One of the disadvantages of the previous route was the potential for α-bromination products to form from the ketone.71 This was expected to be-come a more significant issue upon scale up due to the higher concentration
of HBr being generated, catalysing enol formation. It would also be possible for HBr-catalysed spirocyclisation to occur, leading to the para product. Since the literature procedure incorporates bromine atoms as blocking groups pre-spirocyclisation, the possibility of changing the order of the reactions starting from 3-hydroxybenzaldehyde was investigated.
The first step in the alternative sequence was the bromination of the ben-zaldehyde, which was attempted in both batch and flow.
Various batch methods were attempted for the synthesis of 2-bromo-5-hydroxybenzaldehyde. The method that gave the highest yield and great-est proportion of monobrominated product used molecular bromine in DCM (Scheme 3.14).
Scheme 3.14 Batch bromination of 3-hydroxybenzaldehyde.
The maximum conversion reached was 78% as determined by 1H NMR spec-troscopy, and the crude material was recrystallised from AcOH to give the pure product in 65% isolated yield.
To mitigate the risks associated with using molecular bromine in batch at scale, flow methods were also considered. Higher dilutions of solutions were used to prevent precipitation of product whilst in the flow reactor. DCM, AcOH and mixtures of these two solvents were considered (Scheme 3.15). The starting material was less soluble in DCM than AcOH, and the maximum conversion observed was only approximately 20% by 1H NMR spectroscopy. This value did not vary according to the flow rate or residence time. It was therefore thought that the low concentration of starting material may be the limiting factor in improving the overall conversion.
OH H O
Br2 (1.1 equiv.) 0.167-0.500 mL min-1
DCM
0.500-1.50 mL min-1
3-8
Scheme 3.15 Flow bromination of 3-hydroxybenzaldehyde in DCM.
AcOH was also considered as a suitable solvent since it was compatible with both bromine and the starting material (Scheme 3.16). Conversion to the mono-brominated product peaked around 60%. As the flow rates were increased, the ratio of mono- to di-brominated product remained at around 2:1.
OH H O
Br2 (1.1 equiv.) DCM, 0.500-0.800 mL min-1
23 °C
10 mL OH
H O Br
AcOH, 1.50-2.40 mL min-1
OH
Scheme 3.16 Flow bromination of 3-hydroxybenzaldehyde in AcOH/DCM.
To improve the solubility of the starting material in DCM, 10% AcOH was added (Scheme 3.17). The flow rates were varied, and the composition of the resulting mixture was analysed by 1H NMR spectroscopy. The results are sum-marised in Fig. 3.1 below.
OH H O
Br2 (1.1 equiv.) DCM, 0.250-0.900 mL min-1
23 °C 0.750-2.70 mL min-1
OH
Scheme 3.17 Flow bromination of 3-hydroxybenzaldehyde in DCM/AcOH.
Fig. 3.1 Flow bromination of 3-hydroxybenzaldehyde; flow rate vs. composi-tion.
The maximum conversion (88%) was observed at 2.0 mL min−1, but at this flow rate dibromination was competitive with the desired monobromination.
In conclusion, the batch method of bromination gave the best yields of 2-bromo-5-hydroxybenzaldehyde. It would have been preferable to be able to use
flow chemistry, to reduce user exposure to bromine, but this method gave a higher proportion of the undesired dibrominated product. In the future, alternative solvents, dilutions, and reaction temperatures may be considered in flow. One of the causes of this dibromination may be due to the improved mixing in flow, which is normally an advantage. Different mixing pieces may reduce this over-bromination.
Although not optimised in flow, material was prepared allowing the next step to be tested. Hence the Dolliver-Ding conditions developed in the synthesis of 1,5-bis(3-hydroxyphenyl)penta-1,4-dien-3-one were applied to the condensation of 2-bromo-5-hydroxybenzaldehyde with acetone (Scheme 3.18).
OH
Scheme 3.18 Dolliver-Ding aldol condensation of 2-bromo-5-hydroxybenzaldehyde with acetone.
The reaction produced the crude product as an orange solid which was re-crystallised from IPA to give a bright yellow solid.
It was anticipated that the reduction of the brominated pentadienone may occur with simultaneous loss of the aromatic bromides.
