1380 D. Lloyd, C . Reichardt, and M . Struthers

Liebigs Ann. Chem. 1986, 1380- 1386

Bromination of 2,3-Dihydro-6-(hydroxyphenyl)- 1,6diazepinium Salts

Douglas Lloyd * ’, Christian Reichardt * ’, and Margot Struthersa%b’l)

Department of Chemistry, Purdie Building, University of St. Andrews“, St. Andrews, Fife, Scotland, KY16 9ST Fachbereich Chemie der Universitat Marburg ’, Hans-Meerwein-Stral3e, D-3550 Marburg

Received February 4, 1986

2,3-Dihydro-6-(4-hydroxyphenyl)-l,4-diazepinium salts 3a, b are readily mono- (+ 4a, b) and di-brominated (+ 5a, b) at the rneta-postion of the phenyl substituent. 2,3-Dihydro-6-(3- hydroxyphenyl)-l,4-diazepinium salts 6a, b are readily mono-brominated (+ 7a, b) at the para-position of the phenyl substituent. A second bromination (-+ Sa, b) takes place at an ortho-position, surprisingly, since ortho-positions of 6-aryl substituents in 1,4-diazepinium salts are usually not susceptible to electrophilic attack. Mechanistic features of these bro- minations are considered. - 1,2-Dihydro-5-(hydroxyphenyl)-2-oxopyrimidinium salts 11 a, b were not brominated under similar conditions.

Bromierung von 2,3-Dihydro-6-(hydroxyphenyl)-1,4-diazepinium-Salzen

2,3-Dihydro-6-(4-hydroxyphenyl)-1,4-diazepinium-Salze 3a, b werden in der metn-Position dcs Phenylsubstituenten leicht mono- (+ 4a, b) und dibromsubstituiert (-+5a, b). 2,3-Di- hydro-6-(3-hydroxyphenyl)-1,4-diazepinium-Salze 6a, b werden in der para-Position des Phenylsubstituenten leicht monobromsubstituiert (-+ 7a, b). Eine zweite Bromsubstitution (+ Sa, b) findet in ortho-Position statt - uberraschenderweise, da die ortho-Position von 6-Arylsubstitutenten in 1,4-Diazepiniumsalzen einem elektrophilen Angriff gewohnlich nicht zuganglich ist. Uberlegungen zum Mechamsmus dieser Bromsubstitutionen werden ange- stellt. - 1,2-Dihydro-5-(hydroxyphenyl)-2-oxopyrimidinium-Salze 11 a, b werden unter glei- chen Reaktionsbedingungen nicht bromsubstituiert.

2,3-Dihydro-l,Cdiazepinium salts such as 1 characteristically undergo electro- philic substitution (e. g. halogenation’), nitration3’) at the 6-position. This reactivity can be transmitted to the para-position of a phenyl group substituted at the 6-position of the dihydrodiazepinium ring; thus compound 2a readily undergoes bromination and nitration, as shown in the reaction sequence4’.

The reaction involves an intermediate species in which the two rings become coplanar because of their quinonoid structure. Although the dihydrodiazepinium group is a cation, it is, none the less, electron-rich, and activates the benzenoid ring to electrophilic attack. No sign of any product derived from attack at the site ortko to the dihydrodiazepinium ring is observed; it seems likely that there is steric inhibition to attack at these positions.

0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1986 0170-2041/86/0808- 1380 $ 02.50/0

Bromination of 2,3-Dihydro-6-(hydroxyphenyl)-1,4-diazepinium Salts 1381 ~~~

I

2a ( R r H I

2c (R-OCH,) 2b IR=CH31 OCH3

When the para-position of the phenyl ring is blocked by substitution with a methyl (e .g . 2b) or a methoxy group (e .8 . 2c) substitution does not take place4). Presumably attack at the positions ortho to the dihydrodiazepinium ring is again inhibited, 'while attack at the position ortho to the para-methyl or para-methoxy substituents is thought to be deterred by the generation of two vicinal positively charged systems which would ensue in such a reaction4). Although the dihydro- diazepinium cation is electron-rich, it is not possible in this situation to draw canonical mesomeric forms in which electrons can be fed into the arenium cation.

