Estado del arte
2.2. El procesamiento de im´ agenes biom´ edicas
At the beginning of the project, the catalytic efficiency of various Lewis acids in the [3+2] cyclisation of N-tosyl phenylaziridine 26 with 1,3-dimethylindole 101 under the different conditions was examined (Table 1). The aziridines 26 can be obtained by aziridination of the corresponding alkene and this will be discussed in detail in the next section. Cu(OTf)2 was first identified as an effective Lewis acid to promote the formation of pyrroloindole 102, however, only DCE and DCM gave moderate yields with relatively low trans-selectivities when 101 was limiting agent (entries 1-5). This successful [3+2] cyclisation reaction was evidenced by a singlet associated with C8a proton at 5.37 ppm and a triplet corresponding to C3 proton at 3.39 ppm (major product). Additionally, C3a methyl of 102 at 1.27 ppm is upfield in comparison to C3 methyl of 101 at 2.36 ppm. Six aliphatic carbon signals of major product were found in the 13C NMR of 102, suggesting the coupling reaction between 101 and 26 has successfully occurred. High-resolution mass spectrometry indicated the molecular weight of isolated product is 441.1620 g mol-1, which is agreement with the molecular weight of expected cycloadduct 102. Furthermore, the 1D-NOESY indicates the major diastereoisomer of the resulting pyrroloindoline 102 was trans, which is in accordance with the subsequent result of the Chai group.33 Therefore, 1.0 equivalent of 26 and 1.5 equivalents of 101 were then added in the presence of Cu(OTf)2, and the reaction gave 102 in a moderate yield (47%) with significantly increased trans-selectivity (entry 6). Next, 3.0 equivalents of 26 was added to the reaction to enhance the yield and trans-selectivity (entry 7). Other Lewis acids such as Sc(OTf)3 and Ni(acac)2 were also evaluated but no improved results were obtained (entries 8-9), while addition of PdCl2(MeCN)2 considerably increased both yield (82%) and diastereoselectivity (entry 10). Reducing the catalyst loading and equivalents of 101 were detrimental since 102 was isolated in depressed yield with a drop in the trans-selectivity (entries 11-12). It has been proposed that the π-acidity of the Pd(II)-centre could be enhanced by the coordination of benzoquinone (BQ) as a π-accepting ligand.34 BQ was therefore added to the PdCl2(MeCN)2-catalysed reaction(10 mol%) but the depression in both yield and diastereoselectivity were observed (entry 13). Moreover, no reactions were observed
35
with addition of nitrogen-based ligands such as phenanthroline, neocuproine and 2,2'-bipyridine (bpy), which are known to stabilise the Pd(II)-centre (entries 14-16).35 This is likely due to them causing a reduction in Lewis acidity of the Pd(II) centre. Subsequently, MeCN was utilised as solvent but it only lead to significantly reduced conversion and decomposition of 101 (entry 17). In addition,
101 was added to the reaction in 2 portions (each 1.5 eq); however, this did not give improved results
(entry 18).
Table 1: Optimisation of The [3+2] cyclisation of N-tosyl phenylaziridine 26 with 1,3-dimethylindole 101
Entry 26:101
Lewis acid (mol%)
Additive (mol%)
Yield Trans:cis Solvent
1 2.0:1.0 Cu(OTf)2 (10) - 50 1.8:1.0 DCE
2 2.0:1.0 Cu(OTf)2 (10) - trace N/A THF
3 2.0:1.0 Cu(OTf)2 (10) - trace N/A MeOH
a
4 2.0:1.0 Cu(OTf)2 (10) - trace N/A MeCN
5 2.0:1.0 Cu(OTf)2 (10) - 41 1.8:1.0 DCM 6 1.0:1.5 Cu(OTf)2 (10) - 47 3.2:1.0 DCE 7 1.0:3.0 Cu(OTf)2 (10) - 53 3.7:1.0 d CHCl3 8 1.0:3.0 Sc(OTf)3 (10) - 48 2.9:1.0 d CHCl3 9 1.0:3.0 Ni(acac)2 (10) - NR N/A CHCl3 10 1.0:3.0 PdCl2(MeCN)2 (10) - 82 6.5:1 CHCl3 11 1.0:3.0 PdCl2(MeCN)2 (5) - 58 5.3:1.0 CHCl3 12 1.0:1.5 PdCl2(MeCN)2 (10) - 38 6.3:1.0 CHCl3 13 1.0:3.0 PdCl2(MeCN)2 BQ (30) 65 6.2:1.0 CHCl3
36 (10) 14 1.0:3.0 PdCl2(MeCN)2 (10) Phen - N/A CHCl3 15 1.0:3.0 PdCl2(MeCN)2 (10) Neocuproine - N/A CHCl3 16 1.0:3.0 PdCl2(MeCN)2 (10) Bpy - N/A CHCl3 17 1.0:3.0 PdCl2(MeCN)2 (10) - 22b N/A MeCN 18 1.0:3.0c PdCl2(MeCN)2 (10) - 53 6.3:1.0 CHCl3
a Methoxylation of 26 observed. b Conversion. c 101 was added in 2 portions d hydrolysis of 26 observed.
