Practical demethylation of aryl methyl ethers using an odorless thiol reagent.

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Practical demethylation of aryl methyl ethers using an odorless thiol reagent. Chae,J
Title Practical demethylation of aryl methyl ethers using an odorless thiol reagent.
Authors J Chae
Journal Archives of pharmacal research
Issue 3
Issn 0253-6269
Isbn
Doi 10.1007/s12272-001-1156-y
PMID 18409042
Volume 31
Pages 305-9
Keywords
Website [[Website::[1]]]
Publication Year Mar 2008

Abstract


A highly practical method for demethylation of aryl methyl ethers employing a long-chain thiol has been developed. Under the conditions described herein, clean and fast conversions to the desired phenolic compounds have been achieved with a broad range of substrates. Unlike other thiolate-mediated methods, this newly developed protocol features in-situ generation of sodium alkylthiolate using NaOH, and is almost free from foul smells and potentially harmful gases. It therefore provides an attractive option for the demethylation of aryl methyl ethers.


Acronyms

Acronyms
M + => m/z 144
NaSEt => (NaSH) and sodium thioethoxide
d, 8.5 Hz, 2H => (d, J= 8.5 Hz, 2H), 6.72
d, J =1.4 Hz => (dd, J= 8.0, 2.5 Hz, 1 H), 5.39 (bs, 1 H), 13 C-NMR (125 MHz, CDCl 3 )δ 155.7, 132.3 (q, J= 32.0 Hz), 130.6, 124.0 (q, J= 270 Hz), 119.1
d, J= 4.1 Hz => (dd, J= 8.0, 2.5 Hz, 1 H), 5.39 (bs, 1 H), 13 C-NMR (125 MHz, CDCl 3 )δ 155.7, 132.3 (q, J= 32.0 Hz), 130.6, 124.0 (q, J= 270 Hz), 119.1 (d, J =1.4 Hz), 118.0
d, J= 8.0 Hz, 1 H => (dd, J= 8.0, 8.0 Hz, 1 H), 7.23
d, J= 8.5 Hz, 2H => (d, J= 8.5 Hz, 2H), 6.91
d, J= 9.0 Hz, 2 H => (d, J= 9.0 Hz, 2 H), 6.92
d, J= 9.0 Hz, 2H => (d, J= 9.0 Hz, 2 H), 6.97
i => include:
m, 1 H => (m, 1 H), 7.82-7.79
m, 2 H => (m, 1 H), 7.82-7.79 (m, 1 H), 7.51-7.46

INTRODUCTION

  • search compounds, difficulties demethylation aryl methyl ethers, scale reaction greater.
  • plethora methods (Weissman Zewge, 2005; Wuts Greene, 2006), most not to large scale syntheses.
  • example, BBr 3 , most reagent reaction, not option mass production high cost, necessity use equipment precautions handling.
  • Other reagents BCl 3 , TMSI, AlCl 3 /EtSH suffer similar problems, give results.
  • acids, HBr, chosen functional groups substrate reaction conditions.
  • conditions, result demethylation, solubility substrates.
  • alternative method proved use sulfide nucleo-philes.
  • Sodium sulfide (NaSH) and sodium thioethoxide (NaSEt) used last couple decades (Newman al., 1976; Dodge al., 1995).
  • thiols ethanethiol combined hydride

  • employed number cases literature (Nakatani et al., 2002; Ko et al., 2007).
  • gases arise during the reaction and work-up diminish practicality large scale synthesis.
  • reported efficiency sulfide-mediated reaction and author experience gave reason type reaction.
  • issue remained process more to large scale reactions.
  • context, publication by Magano coworkers reported demethylation using water-soluble thiol (Magano al., 2006).
  • utilized 2-(diethylamino)ethanethiol, NaO t Bu generate sulfide nucleophiles.
  • work-up, sulfur-containing compounds extracted aqueous phase, removing compounds pro-duct.
  • range of substrates tested , novel reagent drawback, by author, aryl compounds require electron-withdrawing group conversion.
  • information mind, less thiols used laboratory scale scale.

