An Efficient Copper-Catalyzed Etherification of Aryl Halides

Abstract

An efficient and mild copper-catalyzed ether formation from aryl halides and aliphatic alcohols has been developed. The key to the successful coupling is the use of lithium alkoxide, directly or in situ generated by lithium tert-butoxide, and the corresponding alcohol as solvent.

ligand-free - copper - etherification - aryl halides

References and Notes

<A NAME="RS10110ST-1A">1a</A> Metal-Catalyzed Cross-Coupling Reactions   Dieterich F. Stang PJ. Wiley-VCH; New York: 1998. 

<A NAME="RS10110ST-1B">1b</A> Modern Arylation Methods   Ackermann L. Wiley-VCH; Weinheim: 2009. 

<A NAME="RS10110ST-2">2</A> Among the 22 small molecules marketed theraputic new molecular entities (NMEs) in 2009 alone, seven of them contain either aryl aryl or aryl alkyl ether bonds. For details, see: Hegde S. Schmidt M. In Annual Reports in Medicinal Chemistry   Vol. 45:  Macor JE. Academic Press; London: 2010.  p.467 

<A NAME="RS10110ST-3">3</A> Ullmann F. Ber. Dtsch. Chem. Ges.  1904,  37:  853 

For excellent reviews regarding copper-mediated couplings, see:

<A NAME="RS10110ST-4A">4a</A> Monnier F. Taillefer M. Angew. Chem. Int. Ed.  2009,  48:  6954 

<A NAME="RS10110ST-4B">4b</A> Ley SV. Thomas AW. Angew. Chem. Int. Ed.  2003,  42:  5400 

<A NAME="RS10110ST-4C">4c</A> Ma D. Cai Q. Acc. Chem. Res.  2008,  41:  1450 

<A NAME="RS10110ST-4D">4d</A> Lindley J. Tetrahedron  1984,  40:  1433 

For examples of palladium-catalyzed C-O bond formation, see:

<A NAME="RS10110ST-5A">5a</A> Mann G. Hartwig JF. J. Am. Chem. Soc.  1996,  118:  13019 

<A NAME="RS10110ST-5B">5b</A> Palucki M. Wolfe JP. Buchwald SL.
J. Am. Chem. Soc.  1996,  118:  10333 

<A NAME="RS10110ST-5C">5c</A> Shelby Q. Kataoka N. Mann G. Hartwig JF. J. Am. Chem. Soc.  2000,  122:  10178 

<A NAME="RS10110ST-5D">5d</A> Parrish CA. Buchwald SL. J. Org. Chem.  2001,  66:  2498 

<A NAME="RS10110ST-6A">6a</A> Niu J. Zhou H. Li Z. Xu J. Hu S. J. Org. Chem.  2008,  73:  7814 

<A NAME="RS10110ST-6B">6b</A> Wolter M. Nordmann G. Job GE. Buchwald SL. Org. Lett.  2002,  4:  973 

<A NAME="RS10110ST-6C">6c</A> Lipshutz BH. Unger JB. Tat BR. Org. Lett.  2007,  9:  1089 

<A NAME="RS10110ST-6D">6d</A> Shafir A. Lichtor PA. Buchwald SL. J. Am. Chem. Soc.  2007,  129:  3490 

<A NAME="RS10110ST-6E">6e</A> Cristau HJ. Cellier PP. Hamada S. Spindler JF. Tailefer M. Org. Lett.  2004,  6:  913 

<A NAME="RS10110ST-6F">6f</A> Liu Y.-H. Li G. Yang L.-M. Tetrahedron Lett.  2009,  50:  343 

<A NAME="RS10110ST-6G">6g</A> Buck E. Song ZJ. Tschaen D. Dormer PG. Volante RP. Reider PJ. Org. Lett.  2002,  4:  1623 

<A NAME="RS10110ST-6H">6h</A> Lv X. Bao W. J. Org. Chem.  2007,  72:  3863 

<A NAME="RS10110ST-6I">6i</A> Naidu AB. Sekar G. Tetrahedron Lett.  2008,  49:  3147 

<A NAME="RS10110ST-6J">6j</A> Cai Q. Zou B. Ma D. Angew. Chem. Int. Ed.  2006,  45:  1276 

