G. Toth, A. Lkvai, A. Szollosy

Fused Heterocycles, VII[']

803

Synthesis and Stereochemistry of Tetracyclic Benzodiazepines Gabor Tbth'", Albert LCvaib, and Aron Sz611(lsya

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

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

Received February 22, 1992

Key Word: Benzodiazepines

Benzodiazepines 3a - d have been synthesized by the reaction of exocyclic a$-unsaturated ketones 1 a- d with 1,2-phenyl- enediamine in hot ethanol. Acetylation of compounds 3a- d with a mixture of acetic anhydride and anhydrous pyridine

affords the N-acetyl derivatives 4a- d. Structure and stereo- chemistry of the synthesized compounds have been elucidated by various NMR techniques.

During the past decade we have been engaged in the syn- thesis of fused heterocycles by the reaction of exocyclic a$- unsaturated ketones. Pyrazoline~['-~~, pyrimidine and thi- azine derivatives"], as well as benzothiazepines[61 have been prepared in this way. Structure and stereochemistry of these heterocyclic compounds have been elucidated by various NMR techniques. As a continuation of our previous inves- tigations we report here on the reaction of exocyclic a$- unsaturated ketones 1 a -d with 1,2-phenylenediamine to obtain tetracyclic benzodiazepines.

The reactions of the 1,2-phenylenediamine with chalcones and related a$-unsaturated ketones have been studied by several research groups['-"] and 2,3-dihydro-1,5-benzodi- azepines have been prepared in this way. Few benzodiaze- pines with fused ring systems have also been described in the In our present experiments a$-unsatu- rated ketones l a - d are allowed to react with 1,2-phenyl- enediamine in hot ethanol and benzodiazepines 3 a - c are obtained as stereohomogeneous single products. However, the same reaction of the 3-benzylidene-2-phenylflavanone (1 d) with 1,Zphenylenediamine affords exclusively 3-[a-(2- aminoanilino)benzyl]-2-phenylflavanone (2d) which is then cyclized to give the appropriate benzodiazepine 3 d under acid-catalyzed reaction conditions. Acetylation of com- pounds 3a-d with a mixture of acetic anhydride and an- hydrous pyridine furnishes the N-acetyl derivatives 4a - d (Scheme 1 *)).

Structure and stereochemistry of the compounds prepared together with reference compounds 2e, 3e, and 4e have been studied by various NMR techniques. 'H- and I3C-NMR data

*) The numbering of the hydrogen and carbon atoms applied in the schemes and tables is not in accordance in each case with the IUPAC nomenclature. This modification, however, facili- tates the comparison of the spectroscopically analogous atoms of the compounds under investigation.

Scheme 1

aNH2 NH2 +

l a - d 3a-d

H H Ph

Ph

2d

Ph

2e

4a-d

ayh Ph

3e Y=H 4e Y=CH3CO

of benzodiazepines 3 a - e and 4 a - e, and intermediates 2 d and 2e are summarized in Tables 1 and 2. The conformation of the 2,3-dihydro-l,5-benzodiazepine ring of compound 3e has been investigated by Hunter and Webb"" and it is con- cluded that the boat-boat conformational equilibrium of the seven-membered ring is shifted to the direction where the 7- phenyl group is equatorial. In the case of the appropriate acetyl derivative 4e we have found that the vicinal coupling

Liebigs Ann. Chem. 1992, 803 - 807 0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1992 0170-2041/92/0808 -0803 $ 3.50t .25/0

804 G. Thth, A. LCvai, A. Szolliisy

Table 1. Characteristic 'H chemical shifts and coupling constants of compounds 2-4

3a 3b 3c 3d 4a 4b 4c 4d 3e 4e 2d 2e

1-H 8.45 8.58 8.36 8.27 8.43 8.56 8.28 8.17 7.88 8.00 7.84 7.94

5-Hax 2.98 - - 3.08 - - - - - - -

5-H 2.60 - - 2.64 -

-

- - - - - - - eq

ax

eq

6-H 1.80 3.09 4.04 - 1.79 3.09 3.96 - - - - -

6-H 1.38 2.14 3.75 4.92 1.46 2.28 3.80 4.98 - - 5.48 - 6a-H 3.31 3.45 3.10 3.72 3.35 3.47 3.12 3.71 3.261 3.241 3.50 3.50/

