ISOEUGENOL

ISOEUGENOL


(E)-2-Methoxy-4-(prop-1-enyl) phenol (isoeugenol 6): To 8.0 g of ethyleneglicol placed in a three-neck round-bottom flask of 100 mL are added 7.90 g of KOH (134 mmol), and submerged in a sand bath. To the mixture eugenol 5.0 g (30.5 mmol) is added and the system is refluxed at 160 °C for about approximately 5 hours; at this time the reaction is stopped. The excess of KOH is neutralized with 25 mL of a 6 mol L^-1 hydrochloric acid solution, the mixture is extracted with CHCl₃ (2 × 50 mL) and the organic phase is dried with anhydrous Na₂SO₄and the solvent evaporated under vacuum. After chromatographic column purification, 4.25 g of a brown oil was obtained (85%).


 IR (film) n_max/cm^-1: 3503 (O-H), 3057 (C=CH-Ar), 3014 (CH=CH), 2936, 2930, 2843, 1603, 1506, 1367, 1030, 963. 

¹H NMR (400.1 MHz, CDCl₃): d 1.86 (3H, dd, J 1.5 and 6.6 Hz, CH₃); 3.90 (3H, s, OCH₃); 5.55 (1H, s, OH); 6.08 (1H, dq, J 6.6 and 15.7 Hz, H2'); 6.32 (1H, dd, J 1.5 and 15.7 Hz, H1'); 6.85 (3H, m, H3, H5 and H6). 


¹³C NMR (100.6 MHz, CDCl₃): d 18.3 (CH₃); 55.8 (OCH₃); 107.8 (C5); 114.3 (C6); 119.3 (C3); 123.4 (C4); 130.6 (C2); 130.7 (C1); 144.7 (C2'); 146.5 (C1').

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532008000300024

Journal of the Brazilian Chemical Society

Print version ISSN 0103-5053

J. Braz. Chem. Soc. vol.19 no.3 São Paulo  2008

http://dx.doi.org/10.1590/S0103-50532008000300024 

CHILE

















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Production of 4-hydroxy-3-(1-phenyl-vinyl)-benzoic acid ethylester

EXAMPLE 7
Production of 4-hydroxy-3-(1-phenyl-vinyl)-benzoic acid ethylester

Preparation:
4.98 g (30 mmole) p-hydroxybenzoic acid ethylester
3.06 g (30 mmole) phenylacetylene
31.26 g (120 mmole) tin tetrachloride
22.24 g (120 mmole) tributylamine
150 ml 1,2-dichlorethane
Method:
Under an argon atmosphere, a solution of 4.98 g (30 mmole) phydroxy-benzoic acid ethylester, 3.06 g (30 mmole) phenylacetylene, 31.26 g (120 mmole) tin tetrachloride and 22.24 (120 mmole) tributylamine in 150 ml 1,2-dichlorethane are heated for 1 h with recycling. Then 60 ml 4 M KOH and 30 ml ethanol are added to the reaction mixture and heated for 1 h with recycling. Following cooling, the solution is acidified with 4 M HCl and extracted twice with 150 ml diethylether each time. The purified organic phases are dried through MgSO₄ and the solvent is removed on the rotary evaporator. The remaining residue undergoes absorptive filtering (silica gel, MTBE) and the raw product obtained in this way is cleaned by column chromatography (silica gel, toluene/MTBE=8/1 (v/v)). 2.63 g (9.8 mmole, 33%) 4-hydroxy-3-(1-phenyl-vinyl)-benzoic acid-ethylester are obtained.
Yield: 2.63 g (9.8 mmole, 33%) 4-hydroxy-3-(1-phenyl-vinyl)-benzoic acid-ethylester.  

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.36 (t, ³J=7.1 Hz, 3H, CH₃), 4.33 (q, ³J=7.1 Hz, 2H, OCH₂), 5.44 (d, ²J=0.9 Hz, 1H, ═CH₂), 5.91 (d, ²J=0.9 Hz, 1H, ═CH₂), 6.97 (d, ³J=8.5 Hz, 1H, PhH), 7.34 (m, 5H, PhH), 7.89 (d, ⁴J=2.1 Hz, 1H, PhH), 7.96 (dd, ³J=8.5 Hz, ⁴J=2.1 Hz, 1H, PhH).  

