High temperature bromination Part XXIII: Bromination of octahydro-1 H -indene and octahydro-1 H -4,7-methanoindene

Thermal and photobromination of octahydro-1 H -indene and octahydro-1 H -4,7-methanoindene were investigated. Three isomeric tetrabromides (1,3,4,7-tetrabromo-2,3,4,5,6,7-hexahydro-1 H - indene) were formed along with a smaller amount of tribromoindane and a pentabromide by thermal bromination of octahydro-1 H -indene. The thermodynamically most stable isomers were formed. Morover, thermal and photochemical bromination of octahydro-1 H -4,7-methanoindene furnished bromides resulting regiospecifically from the allylic bromination of the five-membered ring. Furthermore, the double bond formed as the intermediate functional group was also brominated due to its pyramidalization. The mechanism proposed for the formation of product distribution was discussed.


Introduction
The selective functionalization of hydrocarbons is a seminal and challenging process in organic synthesis and industrial chemistry. 2,3Thus, a new chemical process for selective functionalization of alkanes to upgraded products is one of the most promising methods for future organic synthesis.In spite of decades of efforts by a plethora of research groups, only a small number of chemical systems have been described for the transformation of such substrates by metallic [4][5][6][7][8][9] and nonmetallic catalysts, [10][11][12][13][14][15][16] aerobic oxidation, 17 and photochemical oxidation. 18Moreover, studies about the functionalization of rigid and strained bicyclic and tricyclic saturated hydrocarbons are rare in the literature.0] It was remarkable that the reaction proceeded with high regio-and stereoselectivity.Although the calculations demonstrated that the most stable tetrabromide, 2, was formed exclusively, it may well be that this is also a kinetically controlled product.It was not surprising that this configuration is the most stable because dipoledipole interactions between bromine atoms force each other to be as far apart as possible.
Inspired by our encouraging results with decalin (1) and octahydropentalene (3) giving single products with completely different geometries, we decided to investigate the behavior of octahydro-1H-indene (5), which is formed of a fused five-and six-membered ring.Furthermore, we examined the bromination reaction of an octahydropentalene system 6, where the sixmembered ring is incorporated in a bicyclic system.
During the mechanistic evaluation of the bromination of decalin, we showed that the reaction proceeds via the free radical bromination of 1 to give 10 followed by dehydrobromination to generate 11.Subsequent allylic bromination of octalin (11) generated the tetrabromide 2 (Scheme 3).Scheme 3. Formation of tetrabromide 2 over octalin as the intermediate.
As we could not separate 5 and 8, and possible bromination reaction of 5 will proceed via 8, a mixture consisting of 5 and 8 was subjected to bromination reaction.The mixture of 5 and 8 was reacted with 4 equiv. of bromine at 77 °C in CCl4 over 20 min.The 1 H-NMR spectral analysis of the reaction mixture indicated the formation of brominated compounds as well as the formation of some aromatic compounds.Column chromatographic separation provided 12, 13, 14, 15, and 16 in 35.0%, 15.0%, 7.0%, 5.9%, and 3.6% yields, respectively (Scheme 4).Scheme 4. High temperature bromination of the mixture of 8 and 5.
All structures were well characterized by 1 H-, 13 C-, and 2D-NMR experiments (DEPT, COSY, HMQC, HMBC).The dihedral angles between the methylenic protons of the fivemembered ring and its neighboring protons were used to define the configuration of bromine atoms in the compounds 12-16.The 13 C-NMR spectrum of 12 consisted of five distinct carbon resonances, indicating the high symmetry in the molecule.The methylene protons of the fivemembered ring resonate as a triplet (J 5.6 Hz), indicating the equivalency of the methylene protons and the trans-configuration of the bromine atoms connected to the five-membered ring.Because of the observed symmetry in the molecule, the bromine atom at the six-membered ring must also have trans-configuration.Notably, the 1 H-NMR spectrum of 13 is quite different from that of 12, whereas the 13 C-NMR spectrum consists of five distinct signals indicating the symmetry in the molecule.The methylene protons of the five-membered ring appear as an AB system as a doublet of triplets at 3.24 ppm (A-part of AB-system, 2 J 16.9 and 3 J 7.0 Hz) and as a doublet at 2.85 ppm (B-part of AB-system ( 2 J 16.9 Hz).These couplings clearly show the cisconfiguration of the bromine atoms.The observed symmetry in the molecule was in agreement with the following structures 13 and 17.
However, on the basis of NMR data alone, we were not able to distinguish between those structures.By considering the results obtained by bromination of 5 and steric effects associated with the adjacent bromine atoms in 17, we assigned the structure 13 to this compound.Furthermore, we determined the relative energies of those isomers at RB3LYP (6-31G**) level using the SPARTAN'08 mechanic program, indicating that 13 is about 9.43 kcal/mol more stable than the isomer 17.Therefore, we assume that 13 is a thermodynamically controlled product.The assignment of the structure 14 was also accomplished using 1 H-and 13 C-NMR spectral data.The 9-line 13 C-NMR spectrum supports the asymmetry in the molecule.Again, the methylene protons in the five-membered ring resonate as an AB-system as a doublet of doublet of doublets at 3.45 (A-part of AB-system, 2 J 18.3, 3 J 5.7 and 2.2 Hz) and as a doublet at 2.62 ppm (B-part of ABsystem ( 2 J 18. 3 Hz).The fact that one of these protons H-2cis resonates as a doublet (arising from the geminal coupling) indicates again the cis-configuration of the bromine atoms as discussed above.The geometry optimized structure of 14 shows dihedral angles of 92.8° and 93.8° between the vicinal protons H-2cis and the protons H-1 and H-3, which is in good agreement with a cis-configuration.The asymmetrical structure can be only in agreement with the transconfiguration of the bromine atoms in the six-membered ring.