MATERIALS AND METHODS

  • solvents from commercial sources used without purification.
  • All reactions carried nitrogen.
  • Flash column chromatography performed using silica gel 60 (230-400 mesh, Merck).
  • 1 H-NMR 13 C-NMR spectra were recorded Varian 500 instrument with shifts reported ppm solvent peak TMS standard.
  • Gas chromatography analyses performed Hewlett Packard 6890 instrument with HP-1 column mass spectra were recorded by HP 5973 MSD EI (electron impact) ionization method.

General procedure for demethylation

  • Aryl methyl ether (2.0 mmol) NaOH (240 mg, 6.0 mmol) tube.
  • tube N 2 .
  • NMP (2 mL) added reaction mixture followed by 1-dodecanethiol (719 mL, 3.0 mmol).
  • reaction mixture stirred 130 o C aryl methyl ether consumed determined by TLC GC analysis.
  • After reaction mixture allowed cool room temperature, 1N HCl (ca. 10 mL) diluted EtOAc.
  • aqueous phase extracted EtOAc (15 mL×2) layers washed water brine, dried Na 2 SO 4 , concentrated vacuo.
  • Purification product by flash column chroma-tography (EtOAc Hexane) afforded desired product.

1-Naphthol (Table III, entry 1)

  • Yield 98%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 8.20-8.15 (m, 1 H), 7.82-7.79 (m, 1 H), 7.51-7.46 (m, 2 H), 7.44 (d, J= 8.0 Hz, 2 H), 7.30 (dd, J= 8.0, 8.0 Hz, 1 H), 6.80 (d, 8.0 Hz, 1

  • H), 5.34 (s, 1 H).
  • 13 C-NMR (125 MHz, CDCl 3 )δ 151.6, 135.0, 127.9, 126.7, 126.1, 125.5, 124.6, 121.8, 120.9, 108.9.
  • MS (EI) m/z 144 (M + ).

2-Naphthol (Table III, entry 2)

  • Yield 98%.
  • 1 H-NMR (500 MHz, CDCl 3 ) 7.77-7.74 (m, 2 H), 7.67 (d, J= 8.5 Hz, 1 H), 7.44-7.41 (m, 1 H), 7.34-7.31 (m, 1 H), 7.14 (d, J= 2.5 Hz, 1 H), 7.10 (dd, J= 8.5, 2.5 Hz,

  • 1 H), 5.10 (s, 1 H).
  • 13 C-NMR (125 MHz, CDCl 3 )δ 153.6, 134.8, 130.1, 129.2, 128.0, 126.8, 126.6, 123.9, 118.0, 109.7.
  • MS (EI) m/z 144 (M + ).

4-Phenylphenol (Table III, entry 3)

  • Yield 98%.
  • 1 H-NMR (500 MHz, CDCl 3 ) 7.55-7.53 (m, 2 H), 7.49-7.46 (m, 2 H), 7.43-7.40 (m, 2 H), 7.32-7.29 (m, 1

  • H), 6.92-6.89 (m, 1 H), 5.10 (s, 1 H).
  • 13 C-NMR (125 MHz,

  • CDCl 3 )δ 155.3, 141.0, 134.2, 129.0, 128.7, 127.0, 126.9,

2’-Hydroxyacetophenone (Table III, entry 4)

  • Yield 96%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 12.27 (s, 1 H), 7.74 (ddd, J= 7.9, 2.5, 1.5 Hz, 1 H), 7.50-7.46 (m, 1 H), 6.98 (ddd, J= 8.3, 2.5, 1.5 Hz, 1 H), 6.93-6.89 (m, 1 H),

  • 2.64 (s, 3 H).
  • 13 C-NMR(125 MHz,CDCl 3 )δ 204.8, 162.6, 136.7, 131.0, 120.0, 119.2, 118.7, 26.9.
  • MS (EI) m/z 136 (M + ).

