INTRODUCTION:

The extent of studies confirms the increasing interest in benzotropone chemistry in the 1960s¹, and several more recent reports have been concerned with the functionalization and reactivity of the derivatives of benzo-fused cycloheptenones. In spite of this work, little is known about the derivatization and reactivity of bromo-benzotropones. Previously reported the synthesis of structural analogues of substituted-6,7,8,9- tetrahydrobenzocyclohepten-5-ones (Figure 1)^2,3. Some of the bromo derivatives (la-d) showed some activity in murine p388 tests during routine anti-tumor screening⁴, thus a program of structural modification of 2,3-dimethyl benzocyclohepten-5-one (2)⁵ was undertaken in the present investigation to study the structure activity relationship.

Figure 1. Structural analogues of substituted-6,7,8,9-tetrahydrobenzocyclohepten-5-ones

It has been reported⁶ that bromination of tetrahydro benzocycloheptenone with N-bromosuccinimide (NBS) (2 equiv.) gave the 9,9-dibromo derivative. We have repeated the same reaction using NBS (2 equiv.) as a brominating agent on our ketone (2) to see whether the second bromine atom tend to enter into C-9 or C-6 position. This confirmatory work was necessary since there are reports⁷ of NBS reactions which tended to introduce a second bromine atom into benzocycloalkanones at a position α to the carbonyl group rather than in the benzylic position and geminal with the first bromine atom.

EXPERIMENTAL:

General:

All commercially available reagents were used without further purification. Reaction solvents were dried by standard methods before use. Purity of the compounds was checked by TLC using Merck 60F254 silica gel plates. Elemental analyses were obtained with an Elemental Analyser Perkin-Elmer 240C apparatus. ¹H and ¹³C NMR spectra were recorded with a Mercuryplus 400 spectrometer (operating at 400 MHz for ¹H and 100.58 MHz for ¹³C); chemical shifts were referenced to TMS. EI (electron impact) mass spectra (at an ionising voltage of 70 eV) were obtained using a Shimadzu QP5050A quadrupole-based mass spectrometer. IR spectra were recorded with a Perkin-Elmer 881 spectrometer.

General procedure for the synthesis of 2,3-Dimethyl-6,6-dibromo-6,7,8,9-tetrahydrobenzocyclohepten-5-one (3): Bromine (2.0 g, 12 mmole) in carbon tetrachloride (15 mL) was added dropwise to a stirred solution of 2 (1.0 g, 10 mmol) in carbon tetrachloride (50 mL), the solution was then boiled for 1 hr and the solvent was removed under reduced pressure. The residue (1.9 g, 83%) was almost pure dibromoketone (3).m.p. 142.6°C. IR(CHC1₃): υ 1770, 1687 cm^–1; ¹H NMR (CDC1₃): δ 1.90-2.15 (m, 2H, 8-H), 2.90-3.30 (m, 4H, 7 and 9-H), 2.30 (s, 6H, 2 Me), 7.10 (s, 1H, 1-H) and 7.55 (s, 1H, 4-H); MS : m/z= 346 (M⁺. 100%), 318, 272, 241, 238, 191, 173, 163, 145, 133, 115, 105, 93, 85, 82. Anal. Calcd for C₁₃H₁₄Br₂O : C, 45.11 ; H, 4.08%. Found: C, 45.18 ; H, 4.00%.

General procedure for the synthesis of 2,3-dimethyl-6,6,9-tribromo-6,7,8,9-tetrahydrobenzo-cyclohepten-5-one (9):

(a) A solution of the 6,9-dibromoketone 5 (1.5 g, 1 mmole) and phenyl trimethylammonium tribromide (1.69 g) in dry THF (25 mL) was left at room temperature for 24 h. Workup gave the unchanged dibromoketone (5).

(b) A mixture of 6,6-dibromoketone 6 (1.5 g, 3 mmole), NBS (0.5 g), benzoyl peroxide (20 mg) in dry carbon tetrachloride gave after boning (4.5 h) the tribromoketone 9 in 93.3% yield, m.p. 82.6°C. IR (CHC1₃): u 1704 cm^–1; ¹H NMR (CDC1₃): δ 2.80-3.20 (m, 4H, 7 and 8-H), 2.38 (s, 6H, 2 Me), 5.40-5.70 (m, 1H, 9-H), 7.10 (s, 1H, 1-H) and 7.50 (s, 1H, 4-H); MS : m/z = 425 (M⁺), 397, 350, 317, 272, 191, 163, 117 (100%), 105, 91, 82. Anal. Calcd for C₁₃H₁₃Br₃O : C, 36.74 ; H, 3.08%. Found: C, 36.77 ; H, 3.00%.