Dihedral angles
The nine-line 13 C-NMR spectrum of 15 also indicates the presence of an asymmetrical structure.The location of bromine atoms on the carbon skeletons was determined by COSYspectrum.The protons H-1, H-2, and H-3 resonate at 5.11 (H-1) as a broad singlet, at 4.91 (H-3) as a singlet, and at 4.77 ppm (H-2) as a triplet with a coupling of J=1.0 Hz.This coupling mode can be explained only by trans-configuration of the bromine atoms, since the relevant dihedral angles were determined to be 87.8° and 90.0°.Then the configuration of the bromine atoms at the six-membered ring must be trans for an asymmetrical structure. 29Finally, we identified as the last compound 16, which was aromatized under the reaction conditions.
In order to evaluate the relative stabilities of all possible diasteromeric 1,3,4,7tetrabromohexahydroindenes 11-13 and 17-19 we carried out DFT calculations.Our computational investigation of these substituted hexahydroindene derivatives shows that the isomers 11 and 12 are close in energy and they are approximately 4-11 kcal more stable than the other isomers 17-19.In the case of cis-configuration of the substituents in the six-or fivemembered rings the bromine atoms are far from each other.However, if the bromine atoms at 1,7 and 3,4 positions have the cis-configuration, there is a strong dipol-dipol interaction.This interaction increases the relative energy of the compounds.In the case of 18 and 19 the bromine atoms at 1,7 and 3,4 positions have the cis-configuration.Therefore, the energy of these isomers is much higher than that of other isomers.Scheme 5. Suggested mechanism for the formation of the tetrabromides derived from 5.
For the mechanism of formation of the products we propose that the reaction proceeds via the free radical bromination of 5 followed by dehydrobromination to form 8. Subsequent allylic bromination of 8 generates the products 12-16.Once the first bromine is placed at an allylic position, it may direct the second bromine trans to it three carbons removed.If this transdirecting effect continues, the isomer 12 with all bromine atoms trans will be formed (Scheme 5).
In order to clarify the remarkable stereospecificity observed in these tetrabromides 12-13 we incorporated the six-membered ring in a bicyclic system 6, and studied the thermal bromination of compound 6.Thermal bromination of rigid and more strained tricyclic structures are not described in literature.Scheme 6. Synthesis of the starting material 6 and its reaction with Br2 at 77 °C.1] Bromination of octahydro-1H-4,7-methanoindene (6) at 77 °C in CCl4 failed.To start the bromination reaction, first one of the tertiary protons in 6 should be abstracted.We assume that the methylene bridge protons hinder the approach of initially formed bromine radical to abstract one of the tertiary protons and probably the reaction temperature was not high enough to overcome the energy of the transition state for proton abstraction.Therefore, the reaction was carried out in a sealed tube at higher temperatures.Bromination of 6 in a sealed tube at 150 °C provided a mixture of three isolable brominated compounds, 23-25, in 16.0%, 11.0%, and 3.0% yields, respectively (Scheme 7).The bridging methylene protons H8exo and H8endo resonate as an AB-system and the geminal coupling constants between those protons were found to be 10.4-10.9Hz.It was notable that the chemical shifts of the H8exo protons (1.56-1.71ppm) in 23-25 are comparable with that of unsubstituted hydrocarbon 6 (1.48 ppm).However, the chemical shifts of the H8endo protons are moved successively to lower field depending on the number of bromine atoms bonded to C3a and C7a.9][30][31][32][33][34][35] Insertion of one bromine atom at the C3a position causes a remarkable lowfield shift of the proton H8endo (2.10 ppm) due to the steric repulsion caused by bromine atoms.In the case of 23 and 24 there are two bromine atoms; the H8endo proton resonances are shifted down to 2.53 and 2.61 ppm, respectively.The shift effect of the bromine atoms is additive.On the basis of these observations we assigned exo-configuration to the bromine atoms bonded to C3a and C7a carbons.Furthermore, the lack of coupling between the protons H8exo and H7a in 25 clearly indicated the cis-configuration of this proton (related to the adjacent bromine atom).In the case of a trans-configuration of this proton, as shown in 26, a coupling between H8exo and H7a should be observed according to a W" or M" orientation mechanism.13c The carbonyl carbon resonance in 24 appears at 195.9 ppm, showing conjugation with a double bond.The olefinic proton in 24 resonates at 6.48 ppm as a singlet, clearly indicating the -position.Otherwise, this proton resonance should be shifted down to 7.50 ppm or lower.
To rationalize the formation of compounds 23-25 we propose the following mechanism.As discussed above, we assume that the reaction proceeds via the free radical bromination of 6.First, a bromine radical initially formed abstracts one of the protons H3a or H7a forms 27, which is then captured by bromine to give the monobromide 28 (Scheme 8).Dehydrobromination of 28 can generate two isomeric alkenes 29 and 30.Successive allylic bromination followed by dehydrobromination of 29 and 30 through the intermediates 31-36 furnishes the products 23-25.Contrary to the bromination reaction of 1 and 3, in the case of 6 the double bond formed as an intermediate is also further brominated.To explain this outcome, we carried out some calculations on the possible olefins 29 and 30.Scheme 8. Suggested mechanism for the formation of 23-25 derived from 6.The geometry optimization calculations (DFT, B3LYP at 6-311+G** level) carried out on 29 and 30 showed that 29 is about 0.26 kcal/mol more stable than the isomer 30 (Table 2).Therefore, we assume that these two isomers may be formed under the reaction conditions.The double bonds in 29 and 30 are pyramidalized [36][37] in the endo direction.Norbornene and norbornadiene exclusively undergo an exo attack upon treatment with electrophiles.2][43] Since the double bonds in 29 and 30 are pyramidalized, they will undergo an exo-attack by bromine radicals to form 32 and 37, respectively.The formation of the final products can be rationalized by tandem HBr elimination followed by bromine addition as depicted in Scheme 8.The ketone 24 may be formed during chromatography of the reaction mixture on a silica gel column probably by hydrolysis of the corresponding geminal dibromide 34.Photobromination of 6.After bromination of 6 under very harsh conditions (150 °C) we have examined the photobromination reaction of 6 at room temperature in order to prevent eventually the dehydrobromination reaction of brominated intermediates that are initially formed.For this purpose, to a solution of 6 in CCl4 was added 4 eqiv. of bromine and the resulting solution was irradiated for 72 h with 150-W projector lamp at room temperature (Scheme 9).The tetrabromide 38 was separated and characterized as the sole isolable compound.Again, the configuration of the bromine atoms connected to C3a and C7a was assigned as exo due to the lowfield shift (2.61 ppm) of the resonance frequency of the proton H8endo.Scheme 9. Photobromination of 6 at room temperature.
The methylenic H2 and H2′ protons give rise to an AB-system at 2.76 ppm (dd, A-part of ABsystem J22′(gem) 15.2 Hz, J23 7.6 Hz) and 2.60 ppm (ddd, B-part of AB-system J2′2 15.2 Hz, J2′3 13.2 Hz, J2′1 6.0 Hz).The correlations between the methylenic protons and H3 and H1 were clearly observed from the COSY spectrum of the compound.The formation of this tetrabromide can be explained first by the formation of the alkene 29, followed by allylic bromination to give 39, which can be transformed into the final product by addition of bromine radicals to the pyramidalized double bond.The isolation of this product 39 also supports the proposed mechanism shown in Scheme 8.

