Synthesis of diaryl ethers using an easy-to-prepare, air-stable, soluble copper(I) catalyst

Article abstract of DOI:10.1081/SCC-100105338

We have found that bromo(triphenylphosphine)copper(I), an air-stable and soluble copper(I) complex, can be used as a catalyst in the synthesis of diaryl ethers. Using this catalyst, we have synthesized diaryl ethers from electron-rich aryl bromides and electron-rich phenols in the presence of cesium carbonate, in 17-24 h, in NMP. We also found that electron-deficient aryl bromides couple with phenols in the presence of cesium carbonate, in 6 h in NMP at 70°C, without the catalyst.

Full text of DOI:10.1081/SCC-100105338

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SYNTHESIS OF DIARYL ETHERS USING AN EASY-TO-
PREPARE, AIR-STABLE, SOLUBLE COPPER(I) CATALYST
a
b
Rattan Gujadhur & D. Venkataraman
a
Department of Chemistry, University of Massachusetts, Amherst, MA, 01003, U.S.A.
Department of Chemistry, University of Massachusetts, Amherst, MA, 01003, U.S.A.
b
Available online: 15 Aug 2006
To cite this article: Rattan Gujadhur & D. Venkataraman (2001): SYNTHESIS OF DIARYL ETHERS USING AN EASY-TO-
PREPARE, AIR-STABLE, SOLUBLE COPPER(I) CATALYST, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:18, 2865-2879
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SYNTHETIC COMMUNICATIONS, 31(18), 2865–2879 (2001)
SYNTHESIS OF DIARYL ETHERS USING
AN EASY-TO-PREPARE, AIR-STABLE,
SOLUBLE COPPER(I) CATALYST
Rattan Gujadhur and D. Venkataraman*
Department of Chemistry, University of
Massachusetts, Amherst, MA 01003
ABSTRACT
We have found that bromo(triphenylphosphine)copper(I),
an air-stable and soluble copper(I)complex, can be used as
a catalyst in the synthesis of diaryl ethers. Using this catalyst,
we have synthesized diaryl ethers from electron-rich aryl
bromides and electron-rich phenols in the presence of
cesium carbonate, in 17–24 h, in NMP. We also found that
electron-deficient aryl bromides couple with phenols in the
ꢀ
presence of cesium carbonate, in 6 h in NMP at 70 C, without
the catalyst.
The classical copper-mediated Ullmann coupling is the reaction of
choice for the synthesis of aryl ethers and triarylamines in large and indus-
1
,2
ꢀ
trial scales. These reactions often require high temperatures (ꢁ 200 C)and
3
the use of copper salts in greater than stoichiometric amounts. The reaction
,4
*
Corresponding author.
2
865
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
2
866
GUJADHUR AND VENKATARAMAN
is also very sensitive to the substitution on the aryl halide. Due to these
5
–8
limitations, copper salts have largely been supplanted by Pd(0)catalysts.
However, it has been shown by Cohen in 1976 and more recently by others
that if the solubility of the copper salts is increased, then S Ar reactions tend
N
to occur at milder temperatures and with catalytic amounts of the copper
–14
9
salt.
The possibility of milder reaction conditions, combined with its
scope and robustness has renewed the interest in Ullmann-type reactions.
In addition, there is an economic attractiveness for using copper over noble
metals such as palladium.
Soluble copper(I)salts are often air- and moisture-sensitive (e.g.
.
CuðCF SO 0:5C H )and/or require the use of harsh conditions for their
3
3
6
6
1
5
preparation. In order to explore the full scope and mechanistic details of
these copper-catalyzed reactions, there is a necessity for copper(I)salts that
are chemically well-defined, stable, soluble in organic solvents and capable
of systematic modification. In this regard, we are currently studying the use
of copper-phosphine complexes as catalysts in the formation of aryl-carbon
and aryl-heteroatom bonds. As a part of this study, we now report the use of
Cu(PPh ) Br as a catalyst for the synthesis of diaryl ethers from electron-
3
3
rich aryl bromides. This complex is extremely easy to prepare and is stable
to air and ambient moisture.
Addition of CuBr to a hot methanolic solution of triphenylphosphine
2
gives Cu(PPh ) Br (1)as a crystalline white solid. This procedure obvi-
3
3
ates the need to reflux moisture-sensitive copper(I)bromide with triphenyl-
1
6–18
phosphine for 3–4 h, a common procedure for making these complexes.
Using this procedure, Cu(PPh ) Cl and Cu(PPh ) NO have also been pre-
3
3
3 2
3
pared in high yields. Complex 1 is soluble in organic solvents such as THF,
dichloromethane, acetonitrile, chloroform, NMP, DMF, DMSO, toluene
and benzene. However, it is not soluble in diethyl ether, hexane, ethanol
or methanol. It can be stored under air for prolonged times, without any
visible color change.
We chose to explore the synthesis of diaryl ethers using 1 as a catalyst.
There has been a widespread interest in developing general strategies for the
1
9,20
synthesis of diaryl ethers using Cu(I)or Pd(0)as catalysts.
This interest
stems from the importance of diaryl ethers in organic synthesis, their occur-
rence in various biologically interesting compounds and the lack of general
methods for their preparation. Recently, Buchwald and co-workers reported
a general copper-catalyzed synthesis of diaryl ethers from phenols and aryl
.
halides. Buchwald’s protocol calls for the use of CuðCF SO 0:5C H as the
3
3
6
6
catalyst, cesium carbonate as the base, 5 mol% of ethyl acetate and some-
times the use of 1-napthoic acid. We report in here procedures for the syn-
thesis of diaryl ethers that have the following advantages: (a)it dispenses
with the need for the use of any additives or co-solvents; (b)in contrast to