3.07 3.00 3.47

7-H 4.97 5.37 5.14 5.32 6.16 6.53 6.20 6.35 5.11 6.35 4.77 5.19

9-H 6.68 6.62 6.78 6.81 6.96 7.01 6.96 7.04 6.82 7.04 - 3J6a,7 11.3 11.0 11.3 11.3 12.9 12.9 13.2 13.1 8.8/ 13.5/ 6.9 8.3/

3.8 4.6 5.0 - - 5.6 3.9 3.5 - 6.0 4.1 3.7 - 6. 1 - jJ6, 6a

- 3J6,6a4.5 3.0 1.5 1.1 3.0 2.7 0.9 0.9 - - -

- - - - 14.0 13.0 11.8 - 13.5 13.6 12.0 - 6,6

constant of 7-H and the trans-oriented 6a-H protons is en- hanced to 13.3 Hz which is a consequence of a more pro- nounced shift of the boat-boat conformational equilibrium to that direction where the 7-phenyl group is equatorial. Similar high values (11.0- 13.2 Hz) have been measured for the coupling of the protons 7-H and 6a-H in compounds 3a - d and 4a - d proving the antiperiplanar arrangement of these protons of the investigated tetracyclic benzodiaze- pines, i.e. the trans orientation of the 7-phenyl group and the substituents at 6-CH and the equatorial position of the 7-phenyl group in the dominant conformer of the seven- membered ring. The condensed six-membered ring can exist in two half-chair conformers where 6a-H is equatorial (e) in one and axial (a) in the other conformer. This conforma- tional equilibrium is well reflected in the J(6a-H,6-H) cou- pling constants. Since in compound 3a-c and 4a-c cou- pling of the 6-Hz methylene and the 7-H protons are between 0.9 Hz and 6.0 Hz it can be concluded that 6a-H is equa- torial in the dominant conformer and, therefore, gauche- oriented to the neighbouring two C-6 methylene protons.

Scheme 2

3a-c : R = H 4a-c :R=CH3CO

A characteristic decrease of these coupling constants is observed with increasing electronegativity of the substituent X (C -+ S --f 0). Introduction of the 6-phenyl moiety into compounds 3d and 4d increases the number of the possible isomers and conformers. Since the trans relation of 7-H and 6a-H has been proved for these compounds as well, the 6- phenyl group can be either cis or trans if compared with the 6a-H. On the basis of the 1.1-Hz and the 0.9-Hz coupling constants it can be excluded that these protons are antiperi- planar, i.e. the a,a conformer of the trans isomer. Probably, the a,e conformer of the cis isomer can also be excluded since the 50" angle observed on the molecular model is not