¹³C-NMR (100 MHz, CDCl₃): δ [ppm]=14.3 (CH₃), 60.8 (OCH₂), 115.8 (CH_arom), 117.5 (═CH₂), 122.9 (Cq_arom), 126.9 (2×CH_arom) 127.5 (Cq_arom), 128.8 (3×CH_arom), 131.3 (CH_arom), 132.3 (CH_arom), 138.7 (Cq_arom), 144.3 (Cq_olefin), 157.1 (Cq_arom), 166.3 (COOEt).

MS (EI, 70EV): m/z [%]=268 (M⁺, 98), 267 (100), 253 (35) 239 (32), 225 (13), 223 (24), 194 (6), 165 (20), 152 (12), 115 (5), 111 (6), 104 (7).


 http://www.google.com/patents/US6809225


 




 






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2-methoxy-5-methylbenzophenone

Me3SBr was prepared by the reaction of bromine with dimethylsulfoxide (DMSO) by a simplification of a published method [3]. Other methods from DMSO are also known (e.g., by the reaction with benzyl bromide or ethyl bromoacetate [1]). Reaction of DMSO with hydrogen bromide might also lead to Me3SBr, but I could find no literature support for this. Trimethylsulfonium chloride (Me3SCl) analogously forms from the reaction of DMSO with Cl2,[4] but I could find no specific information on the selectivity and no preparative example.

Trimethylsulfonium bromide (Me3SBr):

Into a 20 mL dimethylsulfoxide (DMSO) was slowly and very carefully added 2 mL bromine (39 mmol) dropwise from a micropipette, while stirring in a cooling bath (note 1), at such a rate to maintain the temperature of the reaction mixture at about 40 °C. The reaction is very exothermic and each drop of Br2 makes a hissing noise upon contact with DMSO. The clear yellow solution was left stirring for 3 days at room temperature. It formed a thick yellow slurry which was then diluted with 60 mL acetone. The insoluble product was vacuum filtered, washed with 3×15 mL acetone and left drying under vacuum in a desiccator. There was thus obtained 7.72 g (63%) of a light yellow crystalline powder having a faint “sulfide stench” (note 2): mp 194–198 °C, subl. (lit.[3] 198–200 °C, from EtOH); IR (KBr):



Note 1: The oxidation of DMSO with Br2 is extremely exothermic! Each drop of Br2 would violently react with DMSO (similarly as adding TCCA to DMSO). Adding all the bromine at once can result in accidents and serious injuries! Cooling and good stirring is advised. Do not use an ice bath (mp of DMSO!), but a water bath at about 15 °C will do. Do not upscale the reaction without all the necessary precautions!

Note 2: During the reaction there were no gasses evolved. During the work up some dimethyl sulfide smell was present but not up to any annoying level.


Use of Me3SBr

I looked on the shelves for a phenolic substrate to O-methylate which would be less reactive (e.g., having a hydroxy orto to a carbonyl group) and giving a product that would be solid at room temperature (so that no chromatography would be needed in the reaction work up). I found some old 2-hydroxy-5-methylbenzophenone from Aldrich picking dust on the shelves, which looked like nobody will ever use or miss. I decided to sacrifice it in the name of amateur chemistry.

Not being sure about the reaction temperature required, or best solvent to use, I decided not to waste time reinventing the wheel and used the conditions previously reported to work for tetramethylammonium chloride as a reagent for the methylation of phenols [6]. Since sulfonium salts are more electrophilic than the ammonium counterparts, I used a lower reaction temperature (100 °C instead of 150 °C). It worked just fine.

Methylation of 2-hydroxy-5-methylbenzophenone with trimethylsulfonium bromide:

A mixture of 1.90 g Me3SBr (12 mmol), 2.12 g 2-hydroxy-5-methylbenzophenone (10 mmol), 1.66 g K2CO3 (12 mmol) and 6 mL polyethyleneglycol (PEG400) was stirred for 6 h at 100 °C (note 1). The reaction was checked with TLC at 3 h and there was only one spot for a new product being formed, while the spot of the starting phenol was already faint. The reaction mixture was then worked up by diluting in 100 mL water and extraction into 40 mL diisopropyl ether, which was then washed with 3×40 mL 1M NaOH(aq), 100 mL water and rotavaped to give 2.08 g (92%) of a TLC pure colorless viscous oil. This was crystallized by dissolving it in 30 mL methanol, precipitating the oily product with 10 mL water and leaving this mixture overnight at -16 °C. The solidified product was vacuum filtered and dried under vacuum in a desiccators to give 1.93 g (85%) of 2-methoxy-5-methylbenzophenone as chunks of solids with part of it having crystallized nicely in needles: mp 37–38 °C (lit.[5] 37–38 °C); NMR (300 MHz, CDCl3):