<A NAME="RS10110ST-6K">6k</A> Niu J. Guo P. Kang J. Li Z. Xu J. Hu S. J. Org. Chem.  2009,  74:  5075 

<A NAME="RS10110ST-6L">6l</A> Marcoux J.-F. Doye S. Buchwald SL. J. Am. Chem. Soc.  1997,  119:  10539 

For recent examples of continuing efforts to search for better ligands, see:

<A NAME="RS10110ST-7A">7a</A> Altman RA. Shafir A. Choi A. Lichtor PA. Buchwald SL. J. Org. Chem.  2008,  73:  284 

<A NAME="RS10110ST-7B">7b</A> Maiti D. Buchwald SL. J. Org. Chem.  2010,  75:  1791 

<A NAME="RS10110ST-8">8</A> Zhang J. Zhang Z. Wang Y. Zheng X. Wang Z. Eur. J. Org. Chem.  2008,  5112 

<A NAME="RS10110ST-9">9</A> Chang JWW. Chee S. Mak S. Burananprasertsuk P. Chavasiri W. Chan PWH. Tetrahedron Lett.  2008,  49:  2018 

<A NAME="RS10110ST-10">10</A>

A multikilogram process has been successfully carried out by us based on this protocol.

<A NAME="RS10110ST-11">11</A>

In our original process for the particular drug candidate, the very expensive 3,4,7,8-tetramethyl-1,10-phenanathroline (20 mol%, MW = 236.3. $63.9/g, from Aldrich) was used as ligand.

<A NAME="RS10110ST-12">12</A>

For the consideration of less stable substrate, intead of 110 ˚C as the original literature reported (ref. 6k), 100 ˚C was chosen for screening purpose.

<A NAME="RS10110ST-13">13</A> In the case of NaOt-Bu, toluene is detected as the major product from reduction of 4-bromotoluene. Bacon RG. Ressison SC. J. Chem. Soc. C  1969,  312 

<A NAME="RS10110ST-14">14</A>

Cu(II) salts were found slightly less effective.

<A NAME="RS10110ST-15">15</A>

The presence of other functional groups such as ester, carboxylic acid, nitro, and cyano were not successful under this protocol.

<A NAME="RS10110ST-16">16</A>

General Procedure for the Etherification of Arylbromides
To a 10 mL seal tube were charged alcohol (2.0 mL) and LiOt-Bu (480 mg, 6.0 mmol). The resulting suspension was stirred at r.t. for 5 min to form a clear solution. Arylbromide (2.0 mmol) and CuI (38 mg, 0.2 mmol) were added to the above solution. The mixture was stirred at r.t. for 5 min to form a nearly clear solution which was sealed and stirred at 80-110 ˚C for 18-28 h. The reaction was cooled to r.t. and quenched with AcOH (pH = 7-8) and diluted with CH₂Cl₂. The mixture was washed with H₂O (2 × 5 mL) and solvent removed. The crude residue was purified by silica gel column chromatography to give the desired product. The identity and purity of the products are confirmed by ^¹H NMR, ^¹³C NMR, and HRMS spectroscopic analysis.
5-(Pentyloxy)pyrimidin-2-ol (Table 2, Entry 8)
Off-white solid. ^¹H NMR (400 MHz, CDCl₃): δ = 8.04 (s, 2 H), 3.86 (t, J = 8 Hz, 2 H), 1.77 (m, 2 H), 1.40-1.45 (m, 4 H), 0.94 (t, J = 8 Hz, 3 H) ppm. ^¹³C NMR (100 MHz, CDCl₃):
δ = 157.9, 144.8, 142.2, 70.5, 28.7, 28.0, 22.4, 14.0 ppm. HRMS: m/z calcd for C₉H₁₄N₂O₂: 182.1055; found: 182.1053.
3-(2-Methoxyethoxy)pyridine (Table 2, Entry 9)
Colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 8.35 (s, 1 H), 8.23 (m, 1 H), 7.23 (m, 2 H), 4.17 (t, J = 4 Hz, 2 H), 3.77
(t, J = 4 Hz, 2 H), 3.46 (s, 3 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 155.0, 142.4, 138.0,. 123.8, 121.4, 70.9, 67.7, 59.3 ppm. HRMS: m/z calcd for C₈H₁₁NO₂: 153.0790; found: 153.0785.