N,N-dimethylglycine-promoted ullmann-type coupling reactions of aryl iodides with aliphatic alcohols

Article abstract of DOI:10.1055/s-2007-968010

The Ullmann-type coupling reactions of aryl iodides and aliphatic alcohols occur at 110°C with N,N-dimethylglycine as the ligand, giving aryl alkyl ethers in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-968010

LETTER
243
N,N-Dimethylglycine-Promoted Ullmann-Type Coupling Reactions of Aryl
Iodides with Aliphatic Alcohols
U
llmann-Type Cou
u
pling
R
eacti
i
ons of
Aryl
I
Z
odides
w
ithAlip
h
hatic
A
lcoh
a
ols ng,*a Dawei Ma,a,b Weiguo Caoa
a
Department of Chemistry, Shanghai University, 99 Shangda Lu, Shanghai 200444, P. R. of China
b
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
E-mail: yehao7171@shu.edu.cn
Received 17 August 2006
sion for us to investigate the copper-catalyzed coupling of
aliphatic alcohols with aryl halides using amino acid as
the ligand.
Abstract: The Ullmann-type coupling reactions of aryl iodides and
aliphatic alcohols occur at 110 °C with N,N-dimethylglycine as the
ligand, giving aryl alkyl ethers in good to excellent yields.
In the first stage of the study, we focused on the coupling
between 4-iodoanisole and ethanol. A variety of experi-
mental conditions were examined (see Table 1). The
highest yield (93%) was obtained when we used CuI (10
mol%) as the catalyst, N,N-dimethylglycine (20 mol%) as
the ligand, Cs2CO3 as the base, alcohol as the solvent, and
performed the reaction at 110 °C. Other bases, including
K3PO4, K2CO3 and CsOAc, provided lower yields. Alco-
hol itself was found to be the best solvent, as DMSO,
DMF and dioxane caused much lower yields. Further-
more, using L-proline as the ligand gave an unsatisfying
yield. Because N-(4-methoxyphenyl)-L-proline was iso-
lated in all cases of L-proline as the ligand, we reasoned
that the moderate yield might result from the coupling of
L-proline with 4-iodoanisole. Thus, N,N-dimethylglycine,
a much less reactive ligand toward coupling, was chosen.
Key words: cross-coupling, aliphatic alcohols, catalysis, ligands,
aryl iodides
Aryl alkyl ethers are important solvents and synthetic
building blocks for the production of fragrances, cosmet-
ics, pharmaceuticals and materials.1 The copper-mediated
Ullmann ether synthesis is a classical method for the
synthesis of these compounds.2 However, harsh reaction
conditions, such as high reaction temperature, the usual
requirement of strong bases, stoichiometric quantities of
the copper catalysts, and the low to moderate yields, have
greatly reduced the synthetic scope of this reaction.
Although recent progress in palladium-catalyzed ether
formation reactions has been made in this area,3 the draw-
backs of the catalyst systems, such as air sensitivity, high
cost and toxicity, limit their applications. Thus, copper-
catalyzed systems still hold the advantage of low cost for
large-scale industrial applications and have become at-
tractive due to the mild reaction conditions realized in the
recent years.4–6 For example, Buchwald and co-workers
found a simple and mild method to couple aryl iodides
with excess of alcohol at 110 °C (or 120 °C for few exam-
ples), using 1,10-phenanthroline as the ligand and CuI as
the catalyst.6a Very soon later, they reported the copper-
catalyzed O-arylation of N-substituted b-amino alcohols
at 125 °C in butyronitrile.6b Hosseinzadeh et al. used the
Buchwald group’s protocol to accomplish the etherifica-
tion of aryl iodides, but chose KF–Al2O3 as the base in-
stead of Cs2CO3.6c Recent work in Stockland’s group with
self-assembled octanuclear copper clusters as catalysts
has made it successful to synthesize aryl alkyl ethers in
good yields at 110 °C using an oil bath or with microwave
heating.6d
Using the CuI–N,N-dimethylglycine–Cs2CO3–alcohol
procedure, we studied the C–O coupling reactions be-
tween a number of alcohols and aryl iodides (see Table 2).
It was found that primary alcohols such as methanol,
ethanol, benzyl alcohol, 2-phenylethanol, and 3-methyl-
but-2-en-1-ol can all be successfully transformed to their
corresponding ethers under our conditions. The reaction
also proceeded well with aryl iodide carrying either elec-
tron-donating (e.g. OMe) or electron-withdrawing groups
(e.g. CF3). However, when 4-iodoanisole reacted with N-
Boc-b-aminoethanol, we obtained N-4-methoxyphenyl-
oxazolidinone (entry 17). This is because oxazolidinone,
the product of the self-cyclization of alcohol under the ba-
sic condition, coupled with 4-iodoanisole to give the N-
arylated product. It is notable that a wide range of func-
tional groups such as nitro, keto, aniline, trifluoromethyl
and olefin groups are well tolerated under our conditions.
Although the conversion of substrates with free NH2
groups was almost complete after 20 hours, the desired
products were isolated in comparatively moderate yield as
a result of decomposition of the starting materials.6a
Our group recently observed that amino acids not only ac-
celerated the coupling of themselves with aryl halides,7a,b
but also promoted the coupling reactions of amines and
phenols with aryl halides.7c–e Thus, it was a natural exten-
For the generation of aryl alkyl ethers from secondary
alcohols, it was found that using our protocol, only cyclic
alcohols such as cyclopentanol were coupled with aryl
iodides to give the moderate to good yields. For open-
chain alcohols as isopropanol, just the low yield was
SYNLETT 2007, No. 2, pp 0243–0246
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1.
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2.
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Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-968010; Art ID: W17006ST
© Georg Thieme Verlag Stuttgart · New York