ORDER
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DIARYL ETHERS
2867
.
ðCF SO 0:5C H , Cu(PPh ) Br is easy to prepare and is stable to air and
3
3
6
6
3 3
ambient moisture; (c)Cu(PPh ) Br is soluble in organic solvents; and (d)it
3
3
dispenses with the need for any catalyst for the synthesis of diaryl ethers
from electron-deficient aryl halides and electron-rich phenols under mild
conditions.
We initially examined the propensity of 1 to act as a catalyst for the
formation of diaryl ethers using solvents such as toluene and N-methyl-
pyrrolidinone (NMP). In NMP, we discovered that o- and p-cresol react
with electron deficient aryl bromides such as 1-bromo-4-nitrobenzene and
4
7
1
-bromobenzonitrile with Cs CO to form the corresponding diaryl ether, at
2 3
ꢀ
0 C and in 6 h, even in the absence of the copper catalyst (see Table 1, entries
–4). The reaction was however, incomplete in 6 h when Cs CO was
2
3
replaced with K CO and does not occur if 4-N,N-dimethylaminopyridine
3
2
(
ried out in toluene, in addition to Cs CO , the copper catalyst was also
DMAP)was used as the base. In comparison, when the reaction was car-
2
3
required for the formation of the diaryl ether. These observations suggest
that the formation of diaryl ethers from electron-deficient aryl bromides and
electron-rich phenols might not require any catalysts such as Pd(0), if
Cs CO is used as a base and NMP as the solvent.
2
3
Table 1. Reactions of Electron-Rich Aromatic Bromides with Phenols in NMP or
in Toluene
Isolated
Time Temperature Yields
Catalyst
(mol%)Solvent
0
ꢀ
Entry
R
R
(h)
( C)
(%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
p-NO
p-NO2
p-CN
p-CN
p-CH3
2
p-CH
o-CH3
3
0
0
0
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
6
6
6
70
70
70
70
88
86
80
85
75
70
76
75
61
75
72
0
p-CH
o-CH
3
3
0
6
o-CH3
20
20
20
20
20
20
20
20
20
20
20
20
17
17
19
24
24
24
24
24
24
24
100
100
100
100
100
100
100
100
100
100
100
100
p-CH
p-N(CH
p-OCH3
3
p-CH
p-CH
3
3
3 2
)
p-CH3
o-OCH
o-OH
3
p-CH
p-CH
3
3
1
1
1
1
1
1
1
3
o-CH3
p-CH3
p-CH
o-CH3
p-CN
o-COOCH
3
3
0
o-COOCH
p-CN
3
o-CH
H
o-CH
3
55
60
27
Toluene 24
Toluene 24
p-CH
3
3