Scheme 3

H @pPh N R Ph aNFH R

I t H

H

e P cis

(110

3d,4d trans

Liebigs Ann. Chem. 1992, 803-807

Fused Heterocycles, VII 805

Table 2. I3C chemical shifts for substances 2-4

3a 3b 3c 3d 4a 4b 4c 4d 3e 4e 2d 2e

C-1 126.8 128.2 126.4 126.1 126.8 126.3 126.3 125.9 127.8 127.3 127.4 128.8

C-2 126.7 125.2 122.1 122.5 126.6 125.3 122.0 121.8 128.7 128.7 121.6 128.3

C-3 130.5 130.2 132.5 133.1 130.4 130.3 133.5 134.1 129.9 129.1 136.6 133.3

C-4 128.3 128.2 117.4 118.1 128.7 128.3 117.9 118.5 128.7 128.7 117.9 128.3

C-4a 140.2 136.9 158.1 155.5 140.9 138.4 158.6 155.9 127.8 127.3 160.0 128.8

- C-5 25.9 - - 25.9 -

C-6 24.6 28.8 66.5 75.6 23.5 28.6 65.8 75.0 - - 80.2 -

- - - - - -

C-6a 42.0 41.9 42.9 45.1 40.6 41.3 41.7 44.3 37.6 35.1 57.7' 46.4

C-7 73.7 72.4 71.5 73.7 68.4 67.5 67.3 68.8 70.2 66.956.0' 54.9

C-8a 143.5 142.9 143.1 142.9 138.9 138.4 138.6 138.5 144.7 140.3 135.8 135.8

C-9 121.3 121.4 121.6 121.7 125.2 125.4 125.4 125.4 120.4 125.6 113.6 114.5

C-10 128.2 127.5 128.4 128.7 131.4 131.0 130.5 130.7 126.3 131.2 120.2 120.2

C-11 121.9 122.0 121.9 122.0 125.5 125.5 125.5 125.5 121.0 125.6 118.8 119.4

C-12 125.9 126.8 126.1 126. 1 129. 1 129.1 129.2 129.5 126.8 130.4 116.5 116.5

C-12a 140.2 139.9 139.8 140.5 147.0 146.5 146.7 147.0 139.0 147.7 134.5 135.2

C-14 166.8 163.9 161.3 160.7 168.8 165.3 163.6 162.7 166.9 170.4 193.1 198.5

C-14a 133.4 131.5 121.1 121.1 132.2 130.9 120.3 120.4 138.9 137.6 120.7 136.7

C-1' 137.9 138.5 138.1 138.1 131.1 131.9 131.5 131.1 138.2 130.6 140.8 142.9

C-2',6'126.4 126.4 126.5 127.6 127.6 127.6 127.7 127.8 125.8 126.6 126.8 126.9

C-3' ,5'129.0 128.9 129.0 129.3 128.7 128.8 128.7 128.9 128.2 128.2 128.6 128.9

C-4' 128.1 127.7 127.9 127.7 128.1 128.3 128.3 128.6 128.9 127.9 127.6 127.3

c-2" - 137.4 - - 138.3 - - 137.6 - - - - 126.5 - - 126.8 - C-2",6" - - 126.6 -

C-3",5" - - 128.4 - - 128.5 - - 127.1 -

- - - - 127.7 - - 127.1 - c-4" - 127.5 -

c=o - - - - 170.1 170.1 170.1 170.2 - 170.7 - -

- - -

- -

- - - - 23.0 22.9 22.9 23.0 - 22.9 - CH3

-

+) Tentative assignment.

in accordance with the approx. 1-Hz coupling constant value. Differentiation of the three structures, viz. trans-e,e, cis-a,e, and cis-e,a, can be performed with the help of the 13C chemical shift data. In both conformers of the cis isomer the 6-phenyl group is gauche with respect to C-7 which, because of the known ysteric interaction, should result in a considerable diamagnetic shift if compared with the appro- priate data of compounds 3c and 4c. In contrast, 2.2-ppm and 1.5-ppm paramagnetic shifts have been observed for the

C-7 signal which may be a consequence of the e,e conformer of the trans isomer where the 6-phenyl group is in yonti po- sition with respect to the C-7 atom.

The above discussed structure of compounds 3a -d has been corroborated by 1D proton-proton NOE measure- ments, the results of which are summarized in Table 3. In accordance with the antiperiplanar arrangement of 6a-H and 7-H no NOE has been detected between these two pro- tons. A cis arrangement of 6a-H and the phenyl residue is

Liebigs Ann. Chem. 1992, 803 - 807

806 G. Toth, A. Levai, A. Szollosy

proved by the intensity increase on the 2’,6’-ortho hydrogens of the 7-phenyl group on irradiation of the 6a-H signal. A

Table 3. Results of proton-proton 1D NOE difference experiments on compounds 3a - d

Corn- Irradiated Observed NOE in %

pound proton

6-Hax

6-H

3a

eq

6a-H

7-H

6-Hax

6-H

7-H

3b

eq

6-Hax

6-H

6a-H

7-H

3c

eq

3d 6a-H

7-H

6-H (23); 5-H (3.2); 6a-H (4.9) eq eq

6-Hax (24.7); 5-H (2.3); 5-Hax (3.4); eq

6a-H (3.0); 7-H (2.8); 2’,6’-H (1.8)

6-Hax (4); 6-H

5-Hax (6.3); 6-H

(2.7); 2’,6’-H (8.4) eq

(3.2); 2’,6’-H (9.3) eq

6-H (32.9); 6a-H ( > 1) eq

6-H (29.2); 7-H (> 2) ax

6-H (2.4); 2’,6’-H (16.2); NH (8.4) eq

eq 6-H (22.3); 6a-H ( 5 . 8 )

6-Hax (26.9); 6a-H (3.1); 7-H (5.7)

eq 6-Hax (3.8); 6-H

6-H (1); 2’,6’-H (6.8)

6-H (3.5); 2’,6’-H (9.1); 2”,6”-H (5.6)

6-H (3); 2’,6’-H (11.3)

(2.8); 2’,6’-H (7.8)

eq

Table 4. Observed ‘H-13C long-range correlations by semiselective INEPT for compounds 3 a - c

Compound Selected Appeared on 13C signal of

proton

~

3a 1 -H

5-H eq

7-H

9-H

3b 1 -H

7-H

9-H

3c 1 -H

4-H

6a-H

9-H

C-3, C-4a, C-14

C-4, C-4a, C-6, C-6a, C-14a

C-6a, C-8a, C-1’. C-2’,6’

C-11, C-12a

C-3, C-4a, C-14

C-6, C-6a, C-8a. C-14, C-1’. C-2’,6’

C-11, C-12a

C-3, C-4a, C-14

C-2, C-14a

C-1’ , C-2’, 6’

C-11, C-12a

gauche position of the 6-H2 methylene and 6a-H protons is confirmed by the intensity increase caused by the same ir- radiation of 6-H2. In the case of compound 3d the NOE data are in agreement with its trans structure and with the dominance of the e,e conformer.