Chemoselective reduction of the brominated pentadienone was attempted (Scheme 3.19) using the poisoned palladium-based conditions that had pre-viously proved successful for the reduction of the corresponding 1,5-bis(3-hydroxyphenyl)penta-1,4-dien-3-one (Pd/C, H2, Ph2S, EtOH).
OH
Scheme 3.19 Batch reduction of 1,5-bis(2-bromo-5-hydroxyphenyl)penta-1,4-dien-3-one.
However, even when using a shorter reaction time of 2 h, a mixture of the dibrominated, monobrominated and debrominated pentanones was observed.
The reaction time was not shortened further. The quantity of side-products could be reduced via purification by column chromatography (Hex:EtOAc 1:1 to Hex:EtOAc 0:100), but not completely removed. The desired dibrominated pentanone was the major product from these reactions (Fig. 3.2), but this was still an inefficient method of preparation.
6.50
Fig. 3.2 1H NMR spectra of the desired dibrominated pentanone, compared with the crude product mixture.
We again hoped that more precise contact time using a packed catalyst bed flow reactor may lead to better chemoselectivity. Therefore 1,5-bis(2-bromo-5-hydroxyphenyl)penta-1,4-dien-3-one was dissolved in EtOH to create a stock so-lution of 0.050 mol dm−3, and passed through a cartridge of 10% Pd/C catalyst using the H-Cube reactor (Scheme 3.20).R
OH
Scheme 3.20 Flow reduction of 1,5-bis(2-bromo-5-hydroxyphenyl)penta-1,4-dien-3-one using 10% Pd/C.
Unfortunately again, mixtures of dibrominated, monobrominated and further-more the debrominated pentanones were obtained. The mixtures could not easily be separated but by1H NMR analysis, the major product was the debrominated pentanone.
In an attempt to regulate the catalyst activity, the addition of Ph2S as a catalyst poison with the material being dissolved with the starting material in the EtOH stock solution was considered (Scheme 3.21).
OH
Scheme 3.21 Flow reduction of 1,5-bis(2-bromo-5-hydroxyphenyl)penta-1,4-dien-3-one using 10% Pd/C and Ph2S.
This proved somewhat successful but generated a complicated mixture of di-brominated, monobrominated and debrominated pentadienones, pentanenones and pentanones which was not separated.
It was thought the Pd catalyst might be more prone to inserting into the C-Br bond than an alternative catalyst, and so the catalyst was changed to Raney Ni and a range of reaction temperatures were tested (Scheme 3.22).
OH
Scheme 3.22 Flow reduction of 1,5-bis(2-bromo-5-hydroxyphenyl)penta-1,4-dien-3-one using Raney Ni.
Even at the higher temperatures, approximately only 50% conversion of start-ing material to the mono-reduced pentaenone could be achieved, but as predicted, debromination was not observed. More forcing conditions may be required for full conversion to the di-reduced pentanone, or alternatively recycling the mixture, or employing a slower flow rate, which may increase the conversion.
Although temporarily put aside, this route was returned to after the publica-tion in 2016 of an asymmetric synthesis of SPINOL by the Zhou group.72
In collaboration with Lauriane Peyrical, a bromination procedure using 1,5-bis(3-hydroxyphenyl)pentan-3-one as the starting material was developed (Scheme 3.23).
Scheme 3.23 Bromination of 1,5-bis(3-hydroxyphenyl)pentan-3-one using NBS.
Of particular note was that if the temperature and reaction time were not carefully controlled, dibromination on the aromatic rings was again observed.
However, maintaining the temperature below 0 ◦C and using 2.5 equivalents of NBS over a short reaction time allowed excellent conversions and good isolated yields of the desired product.
In their 2016 paper, Zhou et al. claimed to have used triflic acid to spirocyclise this brominated substrate. These conditions were thus examined and replicated (Scheme 3.24). Triflic acid (10 mol%)
Dichloroethane (anhydrous) 80 °C, 6 h, N2
1-59, 100% crude yield 3-11
Scheme 3.24 Spirocyclisation of the brominated phenol using triflic acid.
However, although full conversion was achieved, the crude product obtained contained several side-products, and was of poor quality.