ORDER
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2
868
GUJADHUR AND VENKATARAMAN
Furthermore, for electron-rich aryl bromides, the reactions were com-
plete in 48 h in the presence of 5 mol% of 1 and 3 eq. of Cs CO , in NMP. The
reactions do not proceed when K CO , KOt-Bu and DMAP were used as
2
3
2
3
bases. Also, in contrast to the reactions with electron-deficient aryl
bromides, the copper catalyst was necessary for diaryl ether formation. In
general, we observed that the reactions were faster in NMP than in toluene.
Scheme 1.
We then probed the effect of the catalyst concentration on the reaction
time. We found that when 1 was increased to 20 mol%, the reactions were
complete (by TLC)in half the time, within 24 h and gave good yields (entries
5–11, Table 1). Similar reaction times and yields were observed, when 1 was
used in stoichiometric amounts. We observed that the reaction mixtures
needed to be well stirred owing to the low solubility of Cs CO in NMP.
All of the diaryl ethers reported in Table 1 have been characterized by
2
3
1
13
H NMR, C NMR and elemental analyses (see supporting information).
The products from entry 1 and entry 6 in Table 1 have also been character-
ized by single crystal x-ray analyses.
From Table 1, it can be surmised that 1 is a very effective catalyst
for the coupling of electron-rich phenols and electron-rich aryl bromides
(
entries 5–11). It is also effective in the coupling of o-substituted aryl
bromides and o-substituted electron-rich phenols (entry 11). However, 1 is
ineffective in the coupling of electron-deficient phenols with electron-rich
bromides (entries 12 and 13). This may be attributed to the delocalization
of the charge on the phenoxide ion, making it a poor nucleophile. In fact,
general methods that have been reported in the literature have focused on
1
1,14,21,22
phenols with electron donating substituents.
In order to develop a
complete set of reaction conditions for the synthesis of diaryl ethers, we are
currently investigating the coupling of electron-deficient phenols with elec-
tron-rich and electron-deficient bromides. We also found that 4-bromo-
benzonitrile can couple with phenol, in toluene, to form the
corresponding diaryl ether in 60% yield (entry 15). In direct comparison,
.
when CuðCF SO Þ 0:5C H was used as the catalyst, 1-napthoic acid was
3
3
6
6
1
1
required as an additive for the diaryl ether formation.
In conclusion, we have shown that bromotris(triphenylphosphine)-
copper(I), Cu(PPh ) Br is an effective catalyst for the formation of diaryl
3
3

ORDER
REPRINTS
DIARYL ETHERS
2869
ethers from electron-rich bromides and phenols. In contrast to other Cu(I)
catalysts, 1 is extremely easy to prepare and is air-stable. We have also
shown that electron-deficient aryl bromides couple with phenols in the pres-
ence of Cs CO , with NMP as the solvent and do not require a catalyst.
2
3
We are currently studying the mechanistic aspects of this reaction and the
efficacy of 1 to act as a catalyst in other S Ar reactions.
N
EXPERIMENTAL
General
All reactions for the synthesis of diaryl ethers were performed under
an inert atmosphere of argon in oven-dried glassware. All reagents and
solvents were purchased from Acros or from Aldrich and were used without
further purification. Cesium carbonate (Acros, 99%)was stored in a glove
box filled with argon. Flash chromatography was performed using ICN
Flash Silica Gel, 230–400 mesh. The reported yields refer to isolated
1
yields of the compounds, deemed pure by elemental analysis, H NMR
1
1
3
13
and C NMR. All products were characterized by H NMR, C NMR
and elemental analyses. NMR spectra were recorded on a Bruker AVANCE
300 MHz spectrometer. Chemical shifts were recorded in parts per million
(
d). The peak patterns are indicated as s, singlet; d, doublet; t, triplet; dd,
doublet of doublets; and m, multiplet. The coupling constants, J, are
reported in Hertz (Hz). The residual solvent peak was used as the internal
reference. Elemental analyses were preformed at the Microanalysis Labora-
tory, University of Massachusetts at Amherst by Dr. Greg Dabkowski. The
reported melting points are uncorrected. X-ray data were collected using a
˚
Nonius kappa-CCD diffractometer with Mo K (ꢀ ¼ 0.71073 A)as the inci-
a
dent radiation. Diffraction data were collected at ambient temperature. The
raw data were integrated, refined, scaled and corrected for Lorentz polar-
ization and absorption effects, if necessary, using the programs DENZO and
SCALEPAK, supplied by Nonius. Structures solutions and refinements
2
were done (on F )using suite of programs such as SIR92, LSQ, SHELXS
o
and SHELXL that are contained within the Nonius’ MAXUS module. All
structures were checked for any missing symmetry using MISSYM of
PLATON.
Synthesis of bromotris(triphenylphosphine)copper(I) (1). In an Erlen-
meyer flask equipped with a Teflon stir bar, methanol (100 mL)was heated
to boiling and triphenylphospine (Acros, 6 g, 22.4 mmol)was slowly added
to the stirring methanol. After the complete dissolution of triphenyl-
phosphine, CuBr (Acros, 99þ%, 1.24 g, 5.27 mmol)was added as a solid,
2