Bromination of 2,3-Dihydro-6-(hydroxyphenyl)-1,4-diazepinium Salts 3 and 6

When, however, there is a hydroxy substituent at the para-position of the 6-phenyl ring, as in 3a,bs), bromination at the meta-position (i .e. ortho to the hydroxy group) occurs very readily, and in good yield. Reaction takes place rap- idly, as bromine in methanol is added to a methanolic solution of the dihydro- diazepinium salts 3a and 3 b, affording the monobromo-substituted salts 4a and 4b.

cloy -

1 R' 1 4a ( R - H ) : 73% 4b (R-CH3): 89%

5 a ( R = H J 87% 5b (R~CH3I :8Oo/o

Liebigs Ann. Chem. 1986

91*

1382 D. Lloyd, C. Reichardt, and M. Struthers

This great difference in reactivity between the 6-(4-hydroxyphenyl) derivatives 3a, b and the 6-(4-methoxyphenyl) derivatives (e. y. 2c) merits discussion. Three variations in mecha- nism which are to be considered are as depicted in the scheme.

H B ~ (+HCIO,

3a ( R - H ) 3b (R-CH,)

Pathway (a) involves an interml

R I d

s 7

Iiate having two vicinal positively charged ring systems; the failure of the methoxy-analogue to bc brominated was thought to be connected with the non-formation of such a species. Pathway (b) invokes the intermediacy of a phenoxide ion. The low acidity of the para-hydroxy group makes this route less likely, especially since a by-product from this reaction is hydrogen bromide which would further suppress the ionisation of the hydroxy group. This leaves pathway (c), which does not involve such problems, as the likeliest.

Dibromination of 3a,b could also be achieved readily by using two molar quantities of bromine in methanolic solution. The second bromine atom was introduced at the other vacant meta-site to give 5a,b in good yields.

In all cases the sites of bromination were readily evident from the 'H and 13C NMR spectra of the products.

6-(3-Hydroxyphenyl)-I ,4-diazepiniuni salts 6a, b5) were readily brominated at the para-position of the phenyl ring to give the monobromo-substituted salts 7a, b. In this case the para-position of the phenyl group is activated to electrophilic substitution by both the hydroxy group and the dihydrodiazepinium ring.

Surprisingly, the salts 6a, b could be dibrominated, with the second bromine atom being introduced at a site ortho to the dihydrodiazepinium ring, affording the salts Sa, b.

Again, the sites of bromination were evident from NMR spectra. Satisfactory elemental analyses could not be obtained for the dibromo derivatives 8 a , b the analyses together with mass spectral data suggest that the products were contam- inated with small amounts of polybrominated material.

Liebigs Ann. Chem. 1986

Bromination of 2,3-Dihydro-6-(hydroxyphenyl)-1,4-diazepinium Salts 1383

-;(""I n +Br, I A=

A 6a (R-HJ 6b (R-CH,)

l d in CH,OH .!"

B

These products 8a,b are the first examples as yet of substitution taking place at an ortho site in a phenyl group attached to the 6-position of a dihydrodiaze- pinium ring!

This unexpected result may be explained as follows. In this case coplanarity of the inter- mediate species (as in A) is no longer enforced, because of conjugative interaction of the meta-hydroxy group with the dihydrodiazepinium dication as shown in formula B. This will greatly lower thc double-bond character of the interannular bond, thereby enabling rotation about it and decreasing the steric hindrance to attack at the ortho-position.

It is noteworthy that no bromination takes place at the para-positions of the benzenoid rings in the outho-substituted 6-aryl-dihydrodiazcpinium salts 9 and lo4'. This provides further evidence For the cffect of ortho-substituents in inhibiting the planarity which is usually necessary for electrophilic substitution in the aryl ring to take place.

9 10

Attempted Bromination of 1,2-Dihydro-5-(hydroxyphenyl)-2-oxopyrimidi- nium Salts 11

Attempts to brominate the related dihydro-oxopyridinium salts 11 a, b5' were unsuccessful, although mass spectra implied that a very small amount of bromo derivatives were formed. Although these dihydro-oxopyrimidinium salts contain

Liebigs Ann. Chem. 1986

1384 D . Llovd. C . Reichardt. and M. Struthers

vinamidinium systems6) which might activate the phenyl rings, this effect is much less marked than in dihydrodiazepinium salts, since in the case of l l a , b the car- bony1 group competes for the excess electrons and hence lowers the nucleophilicity of the vinamidinium systems in this case. The 5-phenyl analogue of 11 a, b also was not brominated’).

