An improved Cu-based catalyst system for the reactions of alcohols with aryl halides

Article abstract of DOI:10.1021/jo702024p

(Chemical Equation Presented) The use of 3,4,7,8-tetramethyl-1,10- phenanthroline (Me₄Phen) as a ligand improves the Cu-catalyzed cross-coupling reactions of aryl iodides and bromides with primary and secondary aliphatic, benzylic, allylic, and propargylic alcohols. Most importantly, by employing this catalyst system, the need to use an excessive quantity of the alcohol coupling partner is alleviated. The relatively mild conditions, short reaction times, and moderately low catalyst loading allow for a wide array of functional groups to be tolerated on both the electrophilic and nucleophilic coupling partners.

Full text of DOI:10.1021/jo702024p

catalyst systems, which facilitate the reaction under mild
conditions, have been reported for the cross-coupling of aliphatic
alcohols with aryl halides.2,6,7
An Improved Cu-Based Catalyst System for the
Reactions of Alcohols with Aryl Halides
Ryan A. Altman, Alexandr Shafir, Alice Choi,
Phillip A. Lichtor, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
FIGURE 1. 1,10-Phenanthroline-based ligands for Cu-catalyzed C-O
bond formation.
ReceiVed September 14, 2007
In 2002, we reported that 10 mol % of CuI in conjunction
with 20 mol % of 1,10-phenanthroline (Phen, Figure 1) could
facilitate C-O bond formation between aryl iodides and
aliphatic alcohols under mild reaction conditions (Cs2CO3/
110 °C/18-38 h); however, in most cases, the use of the alcohol
as a solvent was required to achieve satisfactory yields, thus
rendering the procedure impractical for the use of precious or
highly functionalized alcohols.2 In certain simple cases, toluene
could be utilized as a solvent to reduce the quantity of alcohol
required for the reactions. Recently developed catalysts systems
that employ amino acids as ligands or KF/Al2O3 as the base
have also failed to overcome the required use of excess
quantities of alcohols for these reactions.7 In addition, reactions
of both secondary (2°) cyclic and acyclic alcohols provided the
corresponding products in low yields due to incomplete conver-
sion of the aryl iodides in reasonable time periods (<24 h).2,7
More recently, we reported that the use of a commercially
available ligand, 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4-
Phen, Figure 1), improved the Cu-catalyzed nucleophilic
substitution reactions of aryl iodides and alkyl-substituted vinyl
iodides with amino alcohols and allylic alcohols, respectively;
however, the scope of the reaction was not investigated/explored
beyond these selected substrates.8,9 Herein, we report an in-
depth account of the use of Me4Phen in Cu-catalyzed C-O
bond-forming reactions that presents the scope and limitations
of this catalyst system.
A variety of 1,10-phenanthroline-substituted ligands were
tested in the reaction of 4-iodoanisole with n-hexanol using the
following catalyst system: 5 mol % CuI/10 mol % ligand/Cs2-
CO3/toluene/80 °C/12 h (Table 1). The data presented suggest
that the presence of methyl and phenyl substituents in positions
3-5 of the phenanthroline backbone increase the activity of
the catalyst (entries 1-7). More specifically, the catalytic activity
of the methyl-substituted ligands increases as a function of the
number of methyl substituents present on the Phen core: Phen
< 4-MePhen ∼ 5-MePhen < 4,7-Me2Phen < 5,6-Me2P-hen <
Me4-Phen. Two hypotheses to explain the high activity of the
catalyst systems, which employ methyl-substituted Phen ligands,
are (1) the alkyl substituents might increase the solubility of
the metal catalyst in a nonpolar organic solvent, thus raising
The use of 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4-
Phen) as a ligand improves the Cu-catalyzed cross-coupling
reactions of aryl iodides and bromides with primary and
secondary aliphatic, benzylic, allylic, and propargylic alco-
hols. Most importantly, by employing this catalyst system,
the need to use an excessive quantity of the alcohol coupling
partner is alleviated. The relatively mild conditions, short
reaction times, and moderately low catalyst loading allow
for a wide array of functional groups to be tolerated on both
the electrophilic and nucleophilic coupling partners.
