A literature survey via Reaxys revealed 2 references in which this compound was described as the product. The first synthesis has been published by Corey in the Journal of Organic Chemistry in 1988: N-(benzyloxycarbonyl)-(S)-proline (3) was synthesized in 75.2% yield from proline by reaction with benzyl chloroformate in an aqueous solution at 0–5°C. E. J. Corey, J. Org. Chem., Vol. 53, No. 12, 1988, 2861-2863 seemed to be the best choice for its high yield.
The protection of proline with benzylchloroformate gave a colourless solid, which recrystallized from petrolium ether. The yield of 75.2% is below that reportedin the literature (96%). The purity of the product could not be proofed, since no enough analytic data are available. For the product (3) no GC-MS was recorded, because of its carbon acid group that might damage the mass spectrometry system.
The hydroxide ion of NaOH deprotonates the NH-group of proline to form water and the electron pair of the nitrogen anion undergo a nucleophilic attack to the carbon atom of the carbonyl-group to give (3). The sodium cation forms with chloride anion sodiumchloride that prcipitates. An example for the application of the cyclic amino acid is its use as a pharmaceutical intermidiate, which is used for the synthesis of Eletriptan, a drug for the treatment of migriane.
Table of Contents
1 Results and discussion
1.1 Synthesis of N -(benzyloxycarbonyl)-(S)-proline
1.2 Synthesis of N -(benzyloxycarbonyl)-(S)-proline Methyl Ester
1.3 Synthesis of 2-amino-3-methylbutanol (Valinol)
1.4 Synthesis of (S)-4-isopropyl-2-oxazolidinone
1.5 Synthesis of di- tert -butyl 1-(2,6-diisopropylphenyl)-hydrazine-1,2-dicarboxylate
1.6 Synthesis of 2-(2,6-diisopropyl-phenyl)hydrazin-1-ium chloride
1.7 Synthesis of dimethyl o -tolylboronate
1.8 Synthesis of 1-methyl-4'-methoxybiphenyl
1.9 Synthesis of 2-iodobenzoic acid
1.10 Synthesis of 1,1,2,2-tetraphenylethylen
1.11 Synthesis of 5-hydroxy-3-oxo-5-phenylpentanoic acid methyl ester
2 Experimental Section
2.1 General Procedures
2.1.1 Working method with air and moisture sensitive chemicals
2.1.2 Solvents
2.1.3 Chromatographic methods
2.1.4 Analytical methods
2.1.5 Miscellaneous information
2.2 Synthesis of N -(benzyloxycarbonyl)-(S)-proline
2.3 Synthesis of N -(benzyloxycarbonyl)-(S)-proline methyl ester
2.4 Synthesis of 2-amino-3-methylbutanol (Valinol)
2.5 Synthesis of (S)-4-isopropyl-2-oxazolidinone
2.6 Synthesis of di- tert -butyl 1-(2,6-diisopropylphenyl)-hydrazine-1,2-dicarboxylate
2.7 Synthesis of 2-(2,6-diisopropyl-phenyl)hydrazin-1-ium chloride
2.8 Synthesis of dimethyl o -tolylboronate
2.9 Synthesis of 1-methyl-4'-methoxybiphenyl
2.10 Synthesis of 2-iodobenzoic acid
2.11 Synthesis of 1,1,2,2-tetraphenylethylen
2.12 Synthesis of 5-hydroxy-3-oxo-5-phenylpentanoic acid methyl ester
3 Appendix
3.1 List of abbreviations
3.2 References
3.3 Spectra
3.3.1 N -(benzyloxycarbonyl)-(S)-proline
3.3.2 N -(benzyloxycarbonyl)-(S)-proline Methyl Ester
3.3.3 2-amino-3-methylbutanol (Valinol)
3.3.4 (S)-4-isopropyl-2-oxazolidinone
3.3.5 Di- tert -butyl-1-(2,6-diisopropylphenyl)-hydrazine-1,2-dicarboxylate
3.3.6 2-(2,6-diisopropyl-phenyl)hydrazin-1-ium chloride
3.3.7 Dimethyl o -tolylboronate
3.3.8 1-Methyl-4'-methoxybiphenyl
3.3.9 1,1,2,2-Tetraphenylethylen
3.3.11 5-Hydroxy-3-oxo-5-phenylpentanoic acid methyl ester ]
1 Results and discussion
1.1 Synthesis of N -(benzyloxycarbonyl)-(S)-proline
A literature survey via Reaxys revealed 2 references in which this compound was described as the product. The first synthesis has been published by Corey in the Journal of Organic Chemistry in 1988: N -(benzyloxycarbonyl)-(S)-proline (3) was synthesized in 75.2 % yield from proline by reaction with benzyl chloroformate in an aqueous solution at 0 – 5 ° C. E. J. Corey , J. Org. Chem., Vol. 53, No. 12, 1988, 2861-2863 seemed to be the best choice for its high yield.
