Initial attempts to synthesise a furan ring possessing a substituent at the 3-position focused on a 1956 paper from Burness.77 This method involved the synthesis of epoxide 223 via a Darzens reaction and subsequent thermal rearrangement to furan 224.
Attempts at the Darzen’s reaction gave a mixture of products. Neither purification by distillation nor silica gel chromatography were attempted as it was envisioned that both of these processes could cause
Scheme 113: Silylation of an aromatic nitro group by BSA (a) BSA, DBU, MeCN, 24 h, 82 %
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rearrangement of the epoxide. Evidence for the formation of the desired compound 223a as part of the mixture came from the presence of a peak at δH = 3.59 ppm in the 1H NMR corresponding to the epoxide
proton. This peak integrated correctly for 1H relative to the 6H peak at δH = 3.15 ppm corresponding to the
two methoxy groups. Unfortunately no NMR data for this compound has been published to make a comparison.
Epoxide 223a was then heated at 160 °C according to the procedure described in the original paper. No formation of methanol was observed, although as the reaction was only carried out at a 4.1 mmol scale, the volume evolved would have been very low. 1H NMR analysis of the crude reaction mixture showed no evidence of aromatic protons.
Scheme 116: Attempted synthesis of furan 224a under thermal conditions (a) 160 °C, 8 h
When Burness attempted to synthesise the 3-phenyl analogue 224b via the same route, it was discovered that the presence of an acid catalyst (p-TSA) and an increased reaction temperature of 250 °C were required (Scheme 117). As a result of this experimental observation, Burness reasoned that the rearrangement of the methyl variant was actually catalysed by free hydrogen chloride arising from the presence of a chlorine-containing compound as an impurity. This hypothesis was supported by the fact that a Belstein test of epoxide 223a was positive.
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As a consequence of these results, it was decided to attempt the rearrangement of the epoxide with a variety of acid catalysts (Scheme 118, Table 14).
Entry Acid Equivalents Temperature Time Yield
1 p-TSA 0.15 100 °C 1.5 h tracea
2 p-TSA 0.15 rt 1.5 h 0 %a
3 p-TSA 0.15 rt 78 h tracea
4 CSA 0.15 80 °C 8 h tracea
5 p-TSA 0.15 100 °C (μw) 45 min tracea
6 BF3·OEt2 0.15 rt 72 h 0 %a
7 Cu(OTf)2 0.15 rt 24 h 0 %a
8 NH4Cl 0.10 rt 78 h 0 %
Table 14: Rearrangement of epoxide 223a with acid catalysts. All reactions carried out in toluene. aExtensive decomposition observed
In most cases this lead to decomposition of the starting material with a black-tarry substance being formed. The only exception was that of NH4Cl (Table 14, entry 8) where no reaction was observed. In certain cases
Scheme 118: Attempted synthesis of furan 224a with acid catalysts (a) see Table 14 Scheme 117: Burness’ synthesis of 3-phenyl analogue 224b (a) p-TSA (5 mol %), 250 °C, 42 %
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a trace amount (> 1 %) of the desired furan was isolated (Figure 11). However the extremely low yield and difficulty separating it from the crude meant this route was abandoned.
Figure 11: 1H NMR of product isolated from rearrangement reaction
An alternative route for the synthesis of 3-methyl furans is the introduction of the methyl group via a directed lithiation. Therefore amide 226 was synthesised from 2-furoic acid according to the method of Chadwick et al.78
It was hoped that amide 226 could be selectively reduced to aldehyde 227, which in a separate step could be further reduced to the alcohol required for the synthetic sequence. Unfortunately, the reaction of amide 226 with the ATE complex formed by addition of n-butyl lithium to DIBAL proved unsuccessful and returned only starting material (Scheme 120).
Scheme 119: Synthesis of 3-substituted furan 226 (a) t-butylamine, DIC, DMAP, DCM, rt, 2 h, 40 %; (b) s-BuLi, DME, –78 °C, 1 h then MeI, rt, 16 h, 79 %
H4 H5
H8
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Due to the failure of this reaction, hydrolysis of amide 226 was examined (Scheme 121). This would give acid 228 which could again be reduced to the required alcohol. Unfortunately, under acidic conditions (Table 15, entries 1 and 2) decomposition was observed and under basic conditions there was no reaction (Table 15, entries 3 and 4).
Entry Reagent and solvent Temperature Time Result
1 10 % H2SO4 (aq) reflux 21 h decomposition
2 2M HCl(aq) rt 45 min decomposition
3 2M LiOH(aq) / THF rt 120 h SM
4 2M LiOH(aq) / THF 50 °C 120 h SM
Table 15: Conditions for attempted hydrolysis of amide 226
It was then decided to reduce the amide directly to the amine 229, which was then alkylated with methyl iodide to give quaternary ammonium salt 230 (Scheme 122).
Scheme 120: Attempted reduction of amide 226 to aldehyde 227 (a) DIBAL, n-BuLi, THF, 0 °C, 30 min; then 226, rt for 22h, 50 °C for 28 h
Scheme 121: Attempted hydrolysis of amide 226 (a) See Table 15
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Unfortunately attempts to displace the ammonium functionality with hydroxide failed (Scheme 123, Table 16). In each case 1H NMR analysis of the crude product showed that the starting material had been completely consumed and the presence of compounds containing a 2,3-disubstituted furan ring. However the yields of crude material were always very low (less than 15 % by mass) and no products corresponding to the desired alcohol could be isolated.
Entry Reagents/solvent Time
1 H2O/MeCN 16 h
2 H2O/DMF 69 h
3 KOH/ H2O 24 h
Table 16: Attempted hydrolysis of quaternary ammonium salt 230
2.3.6 – Furans with an ester functionality at the 3-position
Previous work within the group had shown the 3-substituted furans of the form 171 would not undergo rearrangement in the same manner as 2-substituted furans. This is due to the intrinsic electronic properties of the furan ring, whereby the lower electron density at the 3- position is insufficient to weaken the benzylic C-O bond enough for rearrangement to occur.
In section 2.2.3, the instability of esters derived from furan-2-yl(phenyl)methanol was discussed; it was postulated that this was due to the weakness of the doubly benzylic C-O bond. It was hoped that this reactivity could be used to increase the chance of successful dCr reactions of 3-substituted furans. Ester 232 was synthesised from 3-furancarboxaldehyde in two steps (Scheme 124), and proved to be stable enough to isolate and characterise.
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Although thermal stability studies in chloroform showed that ester 232 was stable at 150 °C, when exposed to dCr conditions only decomposition was observed (Scheme 125, Table 17).
Entry Temperature (°C) Time
1 150 3 x 1 min
2 100 2 x 1 min
Table 17: Conditions for attempted dCr of ester 232
2.4 Conclusions
The reactivity of 2-substituted furan esters under dCr conditions has been developed, with both alkyl and electron-poor aryl groups at the benzylic position tolerated. The reaction of the bis (enol) ethers produced from this the dcearboxylative Claisen rearrangement with a number of electrophiles has been studied. It has been shown that aromatic nitro groups are incompatible with dCr conditions and that increasing the electron density of the furan ring leads to decomposition of the starting esters. The dCr reaction works well with esters derived from tosylacetic and cyanoacetic acids; however the use of trifluoromethyl as an activating group means that the desired reaction does not take place. Attempts to use the dCr reaction to form a quaternary centre at the 3- position of the furan failed due to issues with synthesising the required starting materials.
Scheme 125: Attempted dCr of ester 232 (a) BSA, KOAc, PhMe, see Table 17
67 3 Hinckdentine A
3.1 Background