C. R. thanks the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie for financial support. M. S. thanks the British Council for the award of a Scholarship in the Fed. Rep. Germany and the University of St. Andrews for a Research Studentship.

Experimental The same equipment and methods as described in reference’) have been used.

6-(3-Bromo-4-hydroxyphenyl)-2,3-dihydro-l,4-diazepinium Perchlorate (4a): To a stirred solution of 0.29 g (1 .OO mmol) of 2,3-dihydro-6-(4-hydroxyphenyl)-1,4-diazepinium per- chlorate (3a)’) in 10 ml of methanol was added, dropwise, a solution of 0.16 g (1.00 mmol) of bromine in 10 ml of methanol, ensuring that the temperature did not rise above 30°C. After a short time, the reaction mixture was decolourised, signifying the absence of any excess of bromine. Some of the solvent was removed by distillation in vacuo (rotary evapo- rator), and to the remainder was added diethyl ether. The resulting precipitate was filtered off and recrystallised from ethanol containing a few drops of perchloric acid (70%), affording 0.27 g (73%) of 4a as yellow crystals with m.p. 203-205°C. - ‘H NMR ([D,]DMsO): 6 = 3.8 (s; 4H, 2,3-H), 6.8-7.6 (m; 3H, C6H3), 7.9 (d; 2H, 5,7-H), 10.4 (s, broad; 3H, NH and OH). - 13C NMR ([D,]DMsO): 6 = 49.7 (s; C-2,3), 101.3 (s; C-6), 110.4 (s; CBr), 117.4, 129.0, 132.0, and 134.3 (s; phenyl-C), 153.3 (s; COH), 158.0 (s; C-5,7). - MS (70 eV): m/z = 266 and 268 (M+ - HC104).

CllH12BrC1N205 (367.6) Calcd. C 35.94 H 3.29 N 7.62 Found C 35.49 H 3.37 N 7.37

6-(3-Bromo-4-hydroxyphenyl)-2,3-dihydro-l,4-dimethyl-l,4-diazepinium Perchlorate (4b): As described for 4a, with 0.32 g (1.00 mmol) of 2,3-dihydro-6-(4-hydroxyphenyl)-1,4-di- methyl-1,4-diazepinium perchlorate (3b)5), affording 0.35 g (89%) of 4b as pale yellow need- les with m.p. 206-208°C. - ‘H NMR ([D6]DMSO): 6 = 3.5 (s; 6H, NCH,), 3.8 (s; 4H, 2,3-H), 6.9-7.6 (m; 3H, C6H3), 8.0 (s; 2H, 5,7-H), 10.2 (s, broad; IH, OH). - 13C NMR ([D6]DMSO): 6 = 48.4 (s; NCH,), 56.2 (s; C-2,3), 102.0 (s; C-6), 110.3 (s; CBr), 117.2, 129.3, and 133.0 (s; phenyl-C), 153.2 (s; COH), 158.1 (s; C-5,7).

C13H16BrC1N205 (395.6) Calcd. C 39.47 H 4.08 N 7.08 Found C 38.91 H 4.19 N 6.91

6-(3,5-Dibromo-4-hydroxyphenyl/-2,3-dihydro-l,4-diazepinium Perchlorate ((Sa): As given for 4a, with double the amount of bromine, i. e. 0.32 g (2.00 mmol), affording 0.39 g (87%) of5a as pale yellow crystals with m.p. 198-202°C. - ’H NMR ([D,]DMSo): 6 = 3.8 (s; 4H, 2,3-H), 7.6 (s; 2H, C6H2), 8.0 (d; 2H, 5,7-H), 10.4 (s, broad; 3H, NH and OH). - I3C NMR ([D,]DMsO): 6 = 49.8 (s; C-2,3), 101.4 (s; C-6), 112.4 (s; CBr), 132.0 and 134.0 (s; phenyl-C), 150.0 (s; COH), 158.1 (s; C-5,7). - MS (70 eV): m/z = 344, 346, and 348 (M+ -

C11HlIBr2ClNIOS (446.5) Calcd. C 29.59 H 2.48 N 6.27 Found C 29.56 H 2.74 N 6.24

CIO4).

