the chromo-phoric system. The high value of Amax probably indicates t h a t the chromophoric system is conju-ga ted and, therefore, planar. The trans isomer has a subst i tuent on the a-carbon atom and, therefore, according to Woodward 's rule [27], as modified by Fieser and Fieser [28], the maximum might have appeared a t about 285 + 1 0 = 295 nm, but the observed max imum is at about 289 with a lower

20 «M o 15 X 5 10

~ 5

-5 M o -10 X

-15 -15 0

-20

20

'o 15 X

10 10 10

5

- 5 <M 'o-10 ~ -15 <P " - 2 0

Figs. 1-8. UV, CD and ORD Spectra of eis and trans R-( + )-2-ethylidene- and R-(—)-2-benzylidene-5-methyl-cy clohexanones.

extinction coefficient. This probably indicates t h a t 18 is not a perfectly planar arrangement, though the carbonyl group and the olefinic bond may be coplanar. The possibility t h a t the phenyl ring may be coplanar with the olefinic bond is ruled out on the basis of comparison with styrene (21) [29].

The £max appearing a t 267-272 nm in the eis isomer is lower than t h a t of the K band of 21. This probably indicates t h a t the phenyl ring and the olefinic bond do not achieve coplanarity as in styrene. If the chromophoric system in the eis isomer is t reated as t h a t of a disubst i tuted styrene, the expected position of the absorption maximum would be 248 + 20 = 268 nm. The maximum appears a t 272 nm in alcohol.

Another absorption maximum appears in the range 220-221 nm in the spectrum of the eis isomer and in the range 219-223 nm in the case of the trans isomer of the benzylidene compound. Thus the position of this band is similar in the two isomers.

The intensity of this band in the trans isomer is weaker than the intensity of the long wavelength band, but in the eis isomer it is stronger t h a n the intensity of the long wavelength band as well as the same band of the trans isomer, which behaviour is similar to t ha t of trans and eis stilbene (23 and 24) [30, 31].

CD and ORD spectra

The CD and ORD spectra of the isomers of bo th the ethylidene and the benzylidene compounds, recorded in polar and non-polar solvents, are shown in Figs. 1-8 .

The CD and ORD spectra of the trans 2-ethylidene compound (16) in polar solvents (e.g. methanol) shows an apparently simple dichroic absorption a t about 320 nm. However, in non-polar solvents there is a bathochromic shift to 340 nm and there is a clear suggestion of structure within the band

CH,

ö

< § X

c - c % 0 '

< 2 > S CH, < Ö > <

18 xr 19 xr

223 8.670 289 19.750

(nms )

220 273

Erna* 9.350 6.450

20 21 Xr H 0

Xmax Emax 220 12.000 248 286 25.000 282

H H

C-H I H

Emax 14.000

760

< Ö X /h < ° > '

22 x

H /

-C H /

C = C / ^

H 0 •max emax

H

c=c

23 x

285 2.500

max £max 228 16.400 293 27.000

in heptane

24 x max '•max 228 24.000 280 18.500

in ethanol

(Figs. 1-2). The eis compound (17) shows a CD absorption a t a ra ther longer wavelength (325 nm in methanol). Whilst in the ORD the negative maximum is ra ther higher, again the CD band shifts to a longer wavelength in non-polar solvents (340 nm), bu t in this case there is no suggestion of complexity in the band.

The first th ing t h a t is apparent in the CD spectra of the eis and trans benzylidene compounds (18 and 19) is t h a t the introduction of the phenyl group produces a strong negative CD absorption a t about 270-280 nm. The curves of the eis phenyl show very nicely the interaction of the two CD absorption bands to produce anomalous rota tory dispersion exactly like t h a t characteristic of a two-term Drude

equation, yet it is clear t h a t many more t h a n two absorption terms mus t be involved because there are two active bands in the region of observation. I t is noteworthy t h a t the intensity of the CD ab-sorption in methanol of the trans benzylidene isomer (18) is twice t h a t of the eis isomer (19) a t 340 nm, whereas a t 270 nm the ratio is four times.

