In the past, utilising this position has allowed us to explore the diastereoselectivity of the silyl-Prins and aza-silyl-Prins reaction across the heteroatom in the formed heterocycle. In studies on the aza-silyl-Prins reaction it was shown that the 2,6-disubstituted tetrahydropyridines formed had exclusive trans geometry across the heteroatom. It has been proposed in previous work that the large N-substituent contributes to a steric effect known as A1,3 strain. It was believed that the same effect would be present in examples of
the aza-Prins reaction where methyl substituted tosylamines are utilised. Firstly synthesised was 4-methyl-N-(pent-4-en-2-yl)benzenesulfonamide 152 in two steps from the commercially available pent-4-en-2-ol 150 (Scheme 48).
OH NTs O O NHTs a b 150 151 152
Scheme 48. Reagents and conditions: (a) N-Boc-TsNH, PPh3, DIAD, THF, rt, 17h, 69%. (b) TFA,
DCM, rt, 17h, quantitative.
Attempts to obtain this tosylamine via the sodium iodide-catalysed amination methodology were unsuccessful. Success was found following a literature procedure for two steps. Firstly pent-4-en-2-ol 150 was treated with t-butyl tosylcarbamate under Mitsunobu conditions to form the homoallylic tertiary amine 151 in 69% yield. The carbamate function was then cleaved by the action of TFA in DCM to give the required homoallylic tosylamine 152 in quantitative yield.
To explore once again the regioselectivity of the aza-Prins reaction and introduce multiple substituents into the cyclised products, it was attempted to synthesise tosylamines with internal olefins and a C1 methyl group. Therefore (E)-N-(hex-4-en-2-yl)-4- methylbenzenesulfonamide 157 was synthesised in 4 steps from commercially available pent-4-yn-2-ol 153 (Scheme 49). The synthesis of the corresponding (Z)-N-(hex-4-en-2- yl)-4-methylbenzenesulfonamide was unsuccessful.
OH OH OH OTs NHTs a b c d 153 154 155 156 157
Scheme 49. Reagents and conditions: (a) n-BuLi, MeI, THF, -78 °C to rt, 53%. (b) LAH, triglyme, THF, 85 °C, 60%. (c) TsCl, Et3N, DMAP, 0 °C, 40 h, 25%. (d) TsNH2, KOH, NaI, DMSO, 50 °C, 20 h,
31%.
To synthesise the appropriate (E)-olefin, the alkyne methylation of pent-4-yn-2-ol 153 was required. Deprotonation of the alkyne hydrogen with n-butyllithium followed by treatment with iodomethane gave the methyl substituted alkyne 154 in a disappointing 53% yield. To access the (E)-homoallylic alcohol, the alkyne 154 was treated with LAH in a mixture of triglyme and THF to give the required geometric isomer 155 in 60% yield. The alcohol was fully characterised as its tosyl activated alcohol 156 because even after distillation, it remains a mixture with triglyme. The homoallylic alcohol was transformed into the tosyl activated alcohol by the action of tosyl chloride in the presence of triethylamine and 4-dimethylaminopyridine to give (E)-hex-4-en-2-yl 4- methylbenzenesulfonate 156 in 25% yield. As in previous examples, this tosylate 156 underwent sodium iodide catalysed amination to give the required (E)-homoallylic tosylamine 157 in 31% yield.
Next, aza-Prins reactions with 4-methyl-N-(pent-4-en-2-yl)benzenesulfonamide 152 were attempted with an aim to synthesise 2,4,6-trisubstituted piperidines 158. Various different aldehydes were screened, with various temperatures, solvents and Lewis acid being employed, but unfortunately, no positive results were found for generation of cyclised material (Table 24).
. bAza-Prins Cyclisations: Effects of the C1 Position in Homoallyl Amines
Table 24. The aza-Prins reactions involving a C1 substituted tosylamine. NHTs 1.5 eq.LA, solvent RCHO + N Ts R Cl 152 158
Entry R LA solvent Temp. Time Comment
1 n-C7H15 2 (CH2)2Ph 3 c-Hex InCl3 4 n-C7H15 TMSOTf DCM Rt and
reflux 24 h reflux48 h, then No reaction, SM remained
Rt 48 h “ “
Rt 48 h “ “
Rt 48 h “ “
5 (CH2)2Ph InCl3 CH3CN Rt and
reflux 72 h reflux48 h, then “ “
6 (CH2)2Ph FeCl3
anhydrous DCM Rt 70 h consumed, 90% SM
product trace When the three aliphatic aldehydes that had brought the most success in previous examples were screened in the presence of indium trichloride and DCM at room temperature, no reaction was observed (Table 24, entry 1-3). Even when more forcing conditions were attempted with DCM at reflux, still only starting material remained. Also when trimethylsilyl triflate was screened in comparative conditions, again the results were negative. When the solvent was altered for the higher boiling acetonitrile and reflux conditions attempted, still only starting material remained and no trace of any type of cyclised product was observed. Finally it was decided to screen iron(III) chloride and after 70 hours at room temperature, most of the starting material was consumed. However, only trace quantities of product were detected on analysis by GCMS and the rest of the crude mass was unidentifiable. It is highly disappointing that no success was found when this C1 methyl substituted tosylamine was screened as this potentially limits the use of the aza-Prins reaction in other fields such as pharmaceuticals.
Next to be attempted were aza-Prins reactions with (E)-N-(hex-4-en-2-yl)-4- methylbenzenesulfonamide 157. Even though it appears that the C1 methyl group hinders these cyclisation reactions, it was hoped that the internal olefin function would enhance the stability of reaction intermediates. If the six-membered carbocation intermediate 159 is considered, then the adjacent methyl substituent would enhance the stability of the adjacent empty p-orbital via hyperconjugation and so promote the cyclisation step (Figure 15).
N O2S
R
159
Figure 15. Stabilisation of intermediate carbo cation by hyperconjugation.
This is comparable with the β-effect of silicon where there is sufficient overlap between the empty p-orbital and the polarised carbon-silicon σ-orbital to stabilise the intermediate. Our screening studies included alterations in temperature and solvents but no positive results for generation of cyclised material 160 and 161 were observed (Table 25).
Table 25. The aza-Prins reactions involving C1 substituted tosylamine and other substituents.
NHTs InCl3, solvent RCHO + N Ts R Cl N Ts R Cl + 157 160 161
Entry R Solvent Temp. Time Comment
1 (CH2)2Ph DCM Rt and
reflux 72 h reflux72 h, then No reaction, SM remained
2 (CH2)2Ph DCM Rt and
reflux 24 h reflux24 h, then No reaction, SM remained
3 (CH2)2Ph CH3CN Reflux 72 h No reaction, SM
remained
When the standard conditions of indium trichloride and DCM at room temperature were applied to the (E)-isomer 157 and hydrocinnamaldehyde (Table 25, entry 1-2), no progress was observed. When a more forcing reflux temperature was adopted, still only starting material remained (Table 25, entry 1-2). Even when the higher boiling acetonitrile was used at reflux, no positive results were obtained (Table 25, entry 3). It would seem that again the issues surrounding the C1 methyl group of the tosylamine substrate are responsible for the failure of these cyclisation reactions. Even the additional stabilisation
pharmaceuticals. However, heterocycles with fewer substituents are accessible using an aza-Prins reaction mediated by either iron(III) halides or indium trichloride. The use of indium trichloride has identified alternative regioselective routes for this reaction, meaning that pyrrolidines as well as piperidines are accessible.