Chemoselectivity in the Cu-catalyzed O-arylation of phenols and aliphatic alcohols

Article abstract of DOI:10.1039/c1cc12694f

An orthogonal set of Cu-catalysts for the selective mono-arylation of alkyl aryl diols using aryl iodides is presented. Picolinic acid ligated copper catalyst provided phenol O-arylation only, while alkyl aryl ethers are generated by ligand-free copper ca

Full text of DOI:10.1039/c1cc12694f

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COMMUNICATION
Chemoselectivity in the Cu-catalyzed O-arylation of phenols and
aliphatic alcoholsw
Debabrata Maitiab
Received 7th May 2011, Accepted 25th May 2011
DOI: 10.1039/c1cc12694f
An orthogonal set of Cu-catalysts for the selective mono-
arylation of alkyl aryl diols using aryl iodides is presented.
Picolinic acid ligated copper catalyst provided phenol O-arylation
only, while alkyl aryl ethers are generated by ligand-free copper
catalyst in the presence of 2 equivalents NaOt-Bu.
Over the last two decades, metal-mediated cross-coupling
reactions have seen widespread application in the synthesis
of both simple and highly complex molecules.1–6 Prior efforts
have led to the development of many useful chemoselective7–9
methods such as N- or O-arylation of aminoalcohols,10,11
aminophenols,12 and C- or N-arylation13 of oxindoles. In this
context, orthogonal catalyst systems for selective phenol
arylation in presence of free alcohols would be of great interest
to synthetic chemists. Such motifs are also an integral part of a
number of natural products and drug molecules (Fig. 1).14–19
Fig. 1 Selected, bioactive compounds featuring arylated phenols and
aliphatic alcohols.
4-iodotoluene provided the corresponding diaryl ether in
excellent yield and with high levels of chemoselectivity
(Table 1, entry 1). No O-arylation of the aliphatic alcohol
moiety was detected in the crude reaction mixture.
Scheme 1 Cu-catalyzed O-arylation of phenol and aliphatic alcohol.
Although numerous successful methods for the metal-
catalyzed arylation of phenols and aliphatic alcohols exist,20–23
a chemoselective arylation procedure for aliphatic alcohols
(Scheme 1) is challenging due to drastic differences in their
acidity (PhOH pKa B 18 in DMSO and MeOH pKa B 28 in
DMSO).24
This catalyst system was then applied to an array of
coupling partners (Table 1). Following the general protocol,
electron-rich (entry 2) and electron-deficient (entry 3) iodo-
benzenes resulted in selective diarylether formation from
4-hydroxyphenethyl alcohol. The selectivity of this method
was further tested using a substrate with a methoxy substituent
ortho to the phenol moiety and desired diarylether is the only
product (entry 8). In addition, the presence of an ortho methyl
group on the aryl halide was well tolerated (Table 1, entry 4),
however, 10 mol% catalyst loading was required at 120 1C in
order to obtain full conversion.
Use of picolinic acid 1 as the ligand for copper was found to
effect O-arylation of phenols with best substrate scope and
efficiency.12,25 Thus, a catalyst system consisting of 5 mol%
CuI, 10 mol% picolinic acid 1, and K3PO4 in DMSO at 80 1C
was employed for arylation of phenol in presence of aliphatic
alcohol (Table 1). Notably, 4-hydroxyphenethyl alcohol and
Interestingly, this method was also successful for the
selective diarylether formation of heteroaryl substrates. Thus,
2-iodopyrazine (entry 5) could be O-arylated at phenol, as well
as 3-bromoquinoline (entry 6) and iodopyridines (entries 7 and 12).
Although 3-iodothiophene produced the desired ether with
complete selectivity, the reaction only proceeded to 60%
conversion (entry 11) at 10 mol% catalayst loading at 120 1C.
a Department of Chemistry, Indian Institute of Technology Bombay,
Powai, Mumbai 400076, India. E-mail: dmaiti@chem.iitb.ac.in
b Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139, USA
w Electronic supplementary information (ESI) available: Detailed
description of experimental procedures, characterization of all
compounds. See DOI: 10.1039/c1cc12694f
c
8340 Chem. Commun., 2011, 47, 8340–8342
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Table 1 Cu-catalyzed selective phenol arylation
Table 2 Cu-catalyzed selective aliphatic alcohol arylation
Entry O–Ar product Yield (%) Entry O–Ar product Yield (%)
Entry O–Ar product Yield (%) Entry O–Ar product Yield (%)
a
b
c
d
e
10 mol% CuI, 20 mol% 1. 120 1C. ArBr, 110 1C. 90 1C. 12%
diarylated product. 60% conversion.
f
a
b
110 1C. 120 1C.
Chloro- and bromo-substituted diarylethers (entries 8 and 9,
