Ullmann C[sbnd]O coupling of sterically hindered secondary alcohols using excess amount of strongly coordinating monodentate ligands

Article abstract of DOI:10.1016/j.tetlet.2017.01.095

A new effective copper catalyzed C[sbnd]O coupling reaction using excess amount of strongly coordinating monodentate ligands was successfully developed. Among the DMAP-type monodentate ligands, 4-pyrrolidinopyridine afforded the best results. The developed reaction is widely applicable for the synthesis of various hindered or acyclic secondary alkyl-aryl ethers. In this study, a novel and remarkable acceleration of the coupling reaction using excess amount of monodentate ligands was discovered.

Full text of DOI:10.1016/j.tetlet.2017.01.095

Accepted Manuscript
Ullmann C–O Coupling of Sterically Hindered Secondary Alcohols Using Ex-
cess Amount of Strongly Coordinating Monodentate Ligands
Hayato Sugata, Tetsu Tsubogo, Yoshitaka Kino, Hiromi Uchiro
PII:
S0040-4039(17)30139-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.095
TETL 48598
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
16 December 2016
21 January 2017
26 January 2017
Please cite this article as: Sugata, H., Tsubogo, T., Kino, Y., Uchiro, H., Ullmann C–O Coupling of Sterically
Hindered Secondary Alcohols Using Excess Amount of Strongly Coordinating Monodentate Ligands, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.095
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Tetrahedron Letters
journal homepage: www.elsevier.com
Ullmann C–O Coupling of Sterically Hindered Secondary Alcohols Using Excess
Amount of Strongly Coordinating Monodentate Ligands
Hayato Sugata a, Tetsu Tsubogo a, Yoshitaka Kino a, and Hiromi Uchiro a,b,*
a Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
b Division of Fusion of Regenerative Medicine with DDS, Research Institute for Science and Technology (RIST), Tokyo University of Science
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new effective copper catalyzed C-O coupling reaction using excess amount of strongly
coordinating monodentate ligands was successfully developed. Among the DMAP-type
monodentate ligands, 4-pyrrolidinopyridine afforded the best results. The developed reaction is
widely applicable for the synthesis of various hindered or acyclic secondary alkyl-aryl ethers. In
this study, a novel and remarkable acceleration of the coupling reaction using excess amount of
monodentate ligands was discovered.
Available online
Keywords:
C-O coupling
2017 Elsevier Ltd. All rights reserved.
Copper catalyzed
Monodentate ligand
Alkyl aryl ether
Aliphatic alcohol
Introduction
Copper-promoted C–O coupling reaction has been widely
used in synthetic organic chemistry.1 The originally reported
Ullmann coupling reaction2 was conducted in the presence of a
stoichiometric amount of copper salt and limited to the
construction of biaryl ether linkages.3 In 2002, Buchwald and co-
workers reported the first catalytic reaction of aliphatic alcohols
with aryl halides using 1,10-phenanthroline as a bidentate
ligand.4 The reaction conditions were then modified5 and applied
to the synthesis of various alkyl aryl ethers, in good yields, when
used for the C–O coupling reactions of primary or cyclic
secondary alcohols.6 This useful etherification procedure was
recently applied successfully for the direct construction of highly
strained 13-membered macrocycle of Hirsutellone B;7 however,
for sterically-hindered or acyclic secondary alcohols, the
etherification procedure often afforded unsatisfactory results. In
this study, we attempted to develop a new Ullmann-type C–O
coupling reaction for these less reactive substrates.
Entry
Conditions
Yield (%)
3
21
45
47
9
4
2
5
2
2 (recovered)
Results and discussion
1
2
3
4
5
6
7
8
L1, Cs2CO3, 110 °C
L1, Cs2CO3, 140 °C
L2, Cs2CO3, 140 °C
L2, t-BuONa, 140 °C
L2, t-BuOK, 140 °C
L2, K2CO3, 140 °C
L2, Li2CO3, 140 °C
L2, K3PO4, 140 °C
67
0
We first examined the reaction of aryl iodide 1a with β-
cholestanol 2a, used as a model substrate for sterically-hindered
secondary alcohols, under various conditions (Table 1).
2
50
0
2
49
0
0
38
_________
15
8
0
0
32
* Corresponding author at: Faculty of Pharmaceutical Sciences, Tokyo
University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
E-mail address: uchiro@rs.noda.tus.ac.jp
0
0
90
NR
0
quant.
51
48
0