General procedure for the synthesis of dehydrobrominations products:

General procedure for the synthesis of 2,3-dimethylbenzocyclohepten-5-one (4):

A mixture of 6,6-dibromoketone 3 (0.5 g, 1.176 mmole) anhy. lithium chloride (0.15 g, 3 mmole) and dry DMF (30 mL) was boiled and stirred under nitrogen for 3 h. The mixture was cooled and DMF removed under reduced pressure. Water was added, and the mixture was thoroughly extracted with ether. The combined extracts were dried (Na₂SO₄), evaporation of the solvent gave a solid 2,3-dimethylbenzocyclohepten-5-one (4) (75%), which crystallized from ethanol as off-white crystals. m.p 102.4°C. IR (CHC1₃) : u 1667, 1600, 1208 cm^–1; ¹H NMR (CDC1₃): δ 6.60-7.90 (m, 4H, seven-membered ring-H), 2.37 (s, 6H, 2 Me), 7.60 (s, 1H, 1-H) and 8.40 (s, 1H, 4-H); MS : m/z= 184 (M⁺), 156 (100%), 131, 114, 83, 73. Anal. Calcd for C₁₃H₁₂O : C, 84.74 ; H, 6.56%. Found: C, 84.68 ; H, 6.66%.

General procedure for the synthesis of monobromination of 2,3-dimethyl-6,7,8,9-tetrahydrobenzo-cycIohepten-5-one with N-bromosuccinimide (NBS):

A mixture of dimethylbenzocyclohepten-5-one (2) (2.0 g, 10.63 mmole) NBS (1 equiv.) and benzoylperoxide (50 mg) in dry carbontetrachloride (50 mL) was boiled (6h) over a 500 w lamp. Filtration, and evaporation of the CCL₄ gave a thick brown oil. TLC showed four spots. PLC [3 runs of the oil (1.0 g)] gave four bands.

(i)2,3-Dimethyl-6,9-dibromo-6,7,8,9-tetrahydrobenzocyclohepten-5-one (5):

Yield 48%. m.p. 63°C.IR (CHC1₃): u 1770, 1687 cm^–1 ; ¹H NMR (CDC1₃): d 1.95-2.15 (m, 2H, 8-H), 2.85-3.00 (m, 2H, 7-H), 4.85-5.10 (m, IH, 6-H), 5.40-5.65 (m, IH, 9-H), 2.30 (s, 6H, 2 Me), 7.11 (s, IH, 1-H) and 7.50 (s, IH, 4-H). Anal. Calcd for C₁₃H₁₄Br₂O : C, 45.11 ; H, 4.08%. Found: C, 45.13 ; H, 4.02%.

(ii)2,3-Dimethyl-9-dibromo-6,7,8,9-tetrahydrobenzocyclohepten-5-one (6) :

Yield 18%. m.p. 105°C.IR (CHC1₃): u 1770, 1685 cm^–1; ¹H NMR (CDC1₃): d 2.00-3.00 (m, 6,7 and 8-H), 5.40-5.60 (m, IH, CHBr Ar), 2.27 (s, 6H, 2 Me), 7.10 (s, IH, 1-H) and 7.50 (s, IH, 4-H). MS : m/z 267 (M⁺ 100%), 187, 159, 148, 133, 119, 117, 92. Anal. Calcd for C₁₃H₁₅BrO : C, 58.44 ; H, 5.66%. Found: C, 58.51 ; H, 5.68%.

(iii) 2,3-Dimethyl-6-bromo-6,7-dihydrobenzocyclohepten-5-one (7): Yield 19%. m.p. 77°C. IR (CHC1₃):

u 1660, 1670 cm^–1; ¹H NMR (CDC1₃): d 2.40-3.00 (m, 2H, methylene-H), 4.86-5.01 (m, IH, CHBr ), 6.50 and 4.80 (dd, 2H, 8 and 9-H), 2.38 (s, 6H, 2 Me), 7.00 (s, IH, 1-H) and 7.30 (s, IH, 4-H). MS : m/z 265 (M⁺.), 237, 185, 156 (100%), 141, 117, 91, 92, 77. Anal. Calcd for C₁₃H₁₃BrO : C, 58.88 ; H, 4.94%. Found: C, 59.01 ;H, 5.00%.