6-(3,5-Dibromo-4-hydroxyphenyl)-2,3-dihydro-l,4-dimethyl-l,4-diazepinium Perchlorate (5b): As given for 4a, with 0.32 g (1.00 mmol) of 2,3-dihydro-6-(4-hydroxyphenyl)-1,4-di-

Liebigs Ann. Chem. 1986

Bromination of 2,3-Dihydro-6-(hydroxyphenyl)-1,4-diazepinium Salts 1385

methyl-1,4-diazepinium perchlorate (3b)51 and double the amount of bromine, i. e. 0.32 g (2.00 mmolj, affording 0.38 g (80%) of 5b as pale yellow crystals with m.p. 192- 194°C. - 'H NMR ([D6]DMSO): 6 = 3.5 (s; 6H, NCH3), 3.8 (s; 4H, 2,3-H), 7.6 (s; 2H, C~HZ), 8.0 (s; 2H, 5,7-H), 9.3 (s, broad; 1 H, OH). - 13C NMR ([D6]DMSO): 6 = 48.5 (s; NCH,), 56.1 (s; C-2,3), 100.7 (s; C-6), 112.2 (s; CBr), 132.2 and 134.6 (s; phenyl-C), 149.8 (s; COH), 158.1 (s; C-5,7). - MS (70 eV): m/z = 372, 374, and 376 (M+ - Clod).

C13H15Br2C1N205 (474.5) Calcd. C 32.90 H 3.19 N 5.90 Found C 32.64 H 3.46 N 5.60

6- (4-Bromo-3-hydroxyphenyl)-2,3-dihydro-l,4-diazepinium Perchlorate (7a): To a stirred solution of 0.29 g (1 .OO mmol) of 2,3-dihydro-6-(3-hydroxyphenyl)-I,Cdiazepinium per- chlorate (6a)') in 10 ml of methanol was added, dropwise, a solution of 0.16 g (1.00 mmol) of bromine in 10 ml of methanol, ensuring that the temperature did not rise above 30°C. After a short time the reaction mixture was decolourised, signifying the absence of any excess bromine. Some of the solvent was removed by distillation in vacuo (rotary evaporator), and to the remainder was added diethyl ether. The resulting precipitate was filtered off and recrystallised from ethanol containing a few drops of perchloric acid (70%), affording 0.15 g (41%) of 7a as pale yellow crystals with m.p. 258-260°C. - 'H NMR ([D6]DMSO): 6 = 3.8 (s; 4H, 2,3-H), 6.6-7.7 (m; 3H, C6H3), 8.0 (d; 2H, 5,7-H), 10.5 (s, broad; 3H, NH and OH). - 13C NMR ([D6]DMSO): 6 = 49.0 (s; C-2,3), 102.0 (s; C-6), 107.6 (s; CBr), 115.4, 120.0, 133.3, and 139.8 (s; phenyl-C), 154.2 (COH), 157.3 (s; C-57). - MS (70 eV): m/z = 266 and 268 (M+ - Clod).

CllHIZBrC1N2O5 (367.6) Calcd. C 35.94 H 3.29 N 7.62 Found C 37.24 H 3.53 N 7.80

(7a seems to contain traces of unbrominated material.)

6-(4-Bromo-3-hydroxyphenyl)-2,3-dihydro-l,4-dim~thyl-f .I-diazepinium Perchlorate (7 b): As described for 7a, with 0.32 g (1 .OO mmol) of 2,3-dihydro-6-(3-hydroxyphenyl)-l,4-di- methyl-l,4-diazepinium perchlorate (6b)5', affording 0.13 g (33%) of 7b as pale yellow needles with m.p. 172-174°C. - 'H NMR ([D6]DMSO): 6 = 3.5 (s; 6H, NCH3), 3.8 (s; 4H, 2,3- H), 6.7-7.6 (m; 3H, C6H,), 8.0 (s; 2H, 5,7-H); OH signal not observed. - 13C NMR ([D,]DMSOj: 6 = 47.6 (s; NCH,), 55.5 (s; C-2,3), 101.5 (s; C-6), 107.5 (s; CBr), 116.0, 120.3, 132.8, and 140.0 (s; phenyl-C), 154.1 (s; COH), 157.4 (s; C-5,7).