I n the trans benzylidene compound there is little variat ion in wavelength or in intensity on going from the polar to non-polar solvents. Whereas with the eis compound the wavelength of absorption changes f rom 275 nm in methanol to 305 nm in hexane with a variat ion in intensity from 1800 in methanol to 100 in hexane, with the shorter wavelength band the corresponding changes are

CD maxima of eis and trans ethylidene and benzylidene compounds in various solvents [0] X 10~3.

max Methanol Ethanol Iso-propanol Dioxan Cyclohexane Hexane

Ethylidene trans 324-342 + 2.04 + 1.93 + 1.96 + 1.74 + 1.85 CIS 325-341 + 0.77 + 0.64 + 0.58 + 0.54 + 0.56

Benzylidene trans 340-348 + 4.1 + 4.1 + 3.5 + 3.6 + 3.7 + 3.5

276-280 — 32.6 — 34.8 — 33.5 — 34.0 — 33.1 — 34.1 eis 335-362 + 1.8 + 1.8 + 1-4 + 1.1 + 0.2 + 0.1

275-305 — 8.1 — 6.0 — 4.1 — 3.0 — 3.1 — 2.5

from 262 nm to 302 nm and f rom 8100 to 2500 in intensity.

Both the benzylidene compounds (18 and 19) show strong negative CD at or below 300 nm and positive CD at about 340 nm, with fur ther positive peak a t lower wavelengths. The negative por t ion must be due to the phenyl group since this is absent in the ethylidene compounds (16 and 17). All four compounds show positive peaks a t about 340 nm, but where negative peaks appear alongside it is possible t ha t the intensity of the positive peak is reduced by overlap. One of the major factors determining the CD spectrum will be the degree of co-planarity of the chromophores. If it were the case tha t the ethylene link and the C = 0 were both in a horizontal plane then the methyl and hydrogen will also be in t ha t plane and would not contribute to the induced dissymmetry of the chromophore. On the other hand, the methyl group of the cyclo-hexane ring would clearly do so.

The intensity of the CD absorption of the trans ethylidene compound (16) in hexane and methanol is about three times t h a t of the eis compound (17) so t h a t the behaviour of the ethylidene and benzylidene compounds is similar except t ha t there is greater variation in the intensity of the eis benzylidene compound with change of solvent t h a n in the ethylidene series; these facts are consonant with the idea tha t the enone chromophore is more planar in the trans t h a n in the eis form and t h a t there is interaction between the side chain and the carbonyl group in the eis forms which is lessened in polar solvents.

Conformations of eis and trans R-(-f- )-2-ethylidene and R-(—)-2-benzylidene-5-methylcyclohexanones

The consideration of I R , UV, CD, and O R D spectra all lead to the conclusion t h a t the conjugated chromophore - C = C - C = 0 has a nearly planar con-formation in the trans ethylidene and trans benzyl-idene compounds (16 and 18) and a non-planar conformation in the eis isomers (17 and 19). The similarity of ORD curves of R-(+)-pulegone and the eis ethylidene compound (16) suggests t h a t both compounds have a similar conformation. On the basis of the Octant rule Feeley [32] has suggested a chair-like conformation for R-(+)-pulegone; the eis ethylidene and eis benzylidene compounds m a y also be assigned a chair-like conformation (24).

^ a) b) a) R = Me (eis ethylidene compound),

= Ph (eis benzylidene compound). b) R = Me (trans ethylidene compound),

= Ph (trans benzylidene compound).

The trans ethylidene and trans benzylidene com-pounds (16 and 18) cannot have a chair-like con-format ion because of a nearly planar conformation of the chromophore in them. The Drieding models of these compounds suggest an envelope or folded conformation (25).

Experimental R-(+)-pulegone was prepared from commercial

oil of pennyroyal via the bisulphite compound. I t had b .p . 55.5-56/0.5 mm, n™ 1.4848, [a]2« 22.85° neat . R-(+)-pulegone was heated with hydrochloric acid (4M) to give R-(+)-3-methylcyclohexanone, b .p . 165-166°, 1.4470, [a]2^ 11.90° neat.