(iv) 2,3-Dimethyl-6,7-dihydrobenzocyclohepten-5-one (8): Yield 12%. m.p. 118.5°C.

IR (CHC1₃): u 1660, 1672 cm^–1; ¹H NMR (CDC1₃): d 1.60-3.20 (m, 4H, methylene-H), 2.38 (s, 6H, 2 Me), 6.50 and 6.45 (dd, 2H, 8 and 9-H), 7.10 (s, IH, 1-H) and 7.60 (s, 1H, 4-H). MS : m/z 186 (M⁺), 157, 131 (100%), 117, 91. Anal. Calcd for C₁₃H₁₄O : C, 83.82 ; H, 7.58%. Found: C, 84.02 ; H, 7.56%.

General procedure for the synthesis of 2,3-Dimethyl-6-bromobenzocyclohepten-5-one (10):

(a) From the reaction of tribromoketone 9 (1 mmol) and lithium chloride (0.2 g) in DMF (50 mL) the 6-bromoketone (10) (80%) was obtained as pale yellow prisms, m.p. 83.4°C. IR (CHC1₃): u 1630, 1619, 1596 cm^–1; ¹H NMR (CDC1₃): 6 6.40-6.80 (t, 1H, 8-H), 7.30-7.70 (d, 1H, J = 11.3 Hz, 9-H), 7.80-8.20 (d, 1H, J = 9.3 Hz, 7-H), 2.38 (s, 6H, 2 Me), 7.60 (s, 1H, 1-H) and 8.40 (s, 1H, 4-H). MS : m/z 263 (M⁺),239, 235, 207, 194, 188, 179, 162 (100%), 141, 131, 114, 97, 81. Anal. Calcd for C₁₃H₁₁BrO : C, 59.33 ; H, 4.21%. Found: C, 59.12 ; H, 4.28%.

(b) A solution of 2,3-dimethylbenzocyclohepten-5-one (4) (0.5 g) in DMF (5 mL) was treated drop wise at room temperature with bromine (0. 5 g) in DMF (5 mL). After 0.5 h the solution was heated to complete the reaction and then DMF was removed and the residue was separated by column chromatography to afford 2,3-dimethyl-6-bromo benzocyclohepten-5-one (60 mg). The unchanged 2,3-dimethylbenzocyclohepten-5-one (4) (150 mg) was recovered.

RESULTS AND DISCUSSION:

This manuscript describes a facile route for the synthesis of benzotropones. 2,3-Dimethyl-6,7,8,9-tetrahydrobenzo cyclohepten-5-one (2) was brominated with bromine in carbon tetrachloride to give 2,3-dimethyl-6,6-dibromo-6,7,8,9-tetrahydrobenzocyclohepten-5-one (3). The dibromo ketone (3) was converted into the corresponding 2,3-dimethyl benzocyclohepten-5-one (4) by boiling with a solution of lithium chloride in DMF for 1 h (Scheme 1). The dibromo ketone (3), obtained by treatment of (2) with bromine in carbon tetrachloride was clearly shown by its ¹H NMR spectrum to be the 6,6-dibromo derivative (broad triplets at d 2.90-3.30 due to the 7- and 9- methylene groups).

When dimethylketone (2) was treated with NBS (2 equiv.) substitution was observed at C-9 and C-6 yielding the dibromoketone (5) as revealed by the ¹H NMR spectrum (1H multiplets at d 4.85 and 5.40 attributed to the 6- and 9-protons respectively). Dehydrobromination of the 6,9-dibromoderivative (5) with lithium chloride in boiling DMF gave the expected benzotropone (4). An attempt to obtain a monobromo derivative by reaction of (2) and NBS (1 equiv.) gave a mixture of products, including the 6,9-dibromo derivative (5), 2,3-dimethyl-9-bromo-6,7,8,9-tetrahydro benzocyclohepten-5-one (6), 6,7-dihydrobenzocyclo-heptenone (7) and 2,3-dimethyl-6-bromo-6,7-dihydro benzocyclohepten-5-one (8) (Scheme 1). All these compounds were characterized with the help of chemical and spectral evidences.