Note 1: During the course of the reaction there was dimethyl sulfide forming as perceived by its smell. But since this was done in a fume hood this represented no problem. On such a small reaction scale and such a slow reaction rate, this is no problem even out of the fume hood as long as your neighbors don’t mind, but on a larger scale I suggest to recover the dimethyl sulfide by absorption in acetone.




EXAMPLE 1 Production of 2-methoxy-5-methyl-benzophenonehttp://www.google.com/patents/US6809225

Preparation:
5.00 g (23.5 mmole) 2-hydroxy-5-methyl-benzophenone
6.67 g (47.1 mmole) methyliodide
4.50 g (32.6 mmole) potassium carbonate
50 ml abs. acetone
Method:
To a solution of 5.00 g (23.5 mmole) 2-hydroxy-5-methyl-benzophenone and 6.67 g (47.1 mmole) methyliodide in 50 ml abs. acetone 4.50 g (32.6 mmole) potassium carbonate are added. The reaction mixture is then heated for 5 hours with recycling. Following cooling, 50 ml water and 50 ml petroleum ether (30/60) are added to the suspension. The organic phase is separated off, the aqueous phase is extracted twice with 75 ml petroleum ether (30/60) and the purified organic phase is washed twice with 50 ml 10% NaOH solution. The organic phase is then dried through magnesium sulphate and the solvent is removed. 3.80 g (16.8 mmole, 71%) 2-methoxy-5-methyl-benzophenone are obtained.
Yield: 3.80 g (16.8 mmole, 71%) 2-methoxy-5-methyl-benzophenone ¹H-NMR (400 MHz, CDCl₃): δ [ppm]=2.21 (s, 3H, CH₃), 3.56 (s, 3H, OCH₃), 6.77 (d, ³J=8.4 Hz, 1H, PhH), 7.06 (d, ⁴J=1.9 Hz, 1H, PhH), 7.15 (m, 1H, PhH), 7.31 (t, ³J=7.7 Hz, 2H, PhH), 7.43 (m, 1H, PhH), 7.71 (dd, ³J=8.3 Hz, ²J=1.2 Hz, 2H, PhH). ¹³C-NMR (100 MHz, CDCl₃): δ [ppm]=20.3 (CH₃), 55.6 (OCH₃), 111.4 (CH_arom), 128.1 (2×CH_arom), 128.5 (Cq_arom), 129.7 (2×CH_arom), 129.8 (Cq_arom), 129.9 (CH_arom), 132.2 (CH_arom), 132.8 (CH_arom), 137.8 (Cq_arom), 155.2 (Cq_arom), 196.6 (C═O).

References

[1] http://www.google.com/patents/US6809225

[2] (a) K. Yamauchi, T. Tanabe, M. Kinoshita, J. Org. Chem., 44, 1979, 638–639, DOI: 10.1021/jo01318a037 (b) M. Kobayashi, K.Umemura, N. Watanabe, H. Matsuyama, Chemistry Letters, 1985, 1067–1070. (c) M. Kobayashi, K.Umemura, H. Matsuyama, Chemistry Letters, 1987, 327–328. (d) K. Umemura, H. Matsuyama, N. Watanabe, M. Kobayashi, N. Kamigata, J. Org. Chem., 54, 1989, 2374–2383, DOI: 10.1021/jo00271a025 (e) K. Umemura, H. Matsuyama, N. Kamigata, Bull. Chem. Soc. Jpn. 63, 1990, 2593–2600 (f) N. Shibata, A. Matsnev, D. Cahard, Beilstein J. Org. Chem., 6, 2010, 65, DOI: 10.3762/bjoc.6.65
(these are not a result of a full literature review, but see also the references therein)

[3] D. Martin, A. Berger, Journal für Praktische Chemie, 312, 1970, 683–689, DOI: 10.1002/prac.19703120418

[4] J. R. Gauvreau, S. Poignant, G. J. Martin Tetrahedron Letters, 21, 1980, 1319–1322.