respectively) were also generated from 1-chloro-4-iodobenzene
and 1-bromo-4-iodobenzene, respectively. These reactions
further demonstrate the preference of aryl iodides as coupling
partner in copper-catalyzed methodology (Scheme 1).4,20–22
The chain length (entries 1, 4 and 8) and position (entries 1, 7
and 10) of the aliphatic alcohol with respect to the phenol
group have minimal impact in the selectivity of the diarylether
product formation (Table 1). Only when 2-hydroxyphenethyl
alcohol was employed as the coupling partner (entry 10), 12%
of the diarylated product along with 65% of the desired
diarylether were obtained. Formation of a stable chelating
complex is suspected to alter catalyst selectivity in this case.
Previously diarylated product formation was observed in
copper-catalyzed cross-coupling reaction while using chelating
nucleophiles.10,12
used, diaryl ether was the only product formed from 4-hydroxy-
phenethyl alcohol. Employing strong bases such as NaOt-Bu
(or KOt-Bu) in a 1 : 1 ratio with 4-hydroxyphenethyl alcohol
also led to only the diaryl ether product. Interestingly, altering
the base : substrate ratio to 2 : 1 provided selective O-arylation
of the aliphatic alcohol. Thus, using 10 mol% CuI, 1 mmol
4-iodotoluene, 1.1 mmol 4-hydroxyphenethyl alcohol,
2.3 mmol NaOt-Bu in N,N-dimethylformamide (DMF) at
70 1C, the selective O-arylation of aliphatic alcohol was
observed (Table 2, entry 1). Under these conditions, no diaryl
ether formation was seen. It is likely that both the hydroxy
groups in 4-hydroxyphenethyl alcohol are deprotonated under
these conditions and the alkoxy species was arylated selectively
due to its greater nucleophilicity compared to the phenolate.
A series of ligands previously employed in copper-catalyzed
reactions were examined4 and found to have no impact on the
yield or selectivity for this coupling process. By carrying out
the process at 70 1C, the formation of reduced products was
minimized and reasonable reaction rates could be obtained.
The next target was to develop conditions for the analogous
selective alkyl aryl ether formation. Irrespective of the amount
or nature of weak base (e.g. K3PO4, Cs2CO3 and Na2CO3)
c
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Notes and references
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Scheme 2 Cu-catalyzed direct synthesis of CRE 10904.
As shown in Table 2, electron-neutral (entry 1), -rich (entry 2)
and -deficient (entry 3) aryl iodides underwent efficient coupling
under these conditions.
7 N. A. Afagh and A. K. Yudin, Angew. Chem., Int. Ed., 2010, 49,
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Chloride or bromide substituted aryl iodides (entries 8
and 9, respectively) produced the desired products in reasonable
yields. Using the general procedure, heteroaryl ethers from
2-iodopyrazine (entry 5), iodo pyridines (entries 7 and 12) and
3-iodoquinoline (entry 6) were obtained in good yield. Similar
to the phenol arylation protocol, the chain length and position
of the aliphatic alcohol had little impact on the reaction
outcome.
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Of note is that 2-hydroxyphenethyl alcohol generated alkyl
aryl ether only (entry 10). Employing the current method, a
large quantity of the alcohol coupling partner is not required
for the synthesis of alkyl aryl ether. The efficiency of the
methodology developed here is further tested by the one step
synthesis of 2-(2-(4-fluorophenoxy)ethyl)phenol (CRE 10 904,
Scheme 2, yield 50%) the synthesis of which previously
required 4 steps.15,16
In conclusion, an orthogonal set of conditions for the
selective Cu-catalyzed O-arylation of unprotected phenols
and aliphatic alcohols has been discovered. A picolinic
acid (1)-ligated Cu-catalyst can be used to chemoselectively
arylate phenols, a ligand-free Cu-catalyst promotes exclusive
aliphatic alcohol arylation if an excess of strong base is
employed.
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25 D. Maiti and S. L. Buchwald, J. Org. Chem., 2010, 75, 1791–1794.
This activity is supported by an educational donation
provided by Amgen and by funds from the National Institutes
of Health (Grant GM-58160). D.M. sincerely thanks Professor
Steve Buchwald for providing full support to complete this
work. The NMR instruments used for this study were furnished
by funds from the National Science Foundation (CHE 9808061
and DBI 9729592).
c
8342 Chem. Commun., 2011, 47, 8340–8342
This journal is The Royal Society of Chemistry 2011