ORDER
REPRINTS
2
870
GUJADHUR AND VENKATARAMAN
in portions. No special precautions were taken for the exclusion of air.
Upon addition of the copper bromide, a white precipitate was formed.
After the completion of the addition, the contents were stirred for 10 min
and the flask was allowed to cool to ambient temperature. The reaction
mixture was then filtered through a Buchner funnel and the white residue
was washed repeatedly with ethanol and then with diethyl ether. The resul-
tant white solid was dried under dynamic vacuum to give 1 (5.73 g, 85%
ꢀ
yield, mp 164 C). It can also be recrystallized as white needles from hot
methanol. Anal. calc. for Cu(PPh ) Br: C, 69.71; H, 4.64; Cu, 6.83. Found:
3
3
C, 69.67; H, 4.66; Cu, 6.20. We wish to point out that copper was analyzed
using colorimetry, since there was a large interference from phosphorous in
the ICP. For the same reason, we were unable to obtain a satisfactory P
3
1
analysis. P NMR (121 MHz) d 0.5 (s). Crystal data for 1: Trigonal, P3 (no.
ꢀ
˚
˚
˚
1
43), a ¼ 19.2150(3)A , b ¼ 19.2150(3)A , c ¼ 10.6220(3)A , a ¼ 90.00 ,
ꢀ
ꢀ
3
ꢂ3
˚
b ¼ 90.00 , g ¼ 120.00 , V ¼ 3396.39 A , D ¼ 1.364 g cm , Z ¼ 3, number
c
of unique reflections ¼ 7487, number of parameters ¼ 519, R1 (for F > 4
o
ꢁ
(
) ¼ 0.0397 and 0.0581 (all data), wR2 (for F > 4 ꢁ) ¼ 0.1040 and 0.1183
o
all data), GOF ¼ 0.868, residual electron density ¼ þ0.340. The cell con-
stants, contents and the space group are identical to that of the already
reported structure of Cu(PPh ) Br (Cambridge Structural Database
Refcode-FEYVAG).
3
3
Although 1 is stable to air and ambient moisture, we stored it in an
argon-filled glove box. This is primarily due to the ease of setting up reac-
tions, since Cs CO had to be stored in a dry atmosphere as it is extremely
2
3
hygroscopic.
Cu-Catalyzed Coupling of Phenols with Aryl Halides
General procedure A: In an argon-filled glove box, a Pyrex glass tube
2.5 cm in diameter)equipped with a Teflon stir bar and a rubber septum,
(
was charged with cesium carbonate (Acros, 3.0 mmol)and Cu(PPh ) Br
3
3
(
20 mol% with respect to the aryl halide)and was sealed with a rubber
septum. The sealed tube was taken out and the phenol (2 mmol), the aryl
halide (2 mmol)and N-methylpyrrolidinone (15 mL)were injected into the
tube through the septum. The tube was then degassed and backfilled with
argon three times using a long needle. The contents were then stirred at
ꢀ
100 C for times indicated in Table 1. Care was taken to make sure the
contents were well stirred. The reaction mixture was then cooled and filtered
to remove any insoluble residues. Water was then added to the filtrate,
and the aryl ether was extracted in hexane. The combined extracts were
dried with anhydrous Na SO . The solvent was removed under reduced
2
4

ORDER
REPRINTS
DIARYL ETHERS
2871
pressure and the residue was then purified with by flash column chromato-
graphy on silica gel to obtain the analytically pure product.
General procedure B (without the catalyst): In an argon-filled glove
box, a Pyrex glass tube (2.5 cm in diameter)equipped with a Teflon stir
bar, was charged with cesium carbonate (Acros, 3.0 mmol)and was sealed
with a rubber septum. The sealed tube was taken out and the phenol
(
2 mmol), the aryl halide (2 mmol) and N-methylpyrrolidinone (15 mL)
were injected into the tube through the septum. The tube was then degassed
and backfilled with argon three times using a long needle. The contents were
ꢀ
then stirred at 70 C for times indicated in Table 1. Care was taken to make
sure the contents were well stirred. The reaction mixture was then cooled
and filtered to remove any insoluble residues. Water was then added to the
filtrate, and the aryl ether was extracted in hexane. The combined extracts
were dried with anhydrous Na SO . The solvent was removed under
2
4
reduced pressure and the residue was then purified with by flash column
chromatography on silica gel to obtain the analytically pure product.
1-Methyl-4-(4-nitrophenoxy)benzene (entry 1, Table 1). Procedure B
was used to convert p-cresol and 1-bromo-4-nitrobenzene to the title prod-
uct. Purification by flash chromatography (1:3 dichloromethane/hexane)
gave the analytically pure product as white solid (0.40 g, 88% yield).
1
H NMR (300 MHz, CDCl ) d 8.15 (dd, J ¼ 7.0, 2H-H , H
0
), 7.22 (dd,
a
3
a
J ¼ 7.2, 2H; H , H
0
), 6.96 (m, 4H; H , H
d
0
, H , H ), 2.31 (s, 3H-methyl
c
0
b
b
d
c
1
3
protons); C NMR (75 MHz, CDCl ) d 163.6 (C ), 152.1 (C ), 142.2 (C4),
1
0
3
1
1
2
35.1 (C4
0
), 130.7 (C3
0
, C3a ), 125.7 (C , C ), 120.3 (C , C ), 116.6 (C
0.7 (C ). Anal. calcd for C H NO : C, 68.12; H, 4.80. Found: C, 68.04;
0
0
, C2a ),
0
3
3a
2
2a
2
5
13 11
3
ꢀ
H, 4.91; mp 65 C. Crystal data: Orthorhombic, Pbca (no. 61), a ¼
3
˚
˚
˚
˚
7
.4395(2)A , b ¼ 12.4400(3)A , c ¼ 24.8501(7)A , V ¼ 2299.8(1)A , Z ¼ 8,
number of unique reflections ¼ 1573, number of parameters ¼ 154, R1 ¼
2
2
o
ꢃ
2
o
0
.077 (all data), wR ðw ¼ 1=ðs ðF Þ þ 0:0300 ðF ÞÞÞ ¼ 0:064 (all data),
GOF ¼ 2.04, residual electron density ¼ þ0.27.
1-Methyl-2-(4-nitrophenoxy)benzene (entry 2, Table 1). Procedure B was
used to convert o-cresol and 1-bromo-4-nitrobenzene to the title product.

