R O
63, R = Ph
70, R = (p-OMe)Ph 148, R = c-Hex
R OH
NO2 N
N O O
O
i 147
149, R = Ph
150, R = (p-OMe)Ph 151, R = c-Hex
Scheme 37. Screening of aldehydes. i. a) 147, Cu(OAc)2, EtOH, 70°C, 1 h; b) Aldehyde (63, 70 or 148), 140, rt , 20-48 h.
In conclusion, a new application for chiral PyOX-ligands was explored in this paper. The best ligand was found by careful screening of my novel PyOX-ligands. This is of synthetic use in the synthesis of e.g. amino alcohols, if different nitroalkanes from 140 are used to prepare diastereomeric adducts.
NH N O
152
i, ii
N N
O Cl Ru
153
CHO
CHO iii
48 49 50
Scheme 38. Diels-Alder-reaction with PyrOX-catalyst 153. i. t-BuOK, CH2Cl2, rt; ii. [(η6-p- cymol)RuCl2]2, CH2Cl2, 0°C -> rt; iii. a) 153, AgSbF6, acetone, CH2Cl2, rt; b) 48, 49, rt.
In the study by Pfaltz,109 attempts to form the corresponding indolyl ligand species (IndOX) were made. Another attempt to form chiral IndOX-species was made in 2002, giving the racemate as outcome, as mentioned in chapter 2.5.2.55 This species turned, nevertheless, out to be an active pharmaceutical compound.
In the final part of my thesis, a protocol to form a chiral IndOX-compound family was reported. The preparation procedure followed the same strategy as in the preparation of my substituted PyOX-compounds. The indolyl-2-carboxylic acids 154-156 (Scheme 39) were selected to vary the substituent at the 5-position of the indolyl ring from electron donating to withdrawing. The oxazoline ring substituents were introduced by careful selection of amino alcohols (101, 157-159) to give structural variety.
N
H O
X OH
NH O
HN X
HO R
154, X = H 155, X = OMe 156, X = Cl
NH2 R OH
160, X = H, R = t-Bu 161, X = H, R = Bn 162, X = H, R = (R)-Ph 163, X = H, R = i-Bu 164, X = OMe, R = t-Bu 165, X = Cl, R = t-Bu
NH X
N O
R 166, X = H, R = t-Bu 167, X = H, R = Bn 168, X = H, R = (R)-Ph 169, X = H, R = i-Bu 170, X = OMe, R = t-Bu 171, X = Cl, R = t-Bu i
ii 101, R = Bn
157, R = t-Bu 158, R = (R)-Ph 159, R = i-Bu
Scheme 39. Preparation of the IndOX-compound family. i. 154-156, amino alcohol 101 or 157-159, BOP, DIPEA, CH2Cl2, rt, pH = 9, 40-84 %; ii. 160-165, MsCl, NEt3, DMAP, CH2Cl2, rt, 41-68 %.
As Scheme 39 shows, the reaction route consisted of two simple reaction steps performed at room temperature. The ease of this reaction turned out to be a fact, because no chromatographic purifications were needed in the formation of oxazolines 166-171. To ensure the optical purity of the oxazoline ligands, the (S)-enantiomer of 168 was also prepared and the purity ensured by chiral HPLC. All the products were obtained in moderate to good yields in clean reactions, indicating that even better yields could be achieved on laboratory scale using column chromatography.
In conclusion, a novel chiral compound family, the IndOX, is introduced. The target molecules 166-171 could be reached in two simple steps without column chromatography.
The synthesis is tailored to facilitate modification of as well the indole as the oxazoline ring, thus tuneable for many synthetic purposes.
6 Conclusions
In this thesis, the focus was on the preparation of chiral bidentate N,N-oxazoline ligands (PyOX and IndOX) on different supports and in different applications. The key issue was thus to develop an efficient method, mild enough not to racemize the formed oxazolines and also offering the opportunity to modify both rings of the compound core. This thesis was introduced by tailoring a mercapto ester derived chiral PyOX-ligand for attachment on
a gold surface. As this tailored species was attached on a gold nanoparticle, the result was a selective catalyst ligand on a gold nanoparticle smaller than ever achieved in synthetic chemistry! Another method to form supported PyOX-ligands was also created, as a novel polymer-bound amino alcohol linker was synthesized. On this linker, picolinic acids could be attached and the corresponding polymer-bound PyOX-ligands could be formed simultaneously, contrary to earlier studies to first form the ligand and then attach it on the support. A new catalytic application with promising results was also found for PyOX- ligands, i.e. the Henry reaction. To further expand the synthetic value of the optimized PyOX-formation protocol, the pyridine ring was substituted with the indole ring and a novel chiral ligand family, the IndOX, was synthesized by varying the substituents of both rings of its core.
The major contribution of this thesis is the optimization of a synthetic procedure to be applied on conventional ligand synthesis, solid phase synthesis and nanochemistry, very important fields of chemistry nowadays. In addition to this, a new catalytic asymmetric application for most of the new oxazoline compounds, i.e. all PyOX-ligands, was found, broadening the scope of bidentate oxazoline compounds even further to meet the strict demands of synthesis in our days.
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