In our continuing quest to improve metal-catalyzed C-
heteroatom bond-forming reactions, we have developed several
Pd- and Cu-based catalyst systems for the intermolecular
coupling reactions of aliphatic alcohols with aryl halides to
prepare alkyl aryl ethers.1,2 Using Pd-based catalysts, the low
yields observed in the coupling of certain substrates have been
attributed to the slow rate of C-O reductive elimination relative
to â-hydride elimination from the LnPdII(Ar)(alkoxide) inter-
mediate.1a,b,3 In these cases, Cu-based catalyst systems can
provide complementary reactivities, as the analogous intermedi-
ates derived from these catalysts do not readily undergo
â-hydride elimination reactions.4
The substrate scopes and the overall utility of the traditional
Cu-based methods for the synthesis of alkyl aryl ether are
severely limited by (1) the use of superstoichiometric quantities
of Cu, (2) high reaction temperatures, and (3) the use of strong
alkoxide bases.5 Currently, few generally applicable Cu-based
(1) (a) Vorogushin, A. V.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 8146. (b) Torraca, K. E.; Huang, X.; Parrish, C.; Buchwald,
S. L. J. Am. Chem. Soc. 2001, 123, 10770. (c) Parrish, C. A.; Buchwald, S.
L. J. Org. Chem. 2001, 66, 2498.
(2) Wolter, M.; Normann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973.
(5) Lindley, J. Tetrahedron 1984, 40, 1433.
(6) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem.
Soc. 2000, 122, 5043.
(7) (a) Zhang, H.; Ma, D.; Cao, W. Synlett 2007, 243. (b) Hosseinzadeh,
R.; Tajbakhsh, M.; Mohadjerani, M.; Alikarami, M. Synlett 2005, 1101.
(8) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978.
(9) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3490.
(3) For reviews including Pd-catalyzed C-O bond formation, see: (a)
Schlummer, B.; Scholz, U. AdV. Synth. Catal. 2004, 346, 11599. (b) Mucci,
A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 133.
(4) For reviews including Cu-catalyzed C-O bond formation, see: (a)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 2337. (b)
Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
10.1021/jo702024p CCC: $40.75 © 2008 American Chemical Society
Published on Web 11/29/2007
284
J. Org. Chem. 2008, 73, 284-286

TABLE 1. Cu-Catalyzed Reaction of 4-Iodoanisole with n-Hexanol
TABLE 2. CuI/Me4Phen-Catalyzed Cross-Coupling Reactions of
Alcohols with Aryl Iodides and Bromidesa
Using 1,10-Phenanthroline-Derived Ligandsa
entry
ligand
conversion (%)
yield (%)
1
2
3
4
5
6
7
8
9
1,10-phenanthroline (Phen)
4-Me-Phen
5-Me-Phen
4,7-Me2-Phen
5,6-Me2-Phen
3,4,7,8-Me4-Phen
4,7-Ph2-Phen
neocuproine
4,7-(MeO)2-Phen
4,7-(NMe)2-Phen
4,7-Cl2-Phen
50
56
55
68
64
82
63
10
83
37
35
44
54
51
57
54
79
64
0
66
19
33
10
11
a Reaction conditions: 1.0 mmol of 4-iodoanisole, 1.5 mmol of n-
hexanol, 0.050 mmol of CuI, 0.10 mmol of ligand, 1.5 mmol of Cs2CO3,
and 0.5 mL of toluene under Ar atmosphere at 80 °C for 12 h. Corrected
conversion and yield data were calculated from GC analyses of the crude
reaction mixtures using dodecane as an internal standard.
the effective concentration of catalyst in solution, and/or (2)
the presence of the alkyl substituents on the ligand increases
the σ-donating ability of the nitrogen atoms10 and accelerates
the rate-limiting aryl halide activation step. Neocuproine (2,9-
dimethyl-Phen) is not a good ligand for this transformation and
reinforces the notion that Cu-catalyzed C-heteroatom bond-
forming reactions are extremely sensitive to steric hindrance.4
When 4,7-(MeO)2Phen is employed as a ligand for this
transformation, 1,4-dimethoxybenzene is produced as a byprod-
uct (∼15% GC yield), presumably due to nucleophilic displace-
ment of the methoxy groups of the ligand by n-hexanol, followed
by cross-coupling of the resulting methoxide nucleophile with
the aryl iodide (entry 9). Interestingly, the combined yield of
methoxy- and n-hexyloxy-substituted products (∼81%) when
employing the dimethoxy-substituted ligand is comparable to
the yield of product observed when Me4Phen is used (79%),
suggesting that these two catalyst systems facilitate C-O bond
formation at comparable rates. Other 4,7-bis-heteroatom-
substituted-Phen derivatives provide relatively inactive catalysts
(entries 10, 11).