2
Tetrahedron
However, the desired coupling product 3a was obtained in
poor yield (21%) under the reported reaction condition5 using
3,4,7,8-tetramethyl-1,10-phenanthroline (Me4-phen, L1, Entry 1).
In this case, the reduced side product 4a, from aryl iodide 1a,
was also obtained with 2% yield. The reaction temperature was
found to be a very important parameter. When the reaction was
conducted at 140 °C, the yield of 3a improved to 45%; however,
side product 5a was also obtained in larger quantities (50%,
Entry 2). This undesired side reaction was completely eliminated
using unsubstituted 1,10-phenanthroline (phen, L2, Entry 3) as a
ligand.4 Although the use of cesium carbonate (Cs2CO3) afforded
a trace amount of 4a as another side product, various inorganic
bases were screened. As a result, potassium phosphate (K3PO4)
was employed as the most suitable base. However, we could not
obtain satisfactory results using these minor improvements in the
reported reaction conditions.
The monodentate ligand can cause a fast equilibrium between
complexes IIIb and Ib. Therefore, the active species Ib would be
smoothly produced, proceeded by the next halide activation. In
addition, the strong coordinating ability of monodentate ligand
can provide a more electron-rich and reactive three-coordinate
copper alkoxide complex Ib for the halide activation process.
This type of Ullmann C–N and C–O coupling reaction using a
4-(N,N-dimethylamino)pyridine (DMAP)-type monodentate
ligand was reported by Wong and co-workers;13-15 however, the
reported examples of C–O coupling reaction in this study were
limited to the formation of biaryl ether linkages. Therefore, we
examined this reaction for the existing model reaction to form a
hindered alkyl–aryl–ether linkage (Table 2).
Previous excellent studies on the Ullmann C–O coupling
reaction mechanism8,9 have reported the formation of a three-
coordinate copper (I) alkoxide complex (Ia) to have occurred
earlier than the activation of aryl halide (Fig. 1).
Entry
Ligand (mol%)
Yield (%)
2a (recovered)
In the experiments described above, two equivalents (vs
copper atom) of bidentate L2 ligand were used according to the
reported procedure.4,5 In this reaction condition, a four-coordinate
cationic copper complex IIa should be formed first because the
18-electron complex IIa is coordinatively stable and has good
solubility in the reaction solvent.10 Therefore, it was assumed that
the active species of this type of coupling reactions should be
generated via complex IIa.11 If the precise active species of the
next halide activation process is a three-coordinate copper
alkoxide complex Ia, it should be produced via a nucleophilic
attack of the substrate alkoxide on the complex IIa to afford a
relatively unstable five-coordinate copper (I) complex IIIa12 and
subsequent elimination of one equivalent of L2. However, when
L2 type of bidentate ligands are used in the reaction, this
elimination process becomes unfavorable because the complex
IIIa is stabilized by the chelation effect of bidentate ligands.
Therefore, we explored a new reaction condition that uses an
“easily dissociating” monodentate ligand (Figure. 2).
3a
40
48
1
2
L3 (40)
L2 (20)
56
51
Contrary to our expectation, the model reaction using 40
mol% of DMAP (L3) with 10 mol% of CuI gave a rather poor
yield (40%, Entry 1) compared with that of using 20 mol% of L2
(48%, Entry 2). However, we gradually increased the amount of
L3 because the monodentate ligands can easily dissociated upon
heating and the desired copper (I) alkoxide complex might not be
generated in a sufficient equilibrium concentration. In the course
of these experiments, we discovered an unprecedented and
remarkable improvement in the reaction rate and yield by using
an excess amount of the monodentate ligands, i.e., the yield of
the coupling product 3a improved with an increase in the amount
of ligand, reaching up to 76% yield with 120 mol% of L3 (Table
3, Entry 1-7).