Instead, following previous examples, the 1,5-bis(2-bromo-5-hydroxyphenyl)pentan-3-one was spirocyclised using polyphosphoric acid (Scheme 3.25).
Scheme 3.25 Spirocyclisation of the brominated phenol using polyphosphoric acid.
The spirocyclised product was obtained in moderately high yield and high quality.
Debromination of this compound would give the desired o-SPINOL in 5 steps.
Based upon our previous experiments using palladium catalysis and the ease of dehalogenation, a palladium-based debromination was attempted (Scheme 3.26).
Br
Scheme 3.26 Attempted palladium-based debromination of Br-SPINOL.
Unfortunately a complex mixture of products was obtained, along with a quantity of the starting material and the desired product, as determined by 1H NMR spectroscopy. Indeed, despite several attempts to optimise this transfor-mation, we were unable to improve the outcome. We speculate this may be a
consequence of the phenolic groups which coordinate to the palladium preventing dehalogenation.
Further work in this area should concentrate on achieving this step, ideally in flow. Preliminary experiments were attempted with the H-Cube reactor, butR equipment malfunctions meant that conversion was very low.
3.3 Conclusions on the 3-hydroxybenzaldehyde route
An aldol condensation using 3-hydroxybenzaldehyde and acetone was devel-oped that gave high yields and purity. The flow reduction of the 1,5-bis(3-hydroxyphenyl)penta-1,4-dien-3-one was more efficient, safer, and gave higher yields than the corresponding batch reduction (Table 3.2).
Table 3.2 Comparison of the batch and flow reductions of 1,-bis(3-hydroxyphenyl)penta-1,4-dien-3-one.
Procedure Batch Flow
Isolated yield 91% 81-93%
Reaction time 24 h 2 min
Throughput 0.033 g h−1 1.62 g h−1
Spirocyclisation of the 1,5-bis(3-hydroxyphenyl)pentan-3-one with polyphos-phoric acid was not successful. Alternatively, when run with Eaton’s reagent, a spirobiindane was obtained but this was found to be a mesyl-protected para-spirobiindane rather than the desired ortho diphenol (Scheme 3.27).
O
OH OH
O
OH OH
Br Br
MsO
OMs
Br
OH OH
Br
HO
OH
OH OH
3-1 3-5 3-6
3-11 1-59 1-42
Scheme 3.27 Comparison between regioselectivity of spirocyclisation routes using hydroxybenzaldehydes.
An alternative sequence was also investigated. When proceeding via 2-bromo-5-hydroxybenzaldehyde, the batch bromination with Br2/DCM gave superior yields to the flow set-up, as under flow conditions significant dibromination was
observed. The equivalent aldol reaction proceeded in lower yields but high pu-rity to give 1,5-bis(2-bromo-5-hydroxyphenyl)penta-1,4-dien-3-one. With both the batch and flow reductions of the brominated pentadienone, a mixture of products was obtained, with some debromination observed as well as the desired reduction of the unsaturated ketone.
Performing the reduction of the pentadienone before bromination solved this problem. It has been possible to spirocyclise the brominated pentanone using polyphosphoric acid and phosphotungstic acid to give Br-SPINOL. The final step in this preparation of SPINOL would be debromination, which needs further optimisation.
These routes are summarised in the scheme below (Scheme 3.28).
OH
Scheme 3.28 Reactions from 3-hydroxybenzaldehyde to spirobiindanes.
Since it was discovered that the bromine atoms are indeed required as blocking groups during the spirocyclisation step in order to give the ortho product, the question arises as to whether bromination should be performed before or after the reduction of the unsaturated ketone. It was found to be markedly better to reduce first, and brominate the resulting ketone. It was later found to be possible to spirocyclise this brominated ketone in high yields and purity using rapid microwave heating (Section 4.5). The last remaining hurdle to the desired SPINOL is the debromination of Br-SPINOL to give the final product, believed to be possible after further experimentation. If successful, this would reduce the number of steps required to synthesise SPINOL from six to five, and eliminate the need to use boron tribromide to cleave the methyl protecting groups. At this point, the route starting from 3-methoxybenzaldehyde was investigated in order to attempt to improve the literature procedure.