[5] G. Stadnikoff, A. Baryschewa, Ber., 61, 1928, 1996–1999, DOI: 10.1002/cber.19280610869

[6]





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Synthesis of amino-alkoxy-heptanoic alkyl ester

http://www.google.com/patents/EP1756038A1?cl=en

Example 1 (^'lS,2S)-(l-Hydroxymethyl-2-methyl-butyl)-methyl-carbamic acid tert-butyl ester

39.3g Boc-Melle-OH (0.160 mol; Synthetech) were dissolved in 160ml THF and cooled to 0°C. 240ml IM BH₃-THF (0.24 mol; Fluka) were added at 0°C over 1 h and the clear, colorless reaction mixture was warmed up and stirred at RT for 1 h. The reaction mixture was again cooled to 0°C, 100ml deionized water were carefully added at 0 - 5°C over 0.5 h and after warming up to RT stirring was continued for 1 h. To the colorless solution were added 250ml 10% Na₂CO₃ all at once and after stirring for 1 h the reaction mixture was extracted with 1000ml and 500ml ethyl acetate. The organic layers were washed with brine and dried (Na₂Sθ₄). Removal of the solvent by rotary evaporation gave 36.9g (99.7%) product as colorless oil.

Example 2 (lS,2S)-(l-Formyl-2-methyl-butyl -methyl-carbamic acid tert-butyl ester

To a solution of 37.0g Boc-N-methyl-isoleucinol (160 mmol) in 160ml dichloromethane was added a solution of 5.4g NaHCO₃ (64 mmol) and 1.9g KBr (16 mmol) in 160ml deionized water. The reaction mixture was cooled to 0°C and after the addition of 125mg 2,2,6,6-tetramefhyl-piperidin-l-oxyl (TEMPO, 0.8 mmol), 122.6g 10.2% aqueous sodium hypochlorite (176 mmol Cl₂) were added under stirring over 2.5 h at 0-5°. After additional stirring for 30 min the excess of NaOCl was destroyed by the addition of ca. 1ml 38% aqueous sodium bisulfite and the reaction mixture was warmed up to 20°. The aqueous layer was extracted with 160ml dichloromethane and the organic layers were washed with 10% brine and dried (Na₂SO₄). Removal of the solvent by rotary evaporation afforded 35.7g (97.2%) crude product as a light orange oil. 

Example 3 ( 1 S,2S - ( 1 -Dimemoxymethyl-2-methyl-butyl) -methyl- amine hydrochloride

35.6g Crude aldehyde (160 mmol) were dissolved in 200ml methanol and cooled to ~15°C. 111ml 2.8M HCl-MeOH (0.31 mol HCl) were added all at once and the yellowish solution was stirred at RT for 2 h. 155ml Trimethyl orthoformate (1.42 mol; Fluka) were now added and the reaction mixture was stirred at RT over night (18 h). The solvent and the excess of the orthoester were removed by rotary evaporation (40°C/> 10 mbar) and the resulting beige, crystalline residue (33.7g) was dissolved in ca. 310ml isopropyl acetate at ~70°C. After cooling to RT and crystallization at 0°C for 17 h the crystal suspension was filtered and dried (50°C/10 mbar/16 h) affording 29.6g product as white needles, mp. 127-128°C

1H NMR

Example 28

(R)-3-Methoxy-3-fS)-pyrrolidin-2-yl-propionic acid tert-butyl ester hydrochloride

a^ab^Ds^So⁰l^lu^ut^τe^e cooonrmfigguurraatti,on confirmed by X-ray

To a stirred solution of 1.92g of the above described ester (6 mmol) in 30ml ethanol were added 0.20g Pd-C 10% (Degussa) and 0.62g 37% HCl (6.3 mmol). The black suspension was hydrogenated under vigorous stirring at RT for 2 h. The flask was flashed with Ar and the black suspension was filtered. After removal of the solvent by rotary evaporation (40°C/> 10 mbar) the white crystalline residue (1.57g) was dissolved in 7.5ml hot isopropyl acetate at ~80°C. Crystallization at -20°C yielding 1.37g (86%) white crystalline product, [α]o = -36.4 (CHC1₃; c = 1).

1H-NMR:

F.Hoffmann-La Roche Ag

BASEL  SWITZERLAND

METHYL ORANGE

IR






1H NMR







13 C NMR





700 ppm Sweep Width for 15N, 1H, 15N HMBC Methyl orange at 600 MHz