ORDER
REPRINTS
2
872
GUJADHUR AND VENKATARAMAN
Purification by flash chromatography (1:3 dichloromethane/hexane)gave
1
the analytically pure product as yellow oil (0.39 g, 86% yield). H NMR
(
300 MHz, CDCl ) d 8.18 (dd, J ¼ 7.0, 2H; H , H
0
), 7.34–7.16 (m, 3H; Hd,
a
3
a
H , H ), 7.02 (dd, J ¼ 7.7, 1H; H ), 6.92 (dd, J ¼ 7.0, 2H; H , H
0
), 2.22 (s,
b
e
f
c
b
1
3
3
(
(
6
H; methyl protons); C NMR (75 MHz, CDCl ) d 163.3 (C ), 152.2
3
1
C1
0
), 142.1 (C4
C ), 121.0 (C ), 115.8 (C
0
), 131.9 (C ), 130.4 (C ), 127.6 (C ), 125.9 (C
0
0
, C3a ), 125.8
0
3
2
5
3
, C2a ), 15.9 (C ). Anal. calcd for C H NO : C,
7 13 11 3
0
4
6
2
ꢀ
8.12; H, 4.80. Found: C, 68.10; H, 4.85; mp 35 C.
4-(4-Methylphenoxy)benzonitrile (entry 3, Table 1). Procedure B was
used to convert p-cresol and 1-bromo-4-cyanobenzene to the title product.
Purification by flash chromatography (1:3 dichloromethane/hexane)gave
1
the analytically pure product as white solid (0.3 g, 80% yield). H NMR
(
H , H
300 MHz, CDCl ) d 7.62 (dd, J ¼ 8.8, 2H; H , H
0
), 7.24 (dd, J ¼ 8.1, 2H;
3
a
a
0
), 6.90 (m, 4H; H , H
c
0
, H , H ), 2.41 (s, 3H; methyl protons);
d
C NMR (75 MHz, CDCl ) d 161.9 (C ), 152.2 (C ), 134.8 (C4
), 120.2 (C , C ), 118.8 (C ), 117.4 (C
0
b
b
c
d
1
3
0
0
), 133.9
0
3
1
1
(
C , C ), 130.6 (C
3
0
, C3a
0
, C2a ),
0
3a
3
2
2a
5
2
1
6
05.3 (C ), 20.7 (C
4
0
). Anal. calcd for C H NO: C, 80.38; H, 5.26; N,
14 11
5
ꢀ
.69. Found: C, 79.93; H, 5.65; N, 6.24; mp 65 C.
4-(2-Methylphenoxy)benzonitrile (entry 4, Table 1). Procedure B was
used to convert o-cresol and 1-bromo-4-cyanobenzene to the title product.
Purification by flash chromatography (1:3 dichloromethane/hexane)gave