3’-Hydroxyacetophenone (Table III, entry 5)

  • Yield 74%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 7.54 (dd, J =1.5, 3.0 Hz, 1 H), 7.51 (ddd, J= 1.0, 1.0, 7.5 Hz, 1 H), 7.34 (dd, J= 7.8, 7.8 Hz, 1 H), 7.11 (ddd, J= 1.0, 2.5, 8.0 Hz, 1 H), 6.05 (bs, 1 H), 2.61 (s, 3 H).
  • 13 C-NMR (125 MHz, CDCl 3 )δ 200.0, 156.7, 138.5, 130.2, 121.3, 121.1, 114.9,

4’-Hydroxyacetophenone (Table III, entry 6)

  • Yield 99%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 7.91 (d, J= 8.5 Hz, 2H), 6.91 (d, J= 8.5 Hz, 2H), 6.66 (bs, 1 H), 2.59 (s, 3

  • H).
  • 13 C-NMR (125 MHz, CDCl 3 )δ 198.9, 161.7, 131.5, 129.8, 115.8, 26.6.
  • MS (EI) m/z 136 (M + ).

4-Bromophenol (Table III, entry 7)

  • Yield 99%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 7.31 (d, J= 8.5 Hz, 2H), 6.72 (d, 8.5 Hz, 2H), 5.73 (bs, 1 H).
  • 13 C-NMR (125 MHz, CDCl 3 )δ 155.0, 132.7, 117.5, 113.0.
  • MS (EI) m/z 172 (M + ).

3-Bromophenol (Table III, entry 8)

  • Yield 97%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 7.10 (dd, J= 8.0, 8.0, 1 H), 7.08-7.05 (m, 1 H), 7.02 (dd, J= 2.0, 2.0 Hz, 1

  • H), 6.78-6.76 (m, 1 H), 5.24 (s, 1 H).
  • 13 C-NMR (125 MHz, CDCl 3 )δ 156.6, 131.1, 124.2, 123.0, 119.1, 114.5.
  • MS (EI) m/z 172 (M + ).

Ethyl-4-hydroxybenzoate (Table III, entry 9)

  • Yield 45%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 7.96 (d, J= 7.2 Hz, 2 H), 6.88 (d, J= 7.75, 2H), 6.51 (bs, 1 H), 4.36 (q, J

  • = 7.0 Hz, 2H), 1.39 (t, J= 7.0 Hz, 3 H).
  • 13 C-NMR (125

  • MHz, CDCl 3 )δ 167.2, 160.5, 132.2, 122.8, 115.5, 61.2,

4-Hydroxybenzaldehyde (Table III, entry 10)

  • Yield 56%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 9.87 (s, 1 H), 7.82 (d, J= 9.0 Hz, 2 H), 6.97 (d, J= 9.0 Hz, 2H), 6.22 (bs, 1 H).
  • 13 C-NMR (125 MHz, CDCl 3 )δ 191.5, 162.0,

4-Cyanophenol (Table III, entry 11)

  • Yield 93%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 7.56 (d, J= 9.0 Hz, 2 H), 6.92 (d, J= 9.0 Hz, 2 H), 6.31 (bs, 1 H).
  • 13 C-

  • NMR (125 MHz, CDCl 3 )δ 160.6, 134.6, 119.6, 116.8, 103.0.
  • MS (EI) m/z 119 (M + ).

α,α,α-Trifluoro-m-cresol (Table III, entry 12)

  • Yield 88%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 7.37 (dd, J= 8.0, 8.0 Hz, 1 H), 7.23 (d, J= 8.0 Hz, 1 H), 7.11 (s, 1 H), 7.03 (dd, J= 8.0, 2.5 Hz, 1 H), 5.39 (bs, 1 H), 13 C-NMR (125 MHz, CDCl 3 )δ 155.7, 132.3 (q, J= 32.0 Hz), 130.6, 124.0 (q, J= 270 Hz), 119.1 (d, J =1.4 Hz), 118.0 (d, J= 4.1 Hz), 112.6 (d, J= 4.3 Hz).
  • MS (EI) m/z 162 (M + ).