Scheme 1: reaction equation.
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The protection of proline with benzylchloroformate gave a colourless solid, which recrystallized from petrolium ether. The yield of 75.2 % is below that reportedin the literature (96 %) [1]. The purity of the product could not be proofed, since no enough analytic data are available. For the product (3) no GC-MS was recorded, because of its carbon acid group that might damage the mass spectrometry system.
The hydroxide ion of NaOH deprotonates the NH-group of proline to form water and the electron pair of the nitrogen anion undergo a nucleophilic attack to the carbon atom of the carbonyl-group to give (3). The sodium cation forms with chloride anion sodiumchloride that prcipitates (see scheme 2).
An example for the application of the cyclic amino acid is its use as a pharmaceutical intermidiate, which is used for the synthesis of Eletriptan, a drug for the treatment of migriane. [10]
Scheme 2: reaction mechanism:
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1.2 Synthesis of N -(benzyloxycarbonyl)-(S)-proline methyl ester
A literature survey via Reaxys revealed 2 references in which this compound was described as the product. The first synthesis has been published by Corey, in the Journal of Organic Chemistry in 1988: N -(benzyloxycarbonyl)-(S)-proline (3) was esterified in methanol with boron trifluoride etherate as catalyst to give the methyl ester (5) as an oil in 95 % yield. E. J. Corey , J. Org. Chem., Vol. 53, No. 12, 1988, 2861–2863 is the best choice for its short reaction time and also for its high yield, to the best of my knowledge.
Scheme 3: reaction equation.
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The esterification of N -(benzyloxycarbonyl)-(S)-proline with methanol has given N -(benzyloxycarbonyl)-(S)-proline methyl ester (5) as a yellowish oil in 95 % yield. The yield is much higher than the reported 85% yield of lit. [1]. The purity of the product is not satisfactory, since it is not a colourless oil as given in lit. The GC-MS shows the expected peak at tR = 14.56 min. m/z 263.10 (4 %, [M]+ calc.: 263,29), which proves the presence of the product.
The strong electron-withdrawing effect of the fluorine atoms on boron makes it highly electrophilic and lets it undergo nucleophilic attack by the electron pair of the oxygen of the carbonyl of protected proline. The carbon of the carbonyl group is now positively charged and will also undergoes nucleophilic attack by the oxygen of the methanol. After elemination of a water molecule and the boron trifluoride, N -(benzyloxycarbonyl)-(S)-proline methyl ester (5) is obtained as a colourless oil (see scheme 4).
Scheme 4: reaction mechanism.
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1.3 Synthesis of 2-amino-3-methylbutanol (valinol) (7)[3]
A literature survey via Reaxys revealed 12 references in which this compound was described as the product. The first synthesis has been published by Grotti, Moleculs, 2009:
The amino acid L-Valine was reduced with lithium aluminum hydride in THF and 16 h under reflux at 70 °C to give 2-amino-3-methylbutanol (7) as yellow oil in 90 % yield. M. Grotli, Molecules, 2009, 14, 5124 is the best choice due its high yield.
Scheme 1: reaction equation.
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The reduction of L-Valine (6) with LiAlH4 has given 2-amino-3-methylbutanol (7) as a yellow oil in 90 % yield. The yield is higher than that of litetartur of 80 %. The GC-MS shows the expected peak at t R = 12.56 min. m/z 105.20 (22%, [M+2H]+ calc.: 105.15), which can be assigned to the product, which proves its presence, Thus the available analytical data were consistent with the literature [4] and Thus the purity of the product is satisfactory.
The nucleophilic hydride of AlH4– in the hydride reagent adds irreversible to the electrophilic C in the polar carbonyl group in the carboxylic acid, forming a metal alkoxide complex as an intermediate. Coordinative bonding of the carbonyl oxygen to a Lewis acidic metal (Li or Al) enhances that carbon's electrophilic character. This hydride addition is shown in scheme (5), with the hydride-donating part of the molecule being written as AlH4–. Although the lithium is not shown, it will be present in the products as a cationic component of ionic salts. [5]
Abbildung in dieser Leseprobe nicht enthalten
Scheme 5: reaction mechanism.
Valinol is mainly used to prepare chiral oxazolines, a process which can be achieved via a variety of methods. These oxazolines are principally used as ligands in asymmetric catalysis. [6]
1.4 Synthesis of (S)-4-isopropyl-2-oxazolidinone
A literature survey via Reaxys revealed 8 references in which this compound was described as the product. The first synthesis has been published by Benoit, Tetrahedron, Asymm., 2008: In an oxidative cyclocarbonylation Valinol (7) reacts with diethyl-carbonate (8) and after 3 h under reflux at 130 °C (S)-4-Isopropyl-2-oxazolidinone (9) as yellowish oil in 81 % yield was obtained. David Benoit, Tetrahedron: Asymmetry 19 (2008) 1068–1077 is the best choice to the best of my knowledge due to its high yield and the simplicity to carry out the reaction.