R-(-+-)-2-Ethylidene-5-methylcyclohexanone To sodium hydroxide, 33 ml of 30%, and

R-( + )-3-methylcyclohexanone, 38 g, cooled to 0 °C, was added dropwise, separately, acetaldehyde, 44 g and 77 g of the ketone so as to keep the mixture a t 0 °C. Fur the r portions (5-10 ml) of 30% sodium hydroxide were added over 3 h to a total volume of 75 ml. The reaction mixture was stirred a t 0 °C for a fu r ther 3 h and then allowed to warm up to room tempera ture overnight. The organic layer was separated from the aqueous layer, which was then thrice extracted with ether. The combined organic layers, dried (MgSO^, and distilled under reduced pressure using an insulated column packed with helices, gave a fract ion b .p . 70-72°/2.5 mm, 9.2 g (20%), (the desired products contaminated with star t ing material), this purified by gle, had n ^ 1.4875, [a]f° 79.0° (c = 3, I = 1 in methanol).

C 9H14O Found C 78.2 H 10.7, Calcd C 78.2 H 10.1.

Wi th 2:4-dinitrophenylhydrazine this gave a deri-vative, m .p . 205-206 °C.

CisHxgN 4O4 Found C 56.4 H 5.7 N 17.5, Calcd C 56.6 H 5.7 N 17.6.

R-(-1- )-2-Ethylidene-5-methylcyclohexanone via glyoxalate

Sodium ethoxide, prepared from 5.8 g sodium and 75 ml dry ethanol, was cooled in an ice-salt bath and a chilled mixture of R-(-(-)-3-methylcyclo-hexanone, 28.3 g, and diethyloxalate, 36 g, was added with stirring at such a rate that the tem-perature of the reaction mixture did not rise above 2-3 °C. After leaving overnight at room temperature the mixture was cooled, acidified (3 M H2SO4) and extracted with ether (2 X 100 ml). The dried, extract was distilled, the fraction b.p. 118-120°/1 nam was purified by re-distillation under reduced pressure using a 6" vacuum-jacketted Vigreux column to collect a yellow liquid (31.2 g), b. p. 109-110°/0.6 mm

1.4935, [a]fj 97.6° (c = 4, 1= 1 in methanol). CwHizOi

Found C 62.8 H 7.7, Calcd C 62.3 H 7.5.

To the glyoxalate, 20.3 g, obtained above, stirred with potassium carbonate, 7.0 g, in water, 50 ml, for 20 min, was added dropwise, acetaldehyde, 4.2 g, in water, 6 ml. The mixture was then stirred for 2 h. After acidification (2 M HCl) it was extracted with ether (2 x 100 ml), the ethereal layer washed free from acid and dried (MgS04), and after evaporation of the solvent the yellow liquid was distilled to give a fraction, b.p. 51-53°/]. mm; this purified by re-distillation under reduced pressure with the 6" column gave a colourless liquid, b. p. 54-55°/l .5 mm, 8 g. This was identified as R-(+)-2-ethylidene-5-methylcyclohexanone by IR, whilst g.l.c. showed it to be an isomeric mixture containing the two isomers in the ratio 1:9 eis: trans.

trans R-(-1- )-2-Ethylidene-5-methyleyelohexanone The trans isomer was obtained from the above

enriched isomeric mixture by repeated rapid distilla-tion under reduced pressure using the 6" Vigreux column. The fractions were monitored with NMR until a pure specimen was obtained which had b.p. 72-740/2.5 mm, [a]£° 84.0° (c = 3 in methanol 1=1) .

6 ppm (100 MHz CDC13) 1.00 (d 3H, -CH-CH3), 1.75 (d 3H, =CH-CH3) , 6.71 (q 1H, =CH-CH 3 ) .

vcm-i 2950 (s), 1680 (s), 1612 (w), 1450 (w), 1425 (s), 1400 (m), 1365 (m), 1300 (m), 1255 (s), 1130 (s), 1080 (m), 1000 (m), 970 (m), 930 (w), 893 (w), 855 (m), 820 (s), 710 (s).