3,5-Dimethoxyphenol (Table III, entry 13)

  • Yield 92%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 6.09 (dd, J= 2.0, 2.0 Hz, 1 H), 6.05 (d, J= 2.0 Hz, 2 H), 5.86 (bs, 1 H), 3.75

  • (s, 6H).
  • 13 C-NMR (125 MHz, CDCl 3 )δ 161.8, 157.7, 94.6, 93.4, 55.6.
  • MS (EI) m/z 154 (M + ).

4-i-Propylphenol (Table III, entry 14)

  • Yield 75%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 7.12 (d, J= 9.0 Hz, 2 H), 6.79 (d, J= 9.0 Hz, 2 H), 5.15 (bs, 1 H), 2.91-2.83 (septet, J= 7.0 Hz, 1 H), 1.24 (d, J= 7.0 Hz, 6 H).

  • 13 C-NMR (125 MHz, CDCl 3 )δ 153.7, 141.5, 127.7, 115.3, 33.5, 24.5.
  • MS (EI) m/z 136 (M + ).

2,6-Di-i-propylphenol (Table III, entry 15)

  • Yield 93%.
  • 1 H-NMR (500 MHz, CDCl 3 )δ 7.10 (d, J= 7.5 Hz, 2 H), 6.94 (dd, J= 7.5, 7.5 Hz, 1 H), 4.84 (s, 1 H), 3.20 (septet, J= 7.0 Hz, 2 H), 1.30 (d, J= 7.0 Hz, 12 H).

  • 13 C-NMR (125 MHz, CDCl 3 )δ 150.2, 133.8, 123.7, 120.9, 27.4, 23.0.
  • MS (EI) m/z 178 (M + ).

RESULTS AND DISCUSSION

  • less-odorous thiols from commercial sources cost.
  • Attempts replace thiols alkanethiols whose alkyl chains longer than C8 (Node et al., 2001; Frey al., 2003; Nishide et al., 2004).
  • alkanethiols more than 12 carbons considered compounds high points (cf. 1-dodecanethiol 266-283 o C) (Node et al., 2001; Nishide et al., 2004).
  • Only 1dodecanethiol found supplied by sources quantities, alkanethiols whose chain-lengths longer than C12 use.
  • chose 1-dodecanethiol ( DodSH all following tables) reagent use development demethylation conditions.

  • point view, thiolate-mediated demethylation considered S N 2 substitution aryl methyl ether by thiolate anion.
  • precedents reported in the literature, thiolate nucleo-philes prepared advance using bases such as NaH, NaO t Bu, NaOMe (Nakatani et al., 2002; Ko et al., 2007).
  • bases not

  • large scale synthesis; example, NaH reactivity, evolution H 2 deprotonation.
  • insitu generation thiolate nucleophiles more bases highly terms ease operation and scale-up.

  • find solvents transformation, solvents, DMSO, DMF, NMP, 1,4-dioxane, THF, tested using 1-methoxynaphthalene as substrate NaOH as the base (Table I).
  • 1,4-dioxane THF complete conversion product after 3h temperature reaction mixtures.
  • DMSO, starting material consum-ed, by-products detected after 3 h 130 o C.
  • NaOH solution DMSO heated 3h in absence 1-methoxynaphthalene, odor released similar by-products detected, suggesting DMSO not bases such as NaOH temperature.
  • DMF NMP compared, NMP proved more than DMF terms reaction conversion.

  • thiolate by base.
  • stated , more inorganic bases such as NaOH, LiOH, KOH operation and scalability transformation.
  • idea mind, tested five bases NaOH, LiOH, KOH, NaOMe, KO t Bu.
  • reactions LiOH KOH , NaOH, NaOMe, KO t Bu result conversion to 1-naphthol.
  • Considering cost ease handling, NaOH chosen as the base.

