G. Tbth, F. Janke, A. Lkvai 651

Synthesis and Stereochemistry of the Dibromides of Exocyclic a,p-Unsa tura ted Ketones Gabor Tdth"", Frank Jankea, and Albert LCvaib

Technical Analytical Research Group of the Hungarian Academy of Sciences, Institute for General and Analytical Chemistry of the Technical University", H-1 11 1 Budapest, Gellert t t r 4, Hungary

Department of Organic Chemistry, Kossuth Lajos University ', H-4010 Debrecen, P.O.B. 20, Hungary

Received January 30, 1989

Key Words: Ketones / a$-Unsaturated Ketones / Bromination

7.11~ dibrtimidcs 7- 12 haw bccn synthesized by addition of bro- mint to exocyclic ell-unsaturated ketones 1-6. The rclative con- figurations and the swcocliemistry of the products have been dctermined by NM K methods. Bromination ol3-hcnzylideneflil- wnonc (3) and its thio analogue 5 proved to be highly stereose- Iwtiw.

Recently we investigated the synthesis of fused heterocycles by the reactions of exocyclic a$-unsaturated ketones. We obtained pyrazoline~'-~), benzothiazepines 'I, and benzodiazepines 'I. It is well-known that among the related unsaturated ketones, e.g. chal- cones, the dibromides are advantageous intermediates for the prep- aration of various nitrogen-containing heterocycles6-'). In case of exocyclic a$-unsaturated ketones, however, only few examples are known concerning the utilization of their dibromides for such pur- poses'). Our aim was, therefore, the synthesis and stereochemical studies of dibromides suitable for the synthesis of fused heterocycles.

In our present paper the bromination of compounds 1-6 and the stereochemical investigation of the addition prod- ucts 7 - 12 will be reported. The a,D-unsaturated ketones 1-6, used as starting materials, were E isomers synthesized by known procedures9-").

The ketones 1-6 were allowed to react with bromine in carbon tetrachloride solution to afford the dibromides 7 - 12 (Scheme 1 *), Table 5).

The reaction is probably an anti-type electrophylic addi- tion"). As a result of this reaction racemic mixtures with 3R,CH-S and 3S,CH-R configurations are obtained in the case of 7, 8, 10, and 12. Since in the compounds 9 and 11 one more centre of chirality (C-2 atom) is present, formation of two diastereomers, viz. 2R,3R,CH-S and 2S,3R,CH-S, and the appropriate enantiomers are possible. Under the reac- tion conditions used, however, no diastereomeric mixture was obtained from the starting materials 3 and 5, conse- quently the reaction providing the compounds 9 and 11 is highly stereoselective. Structure elucidation and conforma-

*' The numbering of the hydrogen and carbon atoms applied in Scheme 1 and Tables is not in accordance with IUPAC nomen- clature. This modification, however, facilitates the comparison of the spectroscopically analogous atoms in compounds 7 - 12.

Sgnthese und Stereochemie der Dibrnmide von ewcycl iwhet i or,bungesiittigtm Kctoncn

Die cxocyctisch r,&ungesaitigren Kctciiic 1 - h iiddicrm l31wn> untcr Bildung dcr cntsprechcndcn Uibroniidc 7 - I?. M i ~ i c I s NM R-Mcthadcn wurden die reliitivcn Konfigur;itioricn uritl dic Stereochemic dcr Produktc btsiimmi. I>ic Ihmic rung I 011

3-Ben~ylidcoflnvanon (3) und dcr i~nalogcn l'hiowrhindung 7 c[ - wits sich als huch stcreoselckuv.

tional analysis of the compounds 7 - 12 required the use of thorough NMR investigations, e. g. the measurements of 2D heterocorrelation and 1D proton-proton NOE difference spectra. Spectroscopic properties are summarized in Tables 1-3.

Scheme 1

1-6 7-12

3, 9 Ph H

4, 10

5. 1 1 Ph Me

A common characteristic of the 'H NMR spectra is the well- separated appearance of 5-, 6-, 7-, 8-H signals, and the substantial paramagnetic shift of the 5-H signal which is, first of all, a conse- quence of the anisotropic effect of the peri-carbonyl group'3). In the case of 7 the signals of I-H2 and 2-H, methylene protons are highly overlapped. Differentiation of the connected geminal proton pairs was possible with the help of the 2D carbon - proton correlation map while assignment of the 2-H,, signal was made on the basis of the NOE observed for the phenyl group upon irradiation of 2-H,,. Assignment of the two close 1-H and 2-H axial proton signals was corroborated by a double resonance experiment performed at 500