Semicarbazone of the trans isomer by standard method, m.p. 167-168 °C. C10H17N3O

Found C 61.3 H 8.8 N21.5, Calcd C 61.5 H 8.7 N21.5.

eis R-(-1- )-2-Ethylidene-5-methylcyclohexanone p-Toluenesulphonic acid, 0.5 g, was dissolved in

trans R-(+)-2-ethylidene-5-methylcyclohexanone,

5 g; the solution was immediately distilled under reduced pressure using a 6" vacuum-jacketted Vigreux column. The product, 56-58°/5 mm, 2.5 g, was further purified by fractionation under vacuum, giving the pure isomer, b.p. 60°/6 mm, [a]^ 6.3° (c = 4 in methanol 1=1) . C VHiqO

Found C 78.5 H 10.5, Calcd C 78.2 H 10.1.

<5 ppm (100 MHz CDCI3) 1.01 (d 3H, -CH-CH3), 1.86 (d 3H, =CH-CH3) , 5.71 (m 1H, =CH-CH3) .

v cm - 1 2090 (s), 1685 (s), 1621 (s), 1440 (m), 1410 (w), 1365 (s), 1220 (w), 1205 (w), 1150 (w), 1115 (s), 1090 (m), 995 (w), 970 (s), 920 (b), 893 (s), 875 (w), 822 (m), 695 (s, b).

Semicarbazone prepared by the standard method, m.p.151-152 °C. C10HnN3O

Found C 61.4 H 8.7 N21.6, Calcd C 61.5 H 8.7 N21.5.

Attempted preparations of R-(-{-)-2-ethylidene-5 - methyleyelohexanone

1. via the boron tri fluoride complex: R-( + )-2-formyl-5-methylcyclohexanone, 16 g, in dichloro-methane, 150 ml, under nitrogen yielded with boron trifiuoride etherate, 20 g, a complex with which methyl lithium (25 ml, 1.06 M) gave 1.5 g of the isomeric mixture of R-( + )-2-ethylidene-5-methyl-cyclohexanone identified by IR, refractive index and specific rotation. A large quantity of thick, black residue was not identified.

2. via the enamine: R-( + )-3-methylcyclohex-anone, 14 g, and morpholine, 11 g, refiuxed to-gether in dry toluene, 150 ml, yielded by the elimination of water a mixture of N(zl1-5-methyl-cyclohexenylmorpholin) and N(zl1-3-methylcyclo-hexenylmorpholin). CnH^NO

Found C 72.9 H 10.5 N 7.7, Calcd C 72.9 H 10.5 N 7.7.

R-(-\-)-2-Ethoxy methylene-5-methyleyelohexanone R-(+)-2-Formyl-5-methylcyclohexanone, 29 g,

ethyl orthoformate, 22 g, and methanol (dried), 12 ml, and two drops of concentrated hydrochloric acid were mixed and allowed to stand at room tem-perature for 60 h. The greenish solution was washed with potassium hydroxide solution, 50 ml (10%), and then with water (2 X 50 ml). The ethereal layer was dried (MgS04) and distilled using a 6" vacuum-jacketted Vigreux column. The fraction, b.p. 86 to 870/l mm, 9.6 g, was collected; it had n2^ 1.4892, [a]2D° 9.75° (c = 5 in methanol 1=1) . CioHxsOz

Found C 71.3 H 9.5, Calcd C 71.4 H 9.5.

R-(+)-2-Propylidene-5-methylcyclohexanone By the technique described above, R-(-f)-2-

propylidene-5-methylcyclohexanone, b.p. 65 to 66°/1.5mm, was obtained in 15% yield. After purification by g.l.c. it had rig 1.4838, [a]fj 40.0° (c = 3 in methanol / = 1).

R-(-\- )-2-Butylidene-5-methylcyclohexanone By a similar method, R-( + )-2-butylidene-5-

methylcyclohexanone, b.p. 60°/l mm, was obtained in 12% yield. After purification by preparative g. 1. c. it had riß 1.4768, [a]?? 37.50° (c = 3 in methanol

R-(+)-2-Formyl-5-methylcyclohexanone Pieces of sodium, 11.5 g, sodium-dried ether, 1 1,

R-( + )-3-methylcyclohexanone, 56 g, and ethyl formate, 55 g, in a three-necked flask, were stirred and ethanol, 5 ml, added to initiate the reaction. After 6 h, water, 100 ml, was added, and the mixture washed with ether, the aqueous layer acidified with hydrochloric acid (6 M), ether ex-tracted (2 X 200 ml), the extracts dried (MgS04), and the product distilled under nitrogen (vacuum-jacketted 6" Vigreux column) to give a fraction, 45 g, b.p. 4 8 ^ 9 °C/2.5 mm, riß 1.5002, [a]2g 87.0° (c = 5 in ethanol I = 1).