  • conditions , reaction temperature lower than 130 o C resulted in completion reaction time reaction temperature 100 o C .
  • substrate need optimization functional groups, set reaction temperature 130 o C order to achieve protocol range compounds.

  • scale using reaction protocol developed, shows reaction yields.
  • results demonstrate generality reaction protocol, functional groups under the reaction conditions.
  • substrates with functional groups esters aldehydes afforded desired products only yield (Table III, entries 9 10).
  • case substrate with ester group, by-product identified product, 4-methoxyl acid, substrate with aldehyde group seem-ed under the reaction conditions.
  • Attempts optimize reaction conditions not varying base (LiOH, NaOH, KO t Bu), solvents (DMSO, NMP, DMF), temperature (100-130 o C), amount base no difference.
  • compounds functional groups conditions need reaction conditions order to achieve better results.
  • Not , reacti-vities methyl aryl ethers substitution mechanism.
  • Compounds lacking electron-

  • withdrawing groups show lower reactivities (Table III, entries 1, 2, 3, 13, 14 15), fast conversions electron-withdrawing groups (Table III, entries 4-12).
  • substitution position ring affects demethylation reaction substitutions ortho-position para-position equivalent, similar results substrates in entries 4 6, meta-substituted substrate in entry 5 behaved .
  • Magano result showing mono-demethylation trimethoxybenzene, similar selectivity using developed protocol (Table III, entry 13).
  • aryl methyl ether 2,6-di-i-propyl anisole transformed phenol yield (Table III, entry 15).

  • larger scale synthesis of 1-naphthol 1-methoxynaphtalene carried example demonstrate scalability demethylation protocol.
  • 1-Methoxynaphthalene (63.3 g, 0.400 mol), 1-dodecanethiol (121 g, 0.598 mol), sodium hydroxide (48.0 g, 1.20 mol), NMP (200 mL) added N 2 atmosphere, 500 mL round flask equipped stirring bar.
  • reaction mixture heated 2hat 130 o C, TLC analysis showed complete conversion 1-methoxynaphthalene to 1-naphthol.
  • reaction mixture ice water (300 mL), 6N HCl (220 mL) added cooling bath, bring pH mixture 3.
  • Most product precipitated stage.
  • product collected by filtration, hexanes (100 mL).
  • product purified by recrystallization EtOAc/hexanes yield 52.4 g (91%).

  • demonstrated compound, developed protocol utilized mass production compounds.
  • example, Lasofoxifene, estrogen receptor modulator (Renaud al., 2005) Dihydrexidine, dopamine receptor agonist (Fernandes al., 2006) contain moieties structures, by cleavage aryl methyl ether precursors using method.

  • conclusion, demethylation method using 1-dodacanethiol has developed.
  • advantages methods reported in the literature include: (i) conditions during the reaction and work-up, ( ) avoidance bases such as NaH NaOMe use NaOH, ( ) in-situ generation thiolate, simplifying operation, (iv) chemical yields range of substrates.
  • larger scale synthesis of 1-naphthol has carried following developed protocol, demonstrating utility application

  • work supported by Sungshin Women Uni-versity Research Grants 2006.

Tables

Table

Once we determined that NMP was the most suitable
reaction solvent, we turned our attention to screening for
the base (Table II). In successful transformation, 1-dode-
canethiol (cf. pKa~11) is assumed to be first deprotonated

Table

solvent conversion (%) a yield (%) b
THF c 0 0
Dioxane d 5 5
DMF 45 45
NMP 100 99
DMSO 100 84
a,b GC conversion and GC yield. c Reaction was run at 65 o C.
d Reaction was run at 100 o C

Table

Table III summarizes the results of the demethylation
reactions of aryl methyl ether substrates at the 2 mmol