Irradiation of 6a-H results in an intensity enhancement on the 2’,6’- and 2”,6”-ortho hydrogens of 6- and 7-phenyl group, respectively, and NOE has been observed on 6-H as well. Simultaneous spatial proximity of 6a-H with 7-, 6- phenyl, and 6-H is possible only in the e,e conformer of the trans isomer and in the a,e conformer of the cis isomer. Since the irradiation of 7-H causes an intensity increase unam- biguously on the 6-H and not on the 2”,6”-H protons, the trans-e,e structure is unequivocally proved by this experi- ment.

I3C-NMR data corroborate the condensed tetracyclic structure of 3a-d and 4a-d as well. Besides the known additivity rules[151 assignments have been confirmed by two- dimensional CH-correlation maps and by one-dimensional semiselective INEPT measurements[‘61 optimized for 7-Hz long-range coupling values. Connectivities observed in the semiselective INEPT experiments are compiled in Table 4.

Characteristic “acetylation shifts” are observed when the 13C chemical shifts of compounds 3a -d and 4a -d are com- pared, viz. C-6 (-0.2, -0.9 pprn), C-6a (-0.6, -1.4 pprn), C-7 (-4.2, -5.3 ppm), C-8a (-4.4, -4.6 ppm), C-9 (3.7- 4.0 ppm), C-10 (2.0-3.2 ppm), C-11 (2.6-3.6 pprn), C-12 (2.3-3.4 ppm), C-12a (6.5-6.9 pm), C-14 (1.4-2.3 ppm), C-14a (-0.6, -1.2 ppm), and C-1’ (-6.6, -7.0 ppm) which can advantageously be utilized for the assignments. An up- field shift of the C-7 and C-8a signals is especially charac- teristic. A pronounced conjugation is proved by the fact that the effect of the acetylation can be detected even on the C- 14 signal. A considerable decrease of the chemical shift of the C-1‘ signal may be a consequence of the Y g a u c h e effect of the acetyl group.

The structure of the isolated intermediates 2d and 2e is corroborated by the I3C signal (6 = 198.5 and 193.1) of the conjugated carbonyl group. Despite of the presence of three centres of chirality in compound 2d no sign of a diaster- eomeric mixture has been observed proving the high selec- tivity of this addition reaction.

The authors express their gratitude to the Deutsche Forschungs- gemeinschaft and to the Hungarian Academy of Sciences (Grant Nos. OTKA-1639 and OTKA-1696) for financial support. Our thanks are also due to Mrs. E. Hajnal and Mrs. M. Nagy for their help in the experimental work. Special thanks are due to Prof. Dr. G. Snatzke and to Prof. Dr. H . Duddeck (Bochum) for valuable discussions.

Experiment a1 Melting points are uncorrected. - TLC was performed on Kie-

selgel 60 FZs4 (Merck) using hexane/acetone (7: 3) as the eluent. - The IR spectra were measured from KBr discs with a Perkin-Elmer 283B apparatus. - The NMR spectra were recorded with Bruker AM-400 and AC-250 spectrometers at room temperature. Chemical shifts were determined on the 6 scale. Starting compounds l a - d

Liebigs Ann. Chem. 1992, 803 - 807

Fused Heterocycles, VII 807

were prepared as described earlier by us['73. Reference compounds 2e, 3e, and 4e were synthesized according to known procedure~[~~'~l.

Preparation of Benzodiazepines 3a -c. - General Procedure: A mixture of la , b, or c (10 mmol), 1,2-phenylenediamine (20 mmol), and ethanol (50 ml) was refluxed for 48 h, the solvent evaporated under reduced pressure and the residue crystallized from ethanol to obtain compounds 3a-c.

6,6a,7,8-Tetrahydro-7-phenyl-5H-benzo[b]naphtho[l,2-e][1,4]- diazepine (3a): Yellow crystals, yield 61%, m.p. 185- 186°C. - I R 3 = 1610 cm-' (C=N).