A number of mechanisms for the dehydrobromination have been suggested.^[7] It has been reported^[8] that the efficiency of halide ion as a base in DMF solution is due to the low solvation. The mechanism may involve the elimination of two molecules of hydrogen bromide (Mechanism-I and II Scheme 2) from the corresponding a,a-dibromoketone.

CONCLUSION:

We have made a few conclusion, highly efficient method has been developed higher overall yield. This method overcomes many of the drawbacks associated with previously reported syntheses and offers an industrial feasible procedure for the synthesis of similar molecules is currently underway in our laboratory and exploration of this method for the preparation of variations in dehydrobromination conditions for example collidine could be used to convert dibromoketone into benzocycloheptenone although the reaction was not as clean as that of lithium chloride. Lithium carbonate could be substituted for lithium chloride with little change in yield.

ACKNOWLEDGEMENTS:

PG thank to GVK Innogent Laboratories Pvt. Ltd, for the supporting research facilities and encouragement.

REFERENCES:

1. (a) Pauson P. L. Tropones and Tropolones. Chem. Rev. 1955; 55: 9-136; (b) Nozoe T. Non-Benzenoid Aromatic Compounds, ed. D. Ginsburg, Interscience, New York. 1959; (c) Lloyd D. Carbocyclic Non-Benzenoid Aromatic Compounds, Elsevier, Amsterdam. 1966; (d) Hoff mann R. W. Dehydrobenzene and Cycloalkynes, Academic Press, New York. 1967; (e) Katritzky A. R. and Takeuchi Y. New route to tropones based on the 1,3-dipolar reactivity of heteroaromatic betaines. J. Am. Chem. Soc. 1970; 92: 4134-4136; (f) Hunt D. F, Farrant G. C. and Rodeheaver G. T. Chemistry of (cycloheptatrienone) tricarbonyliron and (cycloheptadienone) tricarbonyliron in highly acidic media. J. Organomet. Chem. 1972; 38: 349-365.

2. Carpenter P. D, Peesapati V and Proctor G. R. Synthesis of structural analogues of 6,7,8,9-tetrahydro-3-hydroxy-2-methoxybenzocycloheptan-5-one. J. Chem. Soc. Perkin 1. 1979; 103-107.

3. Dennis N, Katritzky A. R. and Takeuchi Y. 1,3-Dipolar character of six-membered aromatic rings. Part III. 2-Methyl-3-oxidoisoquinolinium. A novel route to benzotropones. J. Chem. Soc. Perkin Trans. 1. 1972; 2054-2057

4. National Cancer Institute, Bethesda, MD 24014, USA.

5. (a) Al-Lakkis-Wehbe M, Roux L, Charrier C, Alavi S, Le Nouën D, Defoin A, Tarnus C and Albrecht S. Regioselective synthesis of the 1-bromo-4-phenyl-tetrahydro-7-amino-benzocyclohepten-6-one, a subnanomolar aminopeptidase-N/CD13 inhibitor. Tetrahedron. 2012; 68: 6447-6455; (b) Gilmore, Jr. R. C.; Horton, W. J. Seven-membered Ring Compounds. I. 7,8,9,10-Tetrahydrocyclohepta[de]naphthalene. J. Am. Chem. Soc. 1951; 73: 1411-1414.

6. Khan A. M, Proctor G. R and Rees L. Novel aromatic systems. Part IV. Synthesis and dehydrogenation of 4'-hydroxy-1,2-benzocycloheptatrienes. J. Chem. Soc. C. 1966; 990-994.

7. Collington E. W and Jones G. Dehydrobromination of αα-dibromotetrahydrobenzocyclohepten-5-ones: a convenient synthesis of benzocyclohepten-5-ones. J. Chem. Soc. C. 1969; 2656-2661.

8. Parker A. J. The effects of salvation on the properties of anions in dipolar aprotic solvents. Quart. Rev. Chem. Soc. 1962; 16: 163-187.

Received on 01.07.2014 Modified on 20.07.2014

Asian J. Research Chem. 7(8): August 2014; Page 698-701