Using the optimized reaction conditions, a wide variety of
substrates containing useful functional groups can be success-
fully cross-coupled (Table 2). The reaction of our model
substrates (n-hexanol with 4-iodoanisole) proceeds in excellent
yield at temperatures as low as 80 °C using 5% catalyst (entry
1). At 110 °C using 2% and 5% catalyst loading, this same
reaction proceeds in 24 and 12 h, respectively (entries 2, 3).
The catalyst system is tolerant of ortho-substituents on the aryl
halide (entries 4-6), as well as both electron-donating and
withdrawing substituents on the aromatic ring. Aryl iodides can
be selectively cross-coupled in the presence of aryl bromides,
chlorides, and fluorides (entries 8-10). Low-boiling point
alcohols, as well as allyl, propargyl, and benzyl alcohols, furnish
the corresponding aryl ethers in good to excellent yields (entries
7, 8, 10-13). The latter example provides ready access to the
corresponding phenols, as the resulting aryl benzyl ether can
be readily cleaved.11 Remarkably, the catalyst system can
selectively cross-couple alcohols in the presence of an unpro-
tected aniline (entry 11) or aliphatic amines.9 Although the Cu-
a Reaction conditions: 1.0 mmol of ArX, 1.5 of mmol alcohol, 0.050 of
mmol CuI (5%), 0.10 mmol of Me4Phen (10%), 1.5 mmol of Cs2CO3, and
0.50 mL of toluene under an Ar atmosphere. The isolated yields reported
are averages of two or more runs of material judged to be >95% pure by
1H NMR and/or elemental analysis. b GC yield reported. c 2% CuI, 4%
Me4Phen. d GC analysis: 14:1 mixture of I- to Br-substituted products which
were separated by column chromatography. e Inseparable 7:1 mixture of
depicted product and n-hexyl 4-(hexyloxy)benzoate. f 200 mg of 4 Å mol
sieves added to reaction mixture. g One regioisomer detected by GCMS
1
and H NMR. h 10% CuI, 20% Me4Phen. i 130 °C, 0.50 mL of n-hexanol
(10) pKa in H2O: +H-Me4Phen ) 6.31, +H-Phen, ) 4.86. Schilt, A.
A.; Smith, G. F. J. Phys. Chem. 1956, 60, 1546.
used as solvent.
J. Org. Chem, Vol. 73, No. 1, 2008 285

catalyzed reaction of ethyl 4-iodobenzoate with n-hexanol
provides a complex mixture of transesterified and cross-coupled
products, the formation of the transesterified product can be
drastically reduced by employing the tert-butyl ester (entry 14).
Heterocyclic compounds can be employed either as the elec-
trophilic or nucleophilic reactant (entries 12, 13, 15-18).
Products containing water-sensitive functional groups can be
provided in good yields by adding activated molecular sieves
to the reaction mixtures. (entries 17, 18).
The Cu-catalyzed cross-coupling reactions of secondary
alcohols with aryl halides are particularly important reactions,
due to the increased propensity for 2° alcohols to undergo
â-hydride elimination using Pd-based catalyst systems.1 Further,
the complementary uncatalyzed Williamson reactions of 2° alkyl
halides with poorly nucleophilic phenols typically provide low
yields of the aryl alkyl ether products.12 The CuI/Me4Phen-
catalyzed reactions of 2° cyclic alcohols with aryl iodides are
generally slower than the respective primary (1°) alcohol
counterparts (entries 18-20), requiring higher reaction temper-
atures (110 °C compared to 80 °C). However, the reactions of
secondary acyclic alcohols (e.g., isopropyl alcohol and 3-pen-
tanol) with simple aryl iodides are unsuccessful, unless the
reactions are run in neat alcohol. This difference in reactivity
can be exploited to selectively cross-couple a 1° alcohol in the
presence of a 2° alcohol (entry 21). We speculate that this
selectivity difference occurs due to the poor coordinating ability
of the 2° alcohol relative to the 1° alcohol.