244
H. Zhang et al.
LETTER
Table 1 CuI-Catalyzed Coupling Reaction of 4-Iodoanisole and Ethanol under Various Conditions
CuI, amino acid
+
I
EtOH
O
O
O
base (2 equiv)
Entry
Solvent
Base
Ligand
Temp (°C)
Time (h)
Yield (%)b
1
2
DMSO
DMF
Cs2CO3
Cs2CO3
Cs2CO3
CsOAc
K3PO4
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
80
80
80
80
80
80
80
80
80
80
110
24
24
24
24
24
24
24
40
40
40
24
20
7
3
Dioxane
DMSO
DMSO
DMSO
EtOH
8
4
2
5
8
6
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
10
72c
60c
77c
54c,d
93c
7
8
EtOH
N,N-Dimethylglycine
L-Proline
9
EtOH
10
11
EtOH
L-Proline
EtOH
N,N-Dimethylglycine
a Reaction conditions: 4-iodoanisole (2.0 mmol), ethanol (8 mmol), base (4.0 mmol), CuI (0.2 mmol), ligand (0.4 mmol), solvent (2 mL).
b Isolated yield.
c Alcohol itself was used as the solvent.
d CuI (0.4 mmol) and L-proline (0.8 mmol) were used.
obtained (compare entries 10, 11, 19 and 12). However, case in which the coupled product of o-iodobenzene and
both cyclic and open-chain secondary alcohols can be methanol was obtained in much higher yield using our
smoothly arylated under Buchwald’s conditions using catalytic system rather than Buchwald’s (entry 6). Thus,
1,10-phenanthroline as the ligand.
our protocol can be considered a complement to
Buchwald’s.
Still, on comparing our protocol with Buchwald’s,6a we
found that both methods were successfully applied when
aryl iodides coupled with primary alcohols, except in the
Table 2 N,N-Dimethylglycine-Promoted CuI-Catalyzed Coupling Reactions of Aryl Halides with Alcoholsa,8
Entry
1
Aryl iodide
Alcohol
Product
Time (h)
24
Yield (%)b
97
Yield (%)c
88
OH
O
O
O
O
I
I
2
24
24
93
95
78
93
OH
O
O
O
O
39
OH
OH
I
O
O
4
24
92
88
O
I
O
5
6
20
24
50
98
53
17
OH
OH
NH2
NH2
I
O
O
O
O
I
Synlett 2007, No. 2, 243–246 © Thieme Stuttgart · New York

LETTER
Ullmann-Type Coupling Reactions of Aryl Iodides with Aliphatic Alcohols
245
Table 2 N,N-Dimethylglycine-Promoted CuI-Catalyzed Coupling Reactions of Aryl Halides with Alcoholsa,8 (continued)
Entry
7
Aryl iodide
Alcohol
Product
Time (h)
24
Yield (%)b
95
Yield (%)c
92
OH
OH
I
O
8
22
96
90
F3C
F3C
I
O
9
22
22
67
50
58
61
OH
H2N
O
I
H2N
O
10
OH
OH
I
O
O
11
12
40
40
78
25
75d
79
O
I
I
O
O
O
O
O
O
O
OH
13
14
24
24
38
96
OH
Br
I
O
67
81
O
O
OH
O
O
O
15
16
24
24
94
84
OH
OH
I
O
71
Br
I
Br
O
17
18
24
24
88
76
O
O
O
I
OH
O
O
N
H
O
N
O2N
70
86
O2N
OH
I
O
19
24
24
77
80
OH
I
N
O
O
N
N
2010
86
I
OH
N
a Reaction conditions: aryl halide (2.0 mmol), alcohol (2 mL), Cs2CO3 (4.0 mmol), CuI (0.2 mmol), N,N-dimethylglycine·HCl (0.4 mmol), 110 °C.
b Isolated yield.
c Isolated yield for the coupling reaction of aryl iodide with alcohol using Buchwald’s conditions.6a
d Reaction temperature: 120 °C.
Synlett 2007, No. 2, 243–246 © Thieme Stuttgart · New York