Scheme 6: reaction equation.
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The oxidative cyclocarbonylation with diethylether (8) has given (S)-4-isopropyl-2-oxazolidinone (9) as a yellowish oil in 81 % yield. This yield is satisfactory, since the litetartur [7] promises 90 % as a colourless oil. The yellowish colour of the product could have been caused due to impurities, which could have been rid of through a destillation. The GC-MS spektra could not show a matching peak, [1]H- and [13]C-NMR spectra would provide more reliable data on the structure, but was not meassured.
The nucleophilic electron pair of amino-group in the valinol reagent adds to the electrophilic C-atom of the polar carbonyl group of the diethylcarbonate, resulting in the elimination of the ethanolate as a good leaving group. The deprotonation of the hydroxy group by ethanolate initiates the cyclocarbonylation shown in scheme (7) to give (S)-4-isopropyl-2-oxazolidinone (9).
Chiral auxiliaries such as the classical Evans oxazolidin-2-ones have been widely used in the synthesis of natural products and pharmacologically active compounds. [8]
Abbildung in dieser Leseprobe nicht enthalten
Scheme 7: reaction mechanism.
1.5 Synthesis of d i- tert -butyl 1-(2,6-diisopropylphenyl)-hydrazine-1,2-dicarbo-xylate
A literature survey via Reaxys revealed 6 references in which this compound was described as the product. The first synthesis has been published by Klauber, Tetrahedron Lett., 1987: To turn the DIPP bromide into a Grignard needed for the addition of azodicarboxylate (10), 2,6-diisopropylphenylbromide was reacted with magnesium to give the in situ prepared 2,6-diisopropylphenylmagnesiumbromide (DIPPMgBr). This was reacted with azodicarboxylate (10) in THF at –78 °C to give di- tert -butyl-1-(2,6-diisopropylphenyl)-hydrazine-1,2-dicarboxylate (11) as dark orange viskose liquid in 98 % yield. Bredihhin, Tetrahedron, 2008, 64, 6788–6793 is the best choice for its high yield.
Scheme 8: reaction equation.
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The reduction of azodicarboxylate (10) with the in situ prepared DIPPMgBr has given di- tert -butyl-1-(2,6-diisopropylphenyl)-hydrazine-1,2-dicarboxylate (11) as a dark orange viskose liquid in 98 % yield. This yield is very good and exceed that of litetartur [9] (84 %). GC-MS spectrum shows at t R = 8.98 min., m/z 280.9 (3.0 %, [M − Boc]+ calc.: 280.10), which can be assigned to the product. The messured melting point was 120 °C (lit.: [9] 121–122 °C), which indicates an acceptable purity, also the [1]H-, [13]C-NMR and the IR data (see experimental section and appendix) were consistent with the lit.[9].
For clarity, the mechanism has been formulated together with the synthesis of 1.6 (see scheme 10).
1.6 Synthesis of 2-(2,6-diisopropyl-phenyl)hydrazin-1-ium chloride
A literature survey via Reaxys revealed 6 references in which this compound was described as the product. The first synthesis has been published by Klauber, Tetrahedron Lett., 1987: Di- tert -butyl-1-(2,6-diisopropylphenyl)-hydrazine-1,2-dicarboxylate (11) was dissolved in a solution of HCl in dioxane and heated for 1 h at 60 °C to give the produkt 2-(2,6-diisopropylphenyl)hydrazin-1-ium chloride (12) as colourless needles in 51 % yield. Bredihhin, Tetrahedron, 2008, 64, 6788–6793 is the best choice to the best of my knowledge due to the simplicity of the reaction.
Scheme 9: reaction equation.
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The elimination of both Boc-protecting groups from (11) has given 2-(2,6-diisopropyl-phenyl)hydrazin-1-ium chloride (12) as colourless needles in 51 % yield. This yield exceeds also that of litetartur [9] (32 %). The [1]H-NMR, [13]C-NMR spectra (see appendix) shows that the compound (12) was obtained pure. The GC-MS spectrum shows at t R = 10.94 min. a peak with m/z 161.10 (90%, [M – NH4Cl] + calc.: 161.30), which can be assigned as the Product fragmentation peak.