Cl3Hl6BrC1N2O5 (395.6) Calcd. C 39.47 H 4.08 N 7.08 Found C 39.05 H 4.10 N 7.01

6-(2,4-Dibromo-S-hydroxyphenylj-2,3-dihydro-l,I-diazepinium Perchlorate (8a): As de- scribed for 7a, with double the amount of bromine, i. e. 0.32 g (2.00 mmol), affording 0.17 g (38%) of 8a as very pale yellow crystals with m. p. 222-224°C. - MS (70 eV): m/z = 344, 346, and 348 (Mt - Clod). It was not possible to obtain 8a sufficiently pure for NMR spcctra and elemental analysis. It is contaminated with polybrominated products.

CllHllBr2C1N2O5 (446.5) Calcd. C 29.59 H 2.48 N 6.27 Found C 26.01 H 2.15 N 5.43

6-(2,4-Dibromo-5-hydroxyphenylj-2,3-dihydro-l,4-dimethyl-l,4-diazepinium Perchlorate (8b): As given for 7a, with 0.32 g (1.00 mmol) of 2,3-dihydro-6-(3-hydroxyphenyl)-l,4-di- methyl-l,4-diazepinium perchlorate (6b)5' and double the amount of bromine, i. e. 0.32 g (2.00 mmol), affording 0.11 g (23%) of 8b as colourless needles with m.p. 212-215°C. -

Liebigs Ann. Chem. 1986

1386 D. Lloyd, C. Reichardt, and M. Struthers

'H NMR ([D6]DMSO): F = 3.5 (s; 6H, NCH3), 3.8 (s; 4H, 2,3-H), 7.0 (s; 1 H, phenyl-H), 7.9 (s; 3H, 5,7-H and phenyl-H). - MS (70 eV): mlz = 372, 374, and 376 (Mf - C104).

C13HlSBr2CIN205 (474.5) Calcd. C 32.90 H 3.19 N 5.90 Found C 31.44 H 3.28 N 5.37

CAS Registry Numbers

3a: 102536-19-6 / 3 b : 102573-59-1 1 4 a : 102536-21-0 / 4b: 102573-61-5 / Sa: 102536-23-2 J Sb: 102536-25-4 / 6 a : 102536-27-6 1 6 b : 102536-31-2 / 7a: 102536-29-8 7b: 102536-33-4 / 8a: 102536-35-6 / 8 b : 102536-37-8 / l l a : 102536-39-0 / l l b : 102536-41-4

') M. Struthers, Thesis, Univ. of St. Andrews 1982 (the experimental work was carried out in Marburg and St. Andrews).

*) D. Lloyd and D. R. Marshall, J. Chem. SOC. 1958,118. - 2b) C . Barnett, H . P. Cleghorn, G. E. Gross, D. Lloyd, and D. R. Marshall, J . Chem. SOC. C 1966, 93. - ") D. Lloyd, R. H . McDougall, and D. R. Marshall, J. Chem. SOC. C 1966, 780. - *dl A. M. Gorringe, D. Lloyd, F. I. Wasson, D. R. Marshall, and P. A . Duffield, J. Chcm. SOC. C 1969, 1449.

3, 3a) C. Barnett, Chem. Commun. 1967,637. - 3b) C. Barnett, J. Chcm. SOC. C 1967,2436. - 3c) A. M. Gorrin e, D. Lloyd, D. R. Marshall, and L. A. Mulligan, Chem. Ind. (London)

617. 1968, 130. - 3d B A. M. Gorrznge, D. Lloyd, and D. R. Marshall, J. Chem. SOC. C 1970,

4, D. Lloyd, K. S. Tucker, and D. R. Marshall, J. Chem. SOC., Perkin Trans. 1 1981, 726. 5 , D. Lloyd, C. Reichardt, and M. Struthers, Liebigs Ann. Chem. 1986, 1368, preceding

6, D. Lloyd and H. McNab, Angcw. Chem. 88,496 (1976); Angcw. Chcm., Int. Ed. Engl. 15,

') D. Lloyd, H . McNah, and K. S. Tucker, J. Chem. SOC., Perkin Trans. 1 1977, 1862.

paper.

459 (1976).

C15/861

Liebigs Ann. Chcm. 1986