The cross-coupling reactions of aryl bromides are less
successful than their iodide counterparts. At a 10% catalyst
loading, the reaction of benzyl alcohol with 3-bromoanisole
proceeds smoothly (entry 22). However, the Cu-catalyzed
reactions of other aliphatic alcohols are more challenging for
this catalyst system. An aryl bromide can be successfully cross-
coupled in neat n-hexanol at an elevated temperature (130 °C,
entry 23). However, the reactions of both 2° cyclic and acyclic
alcohols do not proceed to full conversion under these and more
rigorous conditions. These data suggest that the efficacy of Cu-
catalyzed cross-coupling reactions of various alcohols with aryl
halides follows the trend benzylic > 1° alkyl > 2° cyclic alkyl
> 2° acyclic alkyl. We suspect that the efficiency of reactions
that employ benzylic alcohols is due, in large part, to their
enhanced acidity relative to other aliphatic alcohols.13
In summary, we have explored the utility of Me4Phen as a
ligand in the Cu-catalyzed cross-coupling reactions of aryl
iodides and bromides with alcohols. With this protocol, the
cross-coupling reactions of aryl iodides with alcohols can be
run under mild conditions without the required use of excess
quantities of nucleophile in the reaction. This catalyst system
complements Pd-based catalyst systems, as well as traditional
Williamson reactions, and nucleophilic substitution reactions
of activated aryl halides for the preparation of alkyl aryl ethers.
We believe that chemists in both academic and industrial
laboratories will find this improved catalyst system useful in
their work.
Experimental Section
General Procedure for the Cu-Catalyzed Cross-Coupling of
Alcohols with Aryl Halides. An oven-dried screw-cap test tube
was charged with CuI (9.5 mg, 0.050 mmol), Me4Phen (24 mg,
0.10 mmol), aryl halide (1.0 mmol, if solid), Cs2CO3 (490 mg, 1.5
mmol), and a magnetic stir bar. The reaction vessel was fitted with
a rubber septum. The test tube was evacuated and back-filled with
dry argon. Aryl halide (1.0 mmol, if liquid) and toluene (0.50 mL)
were then added by syringe. The rubber septum was removed and
the reaction tube was quickly sealed with a Teflon-lined septum.
The vessel was immersed in a preheated oil bath and stirred
vigorously until TLC and/or GC analysis of the crude reaction
mixture indicated that the aryl halide had been completely
consumed. The reaction mixture was allowed to cool to room
temperature, diluted with ethyl acetate (15 mL), filtered through a
plug of silica gel, and further eluted with additional ethyl acetate
(30 mL). The filtrate was concentrated and the resulting residue
was purified by flash chromatography (hexane/ethyl acetate) to
provide the desired product.
Acknowledgment. We thank the National Institutes of
Health (GM58160) for financial support for this project. R.A.A.
is grateful to Pfizer and the National Institutes of Health
(F31GM081905) for predoctoral fellowships. Postdoctoral fund-
ing for A.S. was provided by the National Cancer Institute (NIH/
NCI 5-T32-CA09112-30). A.C. and P.A.L. were sponsored by
the MIT UROP program. A.C. was further supported by a
fellowship provided by Pfizer. We thank Chemetall for the
generous gift of Cs2CO3 and Merck, Amgen, and Boehringer-
Ingelheim for additional unrestricted support. The Varian NMR
instruments used for this publication were furnished by the
National Science Foundation (CHE 9808061 and DBI 9729592).
(11) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons, Inc.: New York, 1999; pp 266-
269.
(12) Smith, M. B.; March J. March’s AdVanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons, Inc.:
New York, 2001; p 477.
(13) pKa in DMSO: BnOH ) 26.9, EtOH ) 29.8. (a) Bordewll, F. G.;
Liu, W. Z. J. Am. Chem. Soc. 1996, 118, 8777. (b) Olmstead, W. N.;
Margolin, Z.; Bordwell, F. B. J. Org. Chem. 1980, 45, 3295.
Supporting Information Available: Experimental procedures
and characterization data for all new and known compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
JO702024P
286 J. Org. Chem., Vol. 73, No. 1, 2008