ORDER
REPRINTS
DIARYL ETHERS
2873
1
the analytically pure product as a white solid (0.35 g, 85% yield). H NMR
300 MHz, CDCl ) d 7.56 (dd, J ¼ 6.9, 2H; H , H ), 7.32–7.14 (m, 3H; Hd,
(
0
a
3
a
H , H ), 6.99 (dd, J ¼ 6.9, 1H; H ), 6.91 (dd, J ¼ 6.97, 2H; H , H
0
), 2.41 (s,
b
e
f
c
b
1
3
3
1
1
H; methyl protons); C NMR (75 MHz, CDCl ) d 160.2 (C ), 150.8 (C
0
0
),
),
3
1
1
32.6 (C , C )130.4 (C ), 128.9 (C2
0
0
), 126.0 (C5
0
0
), 124.1 (C4 ), 119.6 (C6
0
3
3a
3
17.3 (C ), 115.1 (C , C ), 103.6 (C ), 14.4 (C
5
). Anal. calcd for C H NO:
14 11
2
2a
4
7
ꢀ
C, 80.38; H, 5.26. Found: C, 80.17; H, 5.40; mp 70 C.
1-Methyl-2-(4-methylphenoxy)benzene (entry 5, Table 1). Procedure B
was used to convert o-cresol and 1-bromo-4-methylbenzene to the title prod-
uct. Purification by flash chromatography (1:3 dichloromethane/hexane)
gave the analytically pure product as a colorless oil (0.29 g, 75% yield).
1
H NMR (300 MHz, CDCl ) d 7.22 (dd, J ¼ 8.5, 1H; H ), 7.07 (m, 3H; H ,
3
c
f
H , H
b
0
), 6.83 (m, 4H; H , H , H , H ), 2.11 (s, 3H-methyl protons), 2.10 (s,
a
0
b
e
d
a
1
3
3
1
1
H-methyl protons); C NMR (75 MHz, CDCl ) d 155.5 (C ), 154.9 (C ),
0
3
1
1
31.8 (C4
19.1 (C2
0
), 131.3 (C ), 130.1 (C
0
0
, C3a ), 129.6 (C ), 127 (C ), 123.5 (C ),
2 5 4
0
3
3
0
, C2a
), 117.5 (C ), 20.6 (C ), 16.1 (C ). Anal. calcd for C H O:
5 7 14 14
0
6
C, 84.84; H, 7.07. Found: C, 84.62; H, 7.22.
1-Methyl-4-(4-methylphenoxy)benzene (entry 6, Table 1). Procedure A
was used to convert p-cresol and 1-bromo-4-methylbenzene to the title pro-
duct. Purification by flash chromatography (1:3 dichloromethane/hexane)

ORDER
REPRINTS
2
874
GUJADHUR AND VENKATARAMAN
gave the analytically pure product as a white solid (0.27 g, 70% yield).
1
H NMR (300 MHz, CDCl ) d 7.17 (dd, J ¼ 6.5, 4H; H , H , H , H ),
3
a
a
b
b
1
3
); C NMR
7
(
C3a
.1 (dd, J ¼ 6.5, 4H; H , H , H , H ), 2.21 (s, 6H; C , C
0
c
c
d
d
5
5
75 MHz, CDCl ) d 155.2 (C , C
0
), 132.3 (C , C
4
0
), 130 (C , C , C ,
3
0
3
1
1
4
3
3a
0
), 118.5 (C , C , C
0
, C2a
0
). Anal. calcd for C H O: C, 84.84; H,
14 14
2
2a
2
ꢀ
7
.07. Found: C, 84.62; H, 7.07; mp 50 C. Crystal data: Orthorhombic,
˚
˚
˚
P2 2 2 (no. 19), a ¼ 5.9138(1)A , b ¼ 7.8364(2)A , c ¼ 24.6388(8)A ,
1
1 1
3
˚
V ¼ 1141.83(5)A , Z ¼ 4, number of unique reflections ¼ 2167, number of
2
2
o
ꢃ
2
o
parameters ¼ 136, R1 ¼ 0.091 (all data), wR ðw ¼ 1=ðs ðF Þ þ 0:0300 F Þ ¼
0
:047 (all data), GOF ¼ 2.04, residual electron density ¼ þ 0.33.
N,N-Dimethyl-4-(4-methylphenoxy)aniline (entry 7, Table 1). Procedure
A was used to convert p-cresol and 4-bromo-N,N-dimethylaniline to the title
product. Purification by flash chromatography (1:1, dichloromethane/
hexane)gave the analytically pure product as a white solid (0.34 g, 76%
1
yield). H NMR (300 MHz, CDCl ) d 7.13 (dd, 2H; H , H ), 6.96 (dd, 2H;
3
b
b
H , H ), 6.81 (dd, 2H; H , H ), 6.66 (dd, 2H; H , H ), 2.91 (s, 6H; dimethyl
0
protons), 2.21 (s, 3H; methyl protons); C NMR (75 MHz, CDCl ) d 155.1
c
c
d
d
a
a
1
3
3
(
1
7
C1
0
), 146.4 (C ), 145.8 (C ), 129.8 (C
0
0
), 128.4 (C3
). Anal. calcd for C H NO: C, 79.29; H,
0
), 118.9 (C ), 115.7 (C ),
2
0
4
1
4
2
12.5 (C ), 39.7 (C , C ), 19.0 (C
3
5
5a
5
15 17
ꢀ
.48. Found: C, 79.25; H, 7.68; mp 180 C.
1-Methoxy-4-(4-methylphenoxy)benzene (entry 8, Table 1). Procedure A
was used to convert p-cresol and 4-bromoanisole to the title product.