Conclusion
High temperature bromination of saturated bicyclic[4.3.0]system 5 carried out at high temperature results in the formation of three isomeric tetrabromides: 12, 13, and 14.Pentabromide 15 and the aromatic tribromide 16 are formed by sequential HBr elimination followed by bromination reactions.Significantly, the regioselectivity of the high temperature bromination reaction is still preserved even though the stereoselectivity was diminished to a lesser extent in contrast to bromination of decalin (1) and octahydropentane (3).Calculation and product analysis indicate that the major factor contributing to this specificity is the thermodynamic stability of the formed products.Furthermore, the steric interaction between the bromine atoms connected to C-1 and C-7, and C-3 and C-4 dictates that products with these atoms as far apart as possible will predominate.
In the second part of this work, the allylic positions in the six-membered ring in 5 were bridged with a methylene group, so that this system would not allow the bromination reaction at the bridgehead.As expected, high temperature as well as photochemical bromination of 6 resulted in the formation of products arising from allylic bromination of the five-membered ring.
The fact that the double bond was also brominated can be attributed to the pyramidalization of the double bond, which increases the reactivity of the system.

Experimental Section
General.All comercially available compounds were purchased from the Company MERCK.NMR spectra were recorded on a Bruker Instrument Avance Series-Spectrospin DPX-400 Ultrashield instrument CDCl3 with TMS as internal reference.Infrared spectra were recorded on a Matson 1000 FT-IR spectrometer and Vertex 70 series FT-IR spectrometer.Band positions were reported in reciprocal centimeters (cm -1 ).Column chromatographic separations were performed by using Fluka Silica Gel 60 plates with a particle size of 0.063-0.200mm.Thin layer chromatography (TLC) was performed by using 0.25 mm silica gel plates purchased from Fluka.Elemental analysis were carried out at Atatürk University, Department of Chemistry on a LECO CHNS-932 elemental analyzer.

Table 2 .
Relative energies of 29 and 30 calculated at RB3LYP (6-31G**) level using the SPARTAN'08 mechanic program indicated and the bending angles of the double bonds