To form the Grignard a single electron transfer from magnesium to the bromide atom of 2,6-diisopropylphenylbromide gives the 2,6-diisopropylphenylradical, a bromide anion and a magnesium radical cation. The bromide anion binds to the magnesium radical to form magnesiummonobromide radical, now both radicals recombine to give the Grignard DIPPMgBr. The reaction with azodicarboxylate (10) and the following protonation with acetic acid gives the di- tert -butyl-1-(2,6-diisopropylphenyl)-hydrazine-1,2-dicarboxylate (11). To deprotect the hydrazin group and to obtain the product (12) HCl is added (see scheme 10).
Scheme 10: reaction mechanism.
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1.7 Synthesis of dimethyl o -tolylboronate
A literature survey via Reaxys revealed 9 references in which this compound was described as the product. The first synthesis has been published by Koning, Org. Biomol. Chem., 2004: To get the phenylboronic acid, 2-bromtoluone was reacted with BuLi and trimethylborate at –78 °C to give dimethyl-o-tolylboronate (14) as off-colourless crystalls in 98 % yield. Rakhi Pathak, Kantharuby Vandayar, Willem A. L. van Otterlo, Joseph P. Michael, Charles B. de Koning, Org. Biomol. Chem., 2004, 2, 3504 is the best choice due to its high yield, the simplicity of carrying it out and the short reaction time.
Scheme 11: reaction equation.
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In this process, n -butyllithium was reacted with a phenylbromide (13) to provide the corresponding phenyllithium derivative, whereupon a borate was added under the formation of target product phenylboronic acid (14) in almost quantitative yield of 98 % as off-colourless crystalls, which exceed that of litetartur [9] (92 %). The GC-MS spactrum (see appendix) shows the peak at tR = 8.93 min. m/z 91.10 (100%, [M – B(OMe)2]+ calc.: 91.13), which can be assigned to the product fragmentation peak.
The reaction between the bromobenzene (13) and BuLi provides the corresponding phenyllithium derivative. In the second step, trimethyl borate is introduced, which reacts with the phenyllithium intermediate that was produced during the first reaction step to provide the target product phenylboronic acid (14) after treating with HCl (see scheme 12).
Scheme 12: reaction mechnaism.
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1.8 Synthesis of 1-methyl-4'-methoxybiphenyl
A literature survey via Reaxys revealed 6 references in which 1-Methyl-4'-methoxy-biphenyl (16) was described as the product. The first synthesis has been published by Goodson, Org. Synth., 2004: In a Suzuki coupling dimethyl-o-tolylboronate (14) was reacted with 1-iodo-4-methoxybenzene (15), using palldiumacetate as a catalyst and potassiumcarbonate as an additive in aceton/H2O under Argon atmosphere and refluxed for 2 h at 70 °C to give 1-methyl-4'-methoxy-biphenyl (16) as a colourless solid in 49 % yield. Felix E. Goodson, Org. Synth., 2004, 10, 501 is the best choice for its short reaction time, mild conditions and greater catalytic turnover compared to other synthesis (0.02% catalyst is required for complete conversion).
Scheme 13: reaction equation.
Abbildung in dieser Leseprobe nicht enthalten
This a versatile method for synthesizing unsymmetrical biaryls has given by coupling of dimethyl-o-tolylboronate (14) and 1-iodo-4-methoxybenzene (15) 1-methyl-4'-methoxy-biphenyl (16) as a colourless solid in 49 % yield. The literature reports the product as a colourless oil and not as a colourless solid, so that it could not be destilled as recommended in the literature, besides the yield (49 %) is less than that reported in literature [11] (90 %). This low yield could be attributed to the fact that sometimes amounts of phenylated by-products are produced into the product mixture. This occurs during cross-coupling and represents a nonproductive consumption of aryl halides. [11] Another reason for the low yield could be also the deactivation of the catalyst.
The first step is the oxidative addition of palladium to the 1-iodo-4-methoxybenzene (15) to form the organo-palladium species (I–Pd–aryl). This step is the rate determining step in the catalytic cycle. The oxidative addition initially forms the cis -palladium complex, which rapidly isomerizes to the trans -complex. The displacement of the halide from I–Pd–aryl to give the more reactive organopalladium hydroxide (HO–Pd–aryl), because the Pd-O bond is more polar than a Pd-O-bond, thus the palladium hydroxide is more electrophilic (palladium is at the positive end of the dipole). Thereby facilitating the electrophilic transmetalation and forms with the boronate complex the organopalladium species (aryl–Pd–aryl). The next step is the cis / trans -isomerization for a better aryl-aryl-coupling. Reductive elimination of the desired product (16) restores the original palladium catalyst (see scheme 14) [12].
Scheme 14: reaction mechnism.
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[...]
- Quote paper
- Sadik Mejid (Author), 2015, Synthesis of Chemical Compounds. Results, Discussion and Experimental Section, Munich, GRIN Verlag, https://www.hausarbeiten.de/document/475233