246
H. Zhang et al.
LETTER
(4) an der Heiden, M. R.; Frey, G. D.; Plenio, H.
Although the above procedure is clearly successful for the
coupling reaction between aryl iodides and alcohols, us-
ing the same procedure for aryl bromide provided a low
yield of the ether (entry 13). Further studies into the scope
and mechanism of this reaction are currently underway in
our laboratories.
Organometallics 2004, 23, 3548.
(5) For some recent reviews on copper-catalyzed Ullmann-type
reaction, see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett
2003, 2428. (b) Frlan, R.; Kikelj, D. Synthesis 2006, 2271.
(c) Beletskaya, I.; Cheprakov, A. Coord. Chem. Rev. 2004,
248, 2337. (d) Ley, S.; Thomas, A. Angew. Chem. Int. Ed.
2003, 42, 5400.
(6) (a) Wolter, M.; Nordmann, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973. (b) Job, G.; Buchwald, S. L. Org. Lett. 2002, 4,
3703. (c) Hosseinzadeh, R.; Tajbakhsh, M.; Mohadjerani,
M.; Alikarami, M. Synlett 2005, 1101. (d) Manbeck, G. F.;
Lipman, A. Jr.; Stockland, R. A.; Freidl, A.; Hasler, A.;
Stone, J.; Guzei, I. J. Org. Chem. 2005, 70, 244.
(7) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459. (b) Ma, D.; Xia, C. Org. Lett. 2001,
3, 2583. (c) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5,
2453. (d) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799.
(e) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
(8) N,N-Dimethylglycine-Promoted Coupling Reactions of
Aryl Halides with Alcohols; General Procedure: A re-
sealable tube or test tube with a removable cap was charged
with CuI (10 mol%), N,N-dimethylglycine·HCl (20 mol%),
Cs2CO3 (2 equiv), and aryl halide (if solid, 2 mmol). The
tube was evacuated and backfilled with N2 (3 cycles).
Alcohol (2 mL) and aryl halide (if liquid, 2 mmol) were
added by syringe at r.t. under nitrogen. The sealed or capped
tube was put into the oil bath that was preheated to 110 °C
and the reaction mixture was stirred for the time specified.
The cooled mixture was partitioned between H2O (10 mL)
and EtOAc or Et2O (20 mL). The organic layer was
separated, and the aqueous layer was extracted with EtOAc
or Et2O (10 mL) each time until TLC showed no trace of
product left in the aqueous layer. The combined organic
layers were washed with brine, dried over Na2SO4 and
concentrated. Purification of the residue by flash
In conclusion, we have demonstrated that N,N-dimethyl-
glycine is an excellent ligand for Ullmann-type coupling
of aryl iodides and aliphatic alcohols. The present reac-
tion, which worked under our relatively mild conditions
using an experimentally simple catalytic system, was
applicable for a wide scope of substrates. Given these at-
tributes, it should find applications in organic synthesis.
Acknowledgment
The authors are grateful to Education Commission of Shanghai
Municipality (grant 05AX12 and B.99-0303-06-034) for their
financial support.
References and Notes
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Hirama, M. Tetrahedron Lett. 1998, 39, 8707.
chromatography on silica gel [2 × 20 cm, PE (30–60 °C)–
EtOAc or Et2O] gave the desired product.
(9) 4-Benzoxyanisole (Table 2, Entry 3): white solid; mp 60–
62 °C (Lit.6a mp 63 °C). 1H NMR (400 MHz, CDCl3): d =
7.25–7.43 (m, 5 H), 6.91 (d, J = 8.9 Hz, 2 H), 6.83 (d, J = 8.9
Hz, 2 H), 5.02 (s, 2 H), 3.77 (s, 3 H). MS (EI): m/z = 214
[M+], 123, 95, 92, 91, 65, 63, 41.
(10) 3-(3-Methylbut-2-enyloxy)pyridine (Table 2, Entry 20):
yellow oil. 1H NMR (500 MHz, CDCl3): d = 8.32 (s, 1 H),
8.21 (s, 1 H), 7.20 (s, 2 H), 5.46–5.49 (m, 1 H), 4.56 (d, J =
7.0 Hz, 2 H), 1.80 (s, 3 H), 1.75 (s, 3 H). 13C NMR (125
MHz, CDCl3): d = 155.0, 141.9, 139.0, 138.1, 123.8, 121.4,
119.0, 65.1, 25.8, 18.3. MS (EI): m/z = 163 [M+], 162, 95, 69,
68, 67, 41. HRMS (EI): m/z [M+] calcd for C10H13NO:
163.0997; found: 163.1002.
(j) Thompson, A.; Delaney, A.; James, M.; Hamby, J.;
Schroeder, M.; Spoon, T.; Crean, S.; Showalter, H. D. H.;
Denny, W. J. Med. Chem. 2005, 48, 4628.
(2) Lindley, J. Tetrahedron 1984, 40, 1433.
(3) For some recent reports on palladium-catalyzed aryl ether
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S. L. J. Am. Chem. Soc. 2005, 127, 8146. (b) Kataoka, N.;
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Chem. Soc. 2001, 123, 12202. (d) Prim, D.; Campagna, J.-
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1997, 119, 3395. (g) Torraca, K.; Huang, X.; Parrish, C.;
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Synlett 2007, No. 2, 243–246 © Thieme Stuttgart · New York

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