C2,Hz0Nz (324.39) Calcd. C 85.15 H 6.21 N 8.63 Found C 85.62 H 6.17 N 8.64

6,6a,7,8- Tetrahydro- 7-phenylbenzo[b][l]benzothiopyrano[4,3- e][l,l]diazepine (3b): Yellow crystals, yield 59%, m.p. 139- 140°C. - IR: 0 = 1602 cm-' (C=N).

CzzH18N2S (342.36) Calcd. C 77.17 H 5.29 N 8.18 Found C 77.36 H 5.37 N 8.12

6,6a ,7 ,8- Tetrahydro-7-phenylbenzo[ bj [ l ]benzopyrano[4 ,3- e][l,l]diazepine (3c): Yellow crystals, yield 63%, m.p. 178- 179°C. - IR: 3 = 1612 cm-' (C=N).

Cz2H18N20 (326.36) Calcd. C 80.95 H 5.56 N 8.58 Found C 81.12 H 5.48 N 8.64

3-[~(-(2-Aminoanilino) benzylj-2-phenyljlavanone (2d): A mixture of 3-benzylidene-2-phenylflavanone (1 d) (10 mmol), 1,2-phenyl- enediamine (20 mmol), and ethanol (50 ml) was refluxed for 48 h, the solvent evaporated under reduced pressure to afford 2.4 g (63%) of a white crystalline compound; m.p. 191-192°C. - I R C = 1670 cm-' (C=O), 3340 and 3410 (NH2).

C28Hz4N202 (420.47) Calcd. C 79.97 H 5.75 N 6.66 Found C 79.53 H 5.84 N 6.68

6,6a,7,8- Tetrahydro-6,7-diphenylbenzo[b][l]benzopyrano[4,3- e][l,#]diazepine (3d): Compound 2d (0.7 g) was dissolved in a mix- ture of acetone (50 ml) and acetic acid (1.0 ml), and the solution was refluxed for 1 h, then the solvent was evaporated under reduced pressure and the residue crystallized from methanol to yield 0.55 g (82%) of 3 d m.p. 205-206"C, crystalline product. - IR: Q = 1612 cm-' (C=N).

C28H2zN20 (402.46) Calcd. C 83.55 H 5.51 N 6.96 Found C 83.37 H 5.46 N 6.87

Acetylation of 3a-d. - General Procedure: A mixture of com- pound 3a,b,c,or d (0.3 g), acetic anhydride (5.0 ml), and anhydrous pyridine (5.0 ml) was heated at 80°C for 6 h, then poured onto crushed ice. The precipitate was filtered off, washed with water and crystallized from methanol to obtain compounds 4a-d.

8-Acetyl-6,6a,7,8-tetrahydro-7-phenyl-5H-ben~o[b]naphtho[l,2- eJ"1,ljdiazepine (4a): Yellow crystals, yield 8O%, m.p. 212-213°C. - IR: 0 = 1612 cm-l (C=N), 1655 (C=O).

C25H22N20 (366.43) Calcd. C 81.93 H 6.05 N 7.64 Found C 81.79 H 6.17 N 7.55

8-Acetyl-6,6a,7,8-tetrahydro-7-phenylbenzo[b][l]benzothiopyra- no[4,3-e][1,4]diazepine (4b): Yellow crystals, yield 81 %, m.p. 222-223°C. - IR: 3 = 1604 cm-' (C=N), 1668 (C=O).

Cz4HZON20S (384.40) Calcd. C 74.98 H 5.24 N 7.28 Found C 74.79 H 5.17 N 7.35

8-Acetyl-6,6a,7,8-tetrahydro-7-phenylbenzo[b~[l]benzopyra- no[4,3-e][1,4/diazepine (4c): Yellow crystals, yield 79%, m.p. 228-229°C. - IR: 0 = 1612 cm-' (C=N), 1655 (C=O).

C24H2ON202 (368.40) Calcd. C 78.24 H 5.47 N 7.60 Found C 78.39 H 5.41 N 7.56

8-Acetyl-6,6a,7,8-tetrahydro-6,7-diphenylbenzo[b][l]benzopyra- no[4,3-e][1,4]diazepine (4d): Yellow crystals, yield 61 YO, m.p. 231 -232°C. - IR: 3 = 1606 cm-' (C=N), 1660 (C=O).

Calcd. C 81.06 H 5.44 N 6.30 Found C 81.21 H 5.49 N 6.32

C30H24N202 (444.49)

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Liebigs Ann. Chem. 1992, 803-807