Liebigs Ann. Chem. 1989, 651 - 654 0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1989 0170-2O41/89/0707 -0651 $ 02.50/0

652 G. Toth, F. Janke, A. LLtvai

Table 1. ‘H Chemical shifts of compounds 7-12 in CDC13

6 I 8 C-Hex, 2’,6 3’,5‘ 4‘ 2”,6” 3“,5” 4 CH3 X 1eq l a x

2eq 2”X 5

- - - 7 2.96 3.19 2.41 3.13 8.24 1.38 1.54 1.29 6.22 1.60 1.38 7.31 - 8 0 5.28 4.68 8.06 1.12 1.54 1.04 6.03 1.41 1.38 1.36 - - - - 9 0 6.06 - 1.85 1.06 1.50 6.91 5.32 1.62 1.32 1.32 1.55 1.31 1.45 -

- - - 10 s 4.41 3.24 8.21 1.21 1.44 1.30 6.21 1.55 1.31 7.31 - 11 s 2.95 - 1.91 1.15-1.20 1.38 1.10-1.20 4.36 1.41 1.12 - 1.26 ... 1.31 2.33 12”’ 2.12 3.05 2.26 2.50 1.59 1.31 1.43 1.13 5.93 1.55 1.3 - - - -

”) la-H2: 6 = 1.90.

Tab. 2. I3C Chemical shifts of compounds 7- 12 in CDCI3

X 2 3 4 4a 5 6 7 8 8a CH 1‘ 2’,6‘ 3’,5’ 4‘ 1” 2”,6 3”,5” 4” CH3

7 26.0 30.6 68.8 188.4 129.6 129.2 127.1 134.2 128.6 142.4 55.3 136.0 130.9 127.7 128.7 - - - - -

8 0 72.0 64.1 183.7 118.5 128.7 122.5 136.7 118.0 160.2 51.1 135.4 130.3 128.2 129.1 - - - - -

9 0 87.8 69.9 184.2 119.3 127.7 122.0 136.6 117.9 158.2 53.8 134.0 130.0 127.4 128.8 138.7 128.9 126.8 129.9 - 10 S 35.6 68.3 185.5 128.6 131.6 125.8 133.8 127.6 140.4 54.8 135.3 131.0 128.0 129.1 - - - - -

12 31.3/23.9 26.8 70.6 203.0 137.6 129.9 126.8 132.2 128.3 139.7 58.7 136.0 131.5 127.5 128.7 - - - - - 11 S 55.9 82.0 188.1 129.2 130.4 124.7 133.4 127.6 139.4 55.3 134.1 130.9 127.8 137.9 139.0 129.2 126.1 129.2 21.2

Table 3. Results of proton-proton I D NOE difference experiments

Com- pound

Irradiated proton Observed NQE in YO

7 2-Heq 2-H,, I-Ha; 21.9; I-He4 2.1 2’,6‘-H: 5.2

CH,,, 2’,6’-H: 6.9 8 2-H, 2-Heq: 24.3; 2’,6-H: 4.5

2-H.q 2-H,,: 24.9; 2’,6’-H: 2.8 CH,,, 2’,6’-H: 9.6

9 2-H,, 2 .6-H: 8.9 2-H,,: 0.9; 2‘,6’-H: 12.4; 2”,6-H: 3.2

10 2-Ha 2-Heq: 21.0; 2,6’-H: 3.9 2-Heq 2-H,,: 21.0; 2’,6’-H: 2.4 CH,,, 2’,6’-H: 6.0

11 CHexo 2-H,,: 1.3; 2’,6’-H: 9.8 12 CH,,, 2’,6’-H: 11.0

MHz. ‘H spectra of the compounds 8, 10, and 12 can be analysed as first-order spectra. Owing to the introduction of another phenyl group into 9 and 11 the aromatic signal region becomes crowded. Despite of this, e. g. for compound 9, assignments of the signals of 2’-, 6 - H and 2”-, 6”-H were achieved with the help of the NOE intensity enhancement that appeared on irradiation of the CH,,, proton. Characteristic broadening of the 2’-, 6’-H signal indicates hindered rotation of the phenyl group.