Two similar reports concurrently have been published for the pyrroloindoline synthesis using this approach: Cu(I)/chiral diphosphine catalyst system developed by the Chai group (Scheme 24) and Pd(PhCN)2Cl2 system used by Zhao and co-workers (Scheme 25). Therefore, instead of pursuing substrate scope for the reaction uncovered above attention was turned to a new and more versatile substrate, vinylaziridine 103. The aziridines 103 can be obtained by aziridination of 1,3-butadiene and this will be discussed in detail in the next section This substrate was subjected to the [3+2] cycloaddition to give a promising result: the C3-vinyl pyrroloindoline derivative 104 was given in a moderate purified ratio of trans:cis isomers (4.3:1.0), albeit with a low yield (17%) (Scheme 26). The formation of 104 was evidenced by a triplet at 2.80 ppm corresponding to the C3-H of trans-104 in the 1H NMR. In addition, a singlet associated with C8a-H of of trans-104 was found at 5.18 ppm, further supporting occurrence of the cycloaddition of 103. The conservation of C3-vinyl group in 104 was confirmed by its characteristic signals on the purified 1H NMR of 104, including a mutiplet (5.54-5.42 ppm) and two doublets (5.04 ppm and 4.90 ppm, respectively). Moreover, the C2 proton of 101 (6.85 ppm) disappeared in 1H NMR of 104. In addition, 13C NMR of 104 demonstrates seven aliphatic carbon signals, and this result matches the expected structure of 104. The molecular weight that was given from High-resolution mass spectrometry is also in line with the structure of 104 (369.1640 g mol-1). In conclusion, the expected cycloadduct 104 has been synthesised in this
37
reaction.
Scheme 26: Cycloaddition of vinylaziridine 103 to 1,3-dimethylindole 101
After obtaining initial success in the [3+2] cycloaddition of mono-substituted aziridines to indole
101, attention was switched to the 2,2'-disubstituted aziridine 98 as an electrophile. Thus, the
condition shown in Scheme 26 was applied to 98, however, this only resulted in a complicated mixture of unidentified products (Scheme 27). The synthesis of 98 will be discussed in the next section.
Scheme 27: Attempted cycloaddition of aziridine 98
In order for the product to find general utility in synthetic projects, the tosyl unit would have to be removed. It was therefore found that the diasteromeric mixture of 102 could be readily detosylated with Mg/NH4Cl under ultrasound conditions to give the pure trans-106, highlighting the utility of the method developed (Scheme 28). The successful detosylation was evidenced by the absence of tosyl methyl in the 1H NMR of trans-106, and a broad singlet at 2.44 ppm associated with the N1 amine proton resulted from the detosylation was also observed. In comparison with 102, only six aliphatic carbon signals were found in the 13C NMR of trans-106, suggesting the tosyl group has been removed in the reaction. The molecular weight of isolated product is 265.1714 g mol-1, which is approximate to the calculated molecular weight of trans-106 (265.1705 g mol-1). This result further proved that the tosyl group was successfully removed from 102 in this reaction. The
38
Scheme 28: Detosylation of 102
In conclusion, a PdCl2(MeCN)2-catalysed formal [3+2] cycloaddition of phenylaziridine 26 with 1,3-dimethylindole 101 was performed to give a C3-phenyl pyrroloindoline skeleton 102 in an excellent yield (82%) with a good diastereoselectivity (6.5:1.0). Fortunately, the pure
trans-diastereoisomer of detosylated 102 was isolated in a moderate yield (56%) by column
chromatography. In addition, a C3-vinyl pyrroloindoline skeleton 104 was also synthesised from the vinylaziridine 103 with a promising diastereoselectivity (4.3:1.0) under the same conditions, albeit with a low yield (17%). Due to concurrent reports of very similar methods additional substrate was not investigated and attention turned to the synthesis of tryptamine derivatives.
39