C zHwOz Found C 68.6 H 8.6, Calcd C 68.6 H 8.6.

Thermal isomerism of eis R-(-\-)-2-ethylidene-5-m ethylcyclohexanone

The effect of temperature and time on a sample of the eis isomer, 0.1 g, kept under argon in a 0.4" Carius tube was studied. The experiments showed that at 70 °C the eis had isomerised to the trans to the extent of 75% (by g.l.c.) after 11/2 hand 80% after 2 l /2 h. At 100 °C the rate of isomerisation is rather faster but after 2 h reaches the same propor-tion, 80%. At 150 °C, 86% is reached after 1 h but longer exposure produced polymeric products which invalidated the comparison.

trans R- (—)-2-Benzylidene-5-methylcyclohexanone Prepared by a method similar to that of Emerson,

Birum and Longley [9]; m.p. 61-62° and [af£ — 154° (c = 0.5 in methanol Z = l ) , [a]2£ —135° (c = 1.6 in hexane 1=1) [33].

vcm-i (CCI4), 3080 (w), 2940 (s), 1675 (s), 1580 (s), 1575 (m), 1490 (m), 1445 (s), 1260 (s), 1220 (s), 1200 (s), 1135 (s), 932 (m), 892 (m), 862 (m), 695 (s).

eis R-(—)-2-Benzylidene-5-methylcyclohexanone trans R - (—) - 2- Benzylidene- 5 -methylcyclohex-

anone, 15 g, was dissolved in ethanol, 150 ml, and irradiated with UV light (Hanovia medium pressure mercury arc 450 watts immersion type) for 45 min. The solvent-free residue was taken up in petroleum ether 40-60°, 50 ml, and cooled in acetone-C(>2. The yellowish-white crystals, 12 g, (80%), which slowly formed were recrystallised in the usual manner, m.p. 23-24°, [a]2^ —69° ( c = l in methanol Z = l ) , [a]f)° 4.9° (c = 3 in hexane 1=1) [34].

vcm-i (CCI4), 3050 (m), 2960 (s), 1690 (s), 1615 (w), 1495 (m), 1440 (s), 1260 (w), 1205 (s), 1120 (s), 928 (m), 895 (s), 860 (m), 842 (vw), 727 (w), 694 (s).

Instrumental CD spectra were recorded either on a Roussel-

Jouan Dichrographe or on a Fica Spectropol 1 with CD attachment; ORD spectra were recorded on the Fica instrument. In either case 0.1 or 1.0 cells were used, containing approximately 50 mM solutions at 20 °C. Calibration was checked using suitably diluted 10% camphor solution in alcohol which was also measured in a visual Bellingham & Stanley instrument in a 1 dm tube.

IR spectra were recorded on a Perkin Elmer Infrared 137 with bromide disc or, in the case of solution, a 0.025 mm cell was used with the pure solvent as reference.

UV spectra were obtained using a Unicam SP 700. The wavenumber calibration was checked by the 21,584 cm - 1 line of hydrogen.

NMR 100 and 220 MHz and variable temperature spectra were by PCMU, Harwell. 60 MHz were by Perkin Elmer R 10. TMS was used as internal standard throughout.

g.l.c. analytical by Perkin Elmer F 11 using oxygen-free nitrogen as carrier gas. Preparation by Aerograph autoprep 700.

We wish to thank Professor L. F. Rabari, Dr. R. White and the late Dr. D. L. Marshall for discus-sions ; Dr. P. M. Collins of Birkbeck College for the use of an apparatus for photo-isomerisation, and Mr. R. Ballah for the analysis of the isomeric mixture of the ethylidene compound by 60 MHz NMR and g.l.c.

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