Assignment of the methylene carbon atoms of 7 and 12 was corroborated by 2D carbon - proton correlation measurements. Aromatic =CH signals of 7-12 were assigned by means of het- eronuclear correlation maps. Assignments of the quaternary C-4a, C-8a, and C-1’ atoms were performed on the basis of known sub- stituent effects J4). Concerning the relative configuration of C-2 in compounds 9 and 11, thc conformation of ring B, and the rotation around the C-3 - CH,,, bond, conclusion can be drawn from the spectroscopic data. In case of 9, J c 2 2 H (153 Hz) was used to de-

termine the configuration of the C-2 atom. The different direct coupling constants were measured for compounds unsubstituted in position 2 which is, on the basis of sugar analogue^'^), a conse- quence of the relative spatial position of the electron pair of the oxygen and the neighbouring CH moiety, e.g. these values are Jc.z,z.H(~~) = 145 Hz and Jc.z,z.H(eq) = 156 Hz in 8. Since the intro- duction of a phenyl group does not influence essentially the direct coupling constant, 2-H is equatorial and, therefore, the phenyl group at C-2 is axial in compound 9. Due to the replacement of oxygen by sulfur in compound 10 two different coupling constants cannot be expected which is in accordance with our observation. Its value is JC.2,2.H = 142 Hz, and, therefore, it cannot be used for the determination of the C-2 configuration in 11. If the phenyl group at C-2 in 11 would be equatorial then it should show a strong interaction with the phenyl group conncected to the exocyclic car- bon atom which could strongly modify the chemical shift values of the protons of both phenyl groups. However, such an effect was not detected and, therefore, an equatorial orientation of the phenyl group at C-2 is quite improbable in compound 11. Our results are in accordance with those found for other chromanone deriva-

For the determination of the conformation of ring B, the influence of the carbonyl group on the neighbouring protons (5-H and CH,,,) proved to be useful. In case of compounds with ring B unsubstituted at position 2 (7, 8, and 10) a ,,sofa“ conformation appeared to be energetically favoured. In this conformation the C-5 - H-5 bond and the carbonyl group are almost coplanar and this is reflected in the high chemical shift values of 5-H which are 8.24, 8.06, and 8.21 ppm for 7, 8, and 10, respectively. In 12, 9, and 11, S(5-H) is con- siderably lower and AS is -0.65, -0.21, and -0.30 if compared with 7, 8, and 10 which indicates the cessation of the coplanarity between 5-H and the carbonyl group. Structural reasons for this are that in compounds 9 and 11, owing to the ring deformation (flattening) caused by the introduction of an axial phenyl group, the ,,sofa” conformation of the six-membered ring changes to a half- chair, while in substance 12, as a result of the ring enlargement, an energetically more favoured chair conformation comes into being instead of the “sofa” one.

tives 13.16)

Liebigs Ann. Chem. 1989, 651 - 654

Exocyclic a$-Unsaturated Ketones 653

Scheme 2 B'.,

"sofa"

half-chair chair

Inversion of ring B of compound 7 - 12 results in the formation of two conformers in one of which the bromine atom connected to C-3 is axial and in the other one it is equatorial (see Scheme 2). Since the spatial proximity of 2-H,, and the monosubstituted ar- omatic ring was corroborated by NOE difference measurements (see Table 3), it can be concluded that the former conformer pre- dominates. This is in accordance with the fact that in case of 2-halocyclohexanones orbital interaction between the C = 0 group and the axial bromine atom stabilizes the axial orientation of the bromine atom and, as a result of this, the conformer corresponding to this arrangement as well"). The three conformers A, B, and C should be taken into account.

Scheme 3

Br H Ph

Br A

Br

B

Br

c

On the basis of the NOE difference measurements, in the com- pounds 7, 8, and 10, 2-H and CH,,, are not in spatial proximity and, therefore, the participation of B and C conformers is negligible in the conformation equilibrium. According to the NMR measure- ments conformer A predominates in the conformational equilib- rium. To verify this conclusion molecular mechanics calcula- tions 18~19) have been performed where the heat of formation (HOF) of the three energetically favoured rotation conformers (A, B, and C) have been taken into account. The results of these calculations are summarized in Table 4. It can be seen that in the conformational equilibrium conformer A predominates (97%). This corroborates the results of the NOE difference measurement, and is also sup- ported by the 3JC.2,CH(exo) coupling constants in 8 and 10 (6.5 and 6.0 Hz). This vicinal coupling constant depends on the @ c . ~ - ~ . ~ -CH(exo) dihedral angle and its value is approximately 6 Hz for CD = 180" (conformer A) and 2-3 Hz in case of CD = 60" (conformers B and C).