ORDER
REPRINTS
DIARYL ETHERS
2875
Purification by flash chromatography (30% dichloromethane/hexane)gave
1
the analytically pure product as a white solid (0.42 g, 75% yield). H NMR
(
H , H
2
300 MHz, CDCl ) d 7.91 (dd, J ¼ 8.3, 2H; H , H
0
), 7.04 (dd, J ¼ 8.9, 2H;
3
b
b
0
), 6.99–6.89 (m, 4H; H , H
c
0
, H , H ), 3.91 (s, 3H; methoxy protons),
a
0
d
d
c
a
1
3
.41 (s, 3H; methyl protons); C NMR (75 MHz, CDCl ) d 155.9 (C ), 155.5
3
4
(
C1
C2a
8.33; H, 6.66; mp 63 C.
0
), 150.6 (C ), 131.9 (C
0
), 129.9 (C3
0
, C3a
0
), 120.2 (C , C )117.6 (C ,
0
1
4
2
2a
2
0
), 114.6 (C , C ). Anal. calcd for C H O ; C, 78.5; H, 6.54. Found: C,
3
3a
14 14
2
ꢀ
7
1-Methoxy-2-(4-methylphenoxy)benzene (entry 9, Table 1). Procedure A
was used to convert p-cresol and 2-bromoanisole to the title product.
Purification by flash chromatography (30% dichloromethane/hexane)gave
1
the analytically pure product as a white solid (0.26 g, 61% yield). H NMR
(
300 MHz, CDCl ) d 7.13–7.05 (m, 3H, H , H , H ), 7.00 (dd, J ¼ 8.00, 1H;
0 0
c a a b b
3
f
e
d
H ), 6.95–6.83 (m, 4H, H , H , H , H ), 3.91 (s, 3H; methoxy protons), 2.2
1
3
(
s, 3H; methyl protons); C NMR d 155.4 (C ), 151.1 (C
0
), 145.6 (C1
0
0
),
), 117.4 (C2,
), 20.6 (C ). Anal. calcd for C H O : C, 78.5; H,
1
6
1
32.0 (C ), 129.9 (C , C )124.2 (C
0
), 120.9 (C4
0
), 120.2 (C2
4
3
3a
3
C ), 112.6 (C
2
6
0
), 55.8 (C7
0
a
5
5
14 14
2
ꢀ
.54. Found: C, 78.2; H, 6.59; mp 75 C.
1-Methyl-2-(4-methylphenoxy)benzene (entry 10, Table 1). Procedure B
was used to convert o-cresol and 1-bromo-2-methyltoluene to the title

ORDER
REPRINTS
2
876
GUJADHUR AND VENKATARAMAN
product. Purification by flash chromatography (1:3 dichloromethane/hexane)
gave the analytically pure product as a colorless oil (0.29 g, 75% yield).
1
H NMR (300 MHz, CDCl ) d 7.22 (dd, J ¼ 8.5, 1H; H ), 7.16–6.96 (m,
3
c
4
H; H , H , H
f
0
, H ), 6.86–6.76 (m, 3H; H , H , H ), 2.11 (s, 3H; methyl
0
a
b
b
e
d
a
1
3
protons), 2.0 (s, 3H; methyl protons); C NMR (75 MHz, CDCl ) d 155.5
3
(
C ), 154.9 (C
0
), 131.8 (C4
0
), 131.3 (C ), 130.1 (C
0
0
, C3a ), 129.6 (C ), 127
0
1
1
3
3
2
(
C ), 123.5 (C ), 119.1 (C
0
, C2a
calcd for C H O: C, 84.84; H, 7.07. Found: C, 84.83; H, 7.25; mp 155 C.
), 117.5 (C ), 20.5 (C
0
), 16.1 (C ). Anal.
ꢀ
5
4
2
6
7
7
1
4
14
1-Methyl-2-(2-methylphenoxy)benzene (entry 11, Table 1). Procedure B
was used to convert o-cresol and 1-bromo-2-methyltoluene to the title prod-
uct. Purification by flash chromatography (1:3, dichloromethane/hexane)
gave the analytically pure product as a colorless oil (0.29 g, 72% yield).
1
H NMR (300 MHz, CDCl ) d 7.47 (dd, J ¼ 7.3, 2H; H , H
0
), 7.33 (dd,
a
3
a
J ¼ 7.3, 2H; H , H
0
), 7.23 (dd, J ¼ 7.2, 2H; H , H
0
b
), 6.96 (dd, J ¼ 7.5,
c
c
b
1
3
2
1
1
H; H , H
d
0
), 2.51 (s, 6H; methyl protons); C NMR (75 MHz, CDCl ) d
d
3
55.6 (C , C
6
17.6 (C , C
5
0
), 131.3 (C , C
0
0
), 128.8 (C , C
0
0
), 127.0 (C , C
0
), 123.0 (C , C ),
0
6
2
2
1
1
4
4
3
3
), 16.1 (C , C ). Anal. calcd for C H O: C, 84.84; H, 7.07.
7 14 14
5
7
Found: C, 84.82; H, 7.14.
1-Methyl-2-(2-methylphenoxy)benzoate (entry 14, Table 1). Procedure A
was used to convert p-cresol and 1-methyl-2-bromobenzoate to the title pro-
duct. Purification by flash chromatography (1:1, dichloromethane/hexane)

