Synthesis of 8-bromoisoquinolines and a crystal structure of an acyclic secondary amine-borane

8-Bromo-7-methoxyisoquinoline was produced by Jackson’s modification of the Pomeranz-Fritsch ring synthesis accompanied by 8-bromo-3-(8-bromo-7-methoxyisoquinolin-4-yl)-1,2,3,4- tetrahydro-7-methoxy-2-(4-methylphenylsulfonyl)isoquinoline. A mechanism for the formation of the latter is suggested. The ready formation of secondary amine-BH 3 complexes was noted and the X-ray crystal structure of N -(2-bromo-3-methoxybenzyl)aminoacetaldehyde dimethyl acetal boranedetailed.


Introduction
Our interest in the fusion of a third ring to an isoquinoline framework, across the 8-and 1-positions, led to a requirement for 8-bromoisoquinoline or a derivative, so that a chain could be attached at the 8-position via a coupling procedure.8-Bromoisoquinoline appears in the literature three times: it was prepared 1 from isoquinoline by nitration, reduction, diazotisation and Sandmeyer reaction, it was used 2 to prepare 8,8'-biisoquinoline without mention of its method of synthesis, and it was prepared in 31% yield by ring synthesis; 3 we chose to follow the ring synthesis route.

Results and Discussion
Reaction of 2-bromobenzaldehyde with 2,2-dimethoxyethanamine gave the Schiff base 1, borohydride reduction of which produced the 2-bromobenzylamine-acetal 2 (see later for further discussion of this reduction).Conversion to a tosylamide 3 so that Jackson's modification 4 of the Pomeranz-Fritsch isoquinoline ring synthesis could be examined was unrewarding -the expected cyclised product 4 was obtained under strongly acidic conditions, but could not be properly characterised and certainly was not converted to the aromatic isoquinoline under the standard conditions. 4Treatment of 1 with a mixture of phosphorus pentoxide and concentrated sulfuric acid, as described 3 gave only hydrolysis product, however comparable treatment of the benzylamine 2 did produce 8bromoisoquinoline 5 but at best in 6% yield.
Since our ultimate plans were unaffected by the presence of additional substituents on the isoquinoline benzene ring, we turned to the prospect of ring synthesising 8-bromo-7methoxyisoquinoline 5 hoping that an electrophilic ring closure would be more efficient at the position para to the methoxy group.8-Bromo-7-methoxyisoquinoline has been prepared from 7methoxy-8-nitroisoquinoline 6 by nitro group reduction, diazotisation, and then Sandmeyer reaction 7 however this would have required a ring synthesis of 7-methoxyisoquinoline.
2-Bromo-3-methoxybenzaldehyde has been synthesised from 2-bromo-3-methoxytoluene by side-chain dibromination then hydrolysis 8 and more recently by Meyers via introduction of the halogen after lithiation of 3-methoxybenzaldehyde. 9Aldehyde from the Meyers route was condensed with 2,2-dimethoxyethanamine giving 6, borohydride reduction then affording the benzylamine-acetal 7 (see later for further discussion of this reduction).After N-tosylation producing 8, heating with p-toluenesulfonic acid in toluene at reflux gave the desired 7-methoxy-8-bromoisoquinoline 9 in 19% yield, together with 27% of a byproduct with a molecular weight of 630 corresponding to a molecular formula C 27 H 24 Br 2 N 2 O 4 S.

OMe
To this byproduct we assign structure 10, the key spectroscopic features leading to this assignment, being 1 H-NMR signals for two geminally coupled methylene groups (δ 4.25 & 4.73) and (δ 3.27 & 3.87) the latter further coupled to a methine proton (δ 5.00), and singlet signals (δ 9.50 and δ 8.10) for two pyridine ring protons at shifts typical for 1-and 3-positions of an aromatic isoquinoline.We envisage the formation of 10 involving ring closure to enamine-tosylamide 11 which then serves two roles: it is protonated to generate iminium species 12 which is then attacked by a second molecule of 11 giving 13 and following losses of proton (® 14) and toluenesulfinic acid, the observed product 10 is generated (Scheme 1).In a test coupling it was shown that 8-bromoisoquinoline 9 reacted in modest yield with hex-1-yne to produce the alkynylisoquinoline 15.