The introduction of a phenyl group into position 2 modifies the conformational equilibrium of the rotation around the C-3 - CH,,, bond so that the ratio of conformer A decreases in favour of con- former B. This results from the following. In conformer A the chem-

--7

Table 4. AE values [kJ/mol] of the A, B, and C rotamers of com- pounds 7-11 CAE = HOF (most favourable conformer) - HOF

(actual conformer)] HOF: heat of formation according to MM2

A B Ratio of A at 25°C C

7 0.0 9.1 13.3 97% 8 0.0 8.8 12.7 97%

10 0.0 12.6 13.8 99% 9 0.8 0.0 4.9 39%

11 0.0 1.9 3.8 60%

ical shift value of the CH,,, proton is considerably enhanced by the neighbouring carbonyl group. In the compounds 7, 8, 10, and 12 this is 6.22, 6.03, 6.27, and 5.93 ppm, respectively. Decrease of the ratio of conformer A, i. e. the increased distance of the CH,,, proton from the carbonyl group results in a decrease of the chemical shift value of the CH,,, proton. This decrease was observed for com- pounds 9 and 11 where the corresponding value was 5.32 and 4.36 ppm, respectively. In the conformers B and C the distance between 2-H,, and CH,,, is decreased. This change was corroborated by NOE difference measurements since irradiation of CH,,, induced in 9 a 0.9% and in 11 a 1.3% NOE of the signal of 2-H,,. The 3JC.2,CH(er,) value proves our assumption because contrary to 3JC.2,CH(exol % 6 Hz belonging to an antiperiplanar arrangement only a 4-Hz value was observed for 9. For this reason, taking into con- sideration the 3JC.2,CH(exol = 2 Hz value belonging to @ = 60" di- hedral angle, participation of conformers B and C increased. Change of the conformational equilibrium may originate from steric interactions. Namely, the introduction of an axial phenyl group into position 2 causes an unfavourable steric interaction between the bromide connected to the exocyclic carbon atom and the phenyl moiety in conformer A which results in an alteration of the con- formational equilibrium in favour of conformers B and C.

Since bromination is an anti-type electrophilic addition we assumed that change of the configuration of the benzyl- idene exo double bond results in the formation of a new dibromo diastereomer. (Z)-3-Benzylideneflavanone 3a was prepared by photochemical isomerisation of compound 3 and bromine addition to the Z isomer was performed as described above. In this case was also obtained a product which proved to be identical with 9 in every respect. This apparent contradiction can be explained that the bromine addition takes place in acidic medium and under such con- ditions the Z isomer is converted into the E isomer faster than bromine is added. To corroborate this assumption, the time dependence of the 'H-NMR spectrum of compound 3 was investigated in CDC13 at room temperature which showed that isomerisation caused by traces of acid takes place rather quickly (tlI2 z 20 min).

The high selectivity of the reaction leading to the for- mation of 9 and 11 can be explained as follows: Since in the compounds 3 and 5 the phenyl group at C-2 is quasi- axial 16.21.22) the attack'of the bromo cation takes place on the opposite side of the phenyl moiety, and in the next step the bromo anion attacks the sterically less hindered and positively polarized exocyclic carbon atom.

The authors are grateful to the OTKA program of the Hungarian Arrrdenij~ of Sciences. One of us (G.T.) thanks the Alexander-ron-

Liebigs Ann. Chem. 1989, 651 -654

654 G. Toth, F. Janke, A. LCvai

Table 5. Physical constants and analytical data of compounds 7 - 12

Com- M.p. Yield Empirical pound C"c1 ("/I formula

Calcd. Found C H C H

7 156") 72.1 C17H14BrZO 51.7 3.5 51.7 3.6 8 124 78.4 C 1 6 H d r ? 0 ~ 48.4 3.0 48.8 3.2

10 170 75.6 C I ~ H I ~ B ~ ~ O S 46.6 2.9 46.8 2.9 9 131 70.2 C22H16Brz02 55.9 3.4 55.6 3.4

11 160 69.8 C23H1&20S 55.0 3.6 55.2 3.7 12 145 67.5 CixHi6BrzO 52.9 3.9 52.8 3.9

a) Ref. 'I: m.p. 153 "C.

Humboldt-Stftung for a fellowship (Ruhr-Universitat, Bochum, FRG). Special thanks are due to Mrs. E. Hajnal for technical as- sistance.

Experimental Melting points are uncorrected. - TLC was performed on Kie-

selgel 60 F254 (Merck) layer using hexane/acetone (7: 3) as eluant. - The NMR spectra were recorded with Bruker AM-400, AM- 500, and AC-250 spectrometers at room temperature. Chemical shifts were determined on the F scale. In the ID measurements 32 K data points were used for the FID. For homonuclear NOE exper- iments a delay time of 3 s was applied. NOE difference and two- dimensional carbon -proton correlated experiments were recorded by using the Bruker software package. In the 2D experiments 1K x 1K data matrixes were transformed.