ORDER
REPRINTS
DIARYL ETHERS
2877
gave the analytically pure product as a colorless oil. (0.13 g, 55% yield).
1
H NMR (300 MHz, CDCl ) d 7.54 (dd, J ¼ 8.1 Hz, 2H; H ), 7.34
3
a
(
t, J ¼ 7.91 Hz, 1H; H ), 7.28 (d, J¼ 7.72 Hz, 1H; H ), 7.22 (m, J ¼ 7.72 Hz,
c
b
1
3
3
H), 7.11 (t, J ¼ 7.75 Hz, 2H; H
0
, H ); C NMR (75 MHz, CDCl ) d 166.8
0
d
c
3
(
C ), 157.2 (C ), 155.0 (C
7
1
C8), 16.57 (C7
4.10; H, 5.83.
0
), 133.8 (C ), 132.2 (C ), 131.8 (C ), 129.9 (C1
), 122.8 (C ), 122.2 (C ), 119.1 (C
6
0
0
),
), 118.8 (C ), 52.48
1
6
4
2
2
27.5 (C4
0
), 124.3 (C3
0
0
0
5
3
5
(
). Anal. calcd for C H ON: C, 74.38; H, 5.78. Found: C,
13 9
7
4-Phenoxybenzonitrile (entry 15, Table 1). Procedure A was used to
convert phenol and 1-bromo-4-cyanobenzene to the title product. However,
toluene was used as the solvent instead of NMP. Purification by flash chro-
matography (1:3 dichloromethane/hexane)gave the analytically pure prod-
1
uct as a white solid. (0.12 g, 60% yield). H NMR (300 MHz, CDCl ) d 7.50
3
(
(
dd, J ¼ 8.1 Hz, 2H; H , H
0
), 7.33 (dd, J ¼ 7.91 Hz, 2H; H Ha
0
), 7.03
), 6.85 (d,
d
d
a,
t, J ¼ 7.72 Hz, 2H; H ), 6.95 (d, J ¼ 7.72 Hz, 2H; H
H
0
b
e
b,
1
3
J ¼ 7.75 Hz, 2H; H , H
0
); C NMR (75 MHz, CDCl ) d 161.5 (C ), 154.6
1
0
c
c
3
(
C ), 134.0 (C , C
1
0
), 130.1 (C , C ), 125 (C ), 120.3 (C , C ), 118.7 (CN),
4 2 2a
0
3
3a
3
3a
117.8 (C2
Found: C, 79.86; H, 4.66.
0
, C2a ), 105.6 (C ). Anal. calcd for C H ON: C 80.0; H, 4.61.
4 13 9 ,
0
1-Methoxy-2-(4-methylphenoxy)benzene(entry16,Table1).ProcedureA
was used to convert p-cresol and 2-bromoanisole to the title product.

ORDER
REPRINTS
2
878
GUJADHUR AND VENKATARAMAN
However, toluene was used as the solvent instead of NMP. Purification by
flash chromatography (1:3 dichloromethane/hexane)gave the analytically
1
13
pure product as a white solid (0.047 g, 27% yield). The H and C NMR
was identical to that of entry 9.
ACKNOWLEDGMENTS
The University of Massachusetts, Amherst start-up funds provided the
financial support for this research. DV gratefully acknowledges a Camille
and Henry Dreyfus New Faculty Award. We thank Dr. Greg Dabkowski of
the Microanalysis lab at the UMass-Amherst for elemental analyses and the
University of Massachusetts Chemistry Department X-ray Structural Labo-
ratory supported by National Science Foundation grant CHE-9974648 for
assistance with the crystallographic analyses.
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4
6
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involve the use of perchloric acid, which has an explosion hazard

ORDER
REPRINTS
DIARYL ETHERS
2879
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Received in the USA November 29, 2000

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