NTs
In each of the borohydride reductions of imines 1 and 6, byproducts which could be easily separated by chromatography from the product amines, were obtained.The 1 H-NMR spectra of these byproducts were much more complex than those of the amines and it was not until we realised that these substances were the amine-boranes 16 and 17 now having a chiral centre at the nitrogen that explanations for the complexity became clear -the hydrogen atoms on the adjacent carbon are now distereotopic.To further confirm the assigned structures, each of the amines was reacted with borane in THF to produce the amine-boranes, quantitatively.Finally, a crystal structure determination on 17 revealed the linked, tetrahedral nitrogen and boron atoms.A Chem3D drawing of 17 made using the X-ray co-ordinates, is shown in Figure 1.
A literature search revealed that this is the first example of a crystal structure of an acyclic secondary amine-borane, involving BH 3 itself. 11We wondered whether the ready formation of these acyclic amine-boranes was related to the structural complexity of the examples described above.Accordingly, ethanamine was condensed with 2-bromobenzaldehyde, the resulting imine 18 with borohydride generating a mixture of the amine 19 and its borane derivative 20.The amine and its borane were separated and it was again shown that this simple amine reacts quantitatively with borane in THF to form 20. It is noteworthy that for this amine/amine-borane pair, and for the two discussed above, in each case the zwitterionic compound runs faster on chromatography.16).To a solution of N-(2bromobenzylidene)aminoacetaldehyde dimethyl acetal 1 (8 g, 29.4 mmol) in a mixture of THF (60 ml), isopropanol (60 ml), and water (30 ml), NaBH 4 (6.7 g, 176.4 mmol) was added and the mixture stirred at room temperature for 2 h.The organic solvents were then evaporated in vacuum.Addition of water and CH 2 Cl 2 followed by separation, drying, and evaporation of the organic phase under reduced pressure gave a yellow oil.Purification by column chromatography over silica gel eluting with CH 2 Cl 2 gave the pure amine-borane 16 (2.1 g, 25%) as a colourless oil; IR (NaCl): νmax 2376 cm -1 ; 1 H-NMR (300 MHz, CDCl 3 ): δ 2.67 (1H, m), 2.78 (1H, m), 3.39 (3H, s), 3.41 (3H, s), 3.77 (1H, dd, J=9. 4

2-Bromo-3-methoxybenzaldehyde.
To a solution of N,N,N'-trimethylethylenediamine (4.1 ml, 32 mmol) in benzene (80 ml) was added n-BuLi (19 ml, 1.6M, 30 mmol) dropwise with cooling.After 15 min at room temperature, m-anisaldehyde (3.7 ml, 30 mmol) was added at 0 C, and the mixture was stirred at room temperature for 15 min.A solution of phenyllithium (50 ml, 1.8M, 90 mmol) in cyclohexane/ether was added with cooling.After the mixture was stirred at room temperature for 6 hours, THF (65 ml) was added and the mixture cooled to -78 C. 1,2-Dibromotetrafluoroethane(8 ml, 67 mmol) was added slowly at -78 C, the cooling bath was removed, and the mixture was allowed to come to rt and stirred for 30 min.The mixture was poured into cold water, vigorously stirred while 10% aq.HCl was added, and product extracted into ether.The combined organic layers were washed with brine, dried, and evaporated under reduced pressure to give an orange oil.Purification by column chromatography over silica eluting with hexane-EtOAc (92:8).The resulting material was recrystallised from hexane, giving 2-bromo-3-methoxybenzaldehyde (5.1 g, 79%) as a white crystalline solid, mp 66-68 °C (lit 9 : 69-70C); IR (NaCl): νmax 1692 cm

General procedure for reaction of secondary amines with BH 3 -THF
To a solution of the amine (1 mmol) in THF (5 ml), BH 3 -THF (1M, 2.6 mmol) was added.The mixture was stirred at rt for 15 min.The solvent was evaporated to dryness to leave the amineborane in quantitative yield.