General Procedure for the Preparation of the Dibromides 7 - 1 2 To a cooled and stirred carbon tetrachloride (20.0 ml) solution of a$-unsaturated ketones 1 - 6 (10.0 mmol) bromine (30.0 mmol), dissolved in carbon tetrachloride (10.0 ml), was added dropwise. The mixture was stirred at room temperature for another 20 min. The reaction mixture was washed with sodium thiosulfate solution, then with water, and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the residue crystallized from methanol to obtain compounds 7 - 12 (Scheme 1, Table 5).

CAS Registry Numbers

1: 6261-32-1 J 2: 30779-90-9 J 3: 22084-15-7 J 4: 74074-09-2 J 5: 119656-90-5 J 6: 53174-96-2 J 7: 119656-91-6 J 8: 119656-92-7 J 9: 119656-93-8 J 10: 119656-94-9 J 11: 119656-95-0 / 12: 119656- 96-1

') A. LCvai, G. Tbth, A. Szollosy, Flavanoids and Bioflavanoids (L. Farkas, M. Gabor, P. Kallay, Ed.), p. 47, AkadCmiai Kiado, Budapest j985. A. Lkvai, A. Szollosy, G. Toth, J. Chem. Res. (S) 1985, 392.

31 G. Toth, A. Szollosy, T. Lorind, T. Konya, D. Szabo, A. Foldesi, A. Ltvai, 4. Chem. Soc,, Perkin Trans. 2, 1989, 319.

4i G. Toth, A. Szollosy, A. Lkvai, H. Duddeck, Org. Magn. Reson. 20 (1982) 133.

5 , G. T6th A. Levai, unpublished results. 6, 6a) N. H.'Cromwell, I. H. Witt, J. Am. Chem. SOC. 65 (1943) 308. - 6b) P. L. Soutwick, D. R. Christman, J . Am. Chem. SOC. 74 (1952) 1886. - 6c)N. H. Cromwell. G. D. Mercer, J. Am. Chem. SOC. 79 (1957) 3819.

71 7a) Gy. Litkei, R. Bognar, P. Szigeti, V. Trapp, Acta Chim. Acad. Sci. Hung. 73 (1972) 95. - 7b) Gy. Litkei, R. Bognar, J. Ando, Acta Chim. Acad. Sci. Hung. 76 (1973) 95.

*) M. G. Joshi, K. N. Wadodkar, Indian J . Chem., Sect. B, 20 (1981) 1090.

') C. R. Rao, K. M. Reddy, A. K. Murthy, Indian J. Chem., Sect. B, 20 (1981) 282.

''I lea) A. LCvai, E. H. Hetey, Pharmazie 33 (1987) 378. - lob) A. Levai, J. B. Schig, Pharmazie 34 (1979) 749. N. R. El-Rayyes, H. M. Ramadan, J. Heterocyclic Chem. 24 (1987) 589.

12) K. P. C. Vollhardt, Organic Chemistry, chapter 12-3, Freeman and Company, New York 1987.

13) 13a) G. Tbth, A. Szollosy, A. Lkvai, G. Kotovych, J. Chem. SOC., Perkin Trans. 2, 1986, 1895. - lib) J. W. ApSimon, W. G. Craig, P. V. Demarco, D. V. Mathieson, L. Saunders, W. B. Whalley, Tetrahedron 23 (1976) 2339.

14) E. Pretsch, J. Seibl, W. Simon, T. Clerc, Strukturaufklurung or- ganischer Verbindungen, Springer, Berlin - Heidelberg - New York 1981.

15) K. Bock, C. Pedersen, Carbohydr. Res. 71 (1979) 319. 16) A. Szollosy, G. Toth, A. Levai, Z. Dinya, Acta Chim. Acad. Sci.

Hung. 112 (1983) 343. 17) 17a) N. L. Allinger J. C. Tai, M. 4. Miller, J. Am. Chem. SOC. 88

(1966) 4495. - 17') D. Cantacuzene, M. Tordeux, Can. J . Chem. 54 (1976) 2759. - j7') 0. Eisenstein, N. T. Ahn, Y. Jena, A. Devaguet, J. Cantacuzene, L. Salen, Tetrahedron 30 (1974) 1717.

") N. L. Allinger, J. Am. Chem. SOC. 99 (1977) 8127. QCPE 395, 318.

20) R. Freeman, G. A. Morris, M. J. T. Robinson, J. Chem. SOC., Chem. Commun. 1976, 754.

2') D. D. Keane, K. G. Marathe, W. I. O'Sullivan, E. M. Philbin, R. M. Simps, P. C. Teague, J. Org. Chem. 35 (1970) 2286.

22) A. Ltvai, A. Szollosy, unpublished results. 114J891

Liebigs Ann. Chem. 1989, 651 -654