20 mol% of L2. In contrast, in the presence of 60 mol% of L2,
the same fraction of coordinating nitrogen atoms as 120 mol% of
L3, the yield of the coupling product 3a (9%) was apparently
lowered. Such a specific and significant acceleration of the
reaction rate on using excess amount of monodentate ligand has
not been reported in studies on copper catalyzed C–O or C–N
coupling reactions.
We next screened other 4-substituted pyridine type
monodentate ligands such as 4-methylpyridine (L4) and 4-
methoxypyridine (L5) (Table 3, Entry 9-14).
A similar
acceleration was observed on using one of these ligands, but the
acceleration gradually lowered with the decreasing electron
donating ability of the 4-substituent on the pyridine ring (Entry 9-
10 and 11-12). In contrast, the use of 4-(N,N-disubstituted
amino)pyridines afforded good results for each case, with 4-
pyrrolidinopyridine (L6) affording the best yield (83%, Entry 13).
In the case of using more hindered 9-azajulolidine (L7), which is
the best ligand as per Wong’s report,13 the yield was lowered
(Entry 14). These results indicated that strongly coordinating and
less sterically hindered ligands are very important for the
observed acceleration in the reaction rate. The solvent effect was
also examined in the C-O coupling reaction with the best ligand
(L6), and toluene was superior to other more polar solvents
(Table 3, Entry 15-17).
Entry
1
Ligand (mol%)
L3 (40)
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
Yield (%)
40
2
L3 (60)
48
3
L3 (80)
65
4
L3 (100)
L3 (120)
L3 (140)
L3 (160)
L3 (120)
L4 (40)
71
5
76
6
75
7
8a
74
NR
13
The coupling reactions of various sterically hindered alcohols
(2b-i) with iodobenzene 1b using 120 mol% of L6 and 10 mol%
copper (I) iodide are demonstrated (Table 4).
9
10
11
12
13
14
15
16
17
L4 (120)
L5 (40)
36
22
L5 (120)
L6 (120)
L7 (120)
L6 (120)
L6 (120)
L6 (120)
58
83
72
45
DMSO
chlorobenzene
46
75
a
The reaction was conducted in the absence of K3PO4. DMF =
Entry
1
Alcohol
Product
Yield (%)
97
N,N-dimethylformamide. DMSO = dimethyl sulfoxide.
2b
2c
3b
3c
This acceleration of the reaction rate obtained on using an
excess amount of L3 is clearly demonstrated through a kinetic
analysis of this reaction (Figure. 3).
2
83
93
3
4
2d
2e
3d
3e
(26)a
92
(19)a
73
5
6
7
2f
2g
2h
3f
3g
3h
(3)a
85
(9)a
87
90
8
2i
3i
(>99% ee)
(>99% ee)
The initial reaction rate (0 to 2 h) for this reaction with 120
mol% of L3 is approximately three times faster than that using

4
Tetrahedron
a Reactions conducted using the phen ligand; CuI (10 mol%),
L2 (20 mol%), Cs2CO3 (200 mol%), toluene, 140 °C, 18 h.
OR
Cu
2 L
L
Cu Cu
L
OR
OR
L
L
L
L
L
Cu OR
L
L
L
- 2 L
IVb
IIIb
Ib
2 L
The desired alkyl aryl ethers 3b-i were obtained from sterically
hindered primary and secondary alcohols in good to high yield
for each case. Specifically, in the reaction of acyclic secondary
alcohols, the yields were greatly improved compared with those
that used the bidentate ligand (L2) (Entry 3-6). In addition, no
racemization of the stereogenic center of (R)-2-phenylethanol
was observed in the coupling reaction (Entry 8).
- 2 L
L
2
Cu OR
L
Ib
Scheme 3. A plausible equibrium between three kinds of copper
species in the presence of excess amount of monodentate ligands.
Thus, we developed a new, effective copper catalyzed C–O
coupling reaction using an excess amount of strongly
coordinating monodentate ligand. Therefore, we considered the
advantage of using an excess amount of monodentate ligand. An
interesting report concerning the chemical property of the three-
coordinate copper phenoxide complex Ic was presented by
Hartwig and co-workers.16 According to this study, the complex
Ic is in equilibrium with a polarized binuclear complex IVc
through a disproportionation process (Scheme 1).
Conclusions
In conclusion, a new effective copper catalyzed C–O coupling
reaction using excess amount of strongly coordinating
a
monodentate ligand was successfully developed. The reaction is
widely applicable for the construction of hindered or acyclic
secondary alkyl–aryl ether linkages. In the course of this study, a
novel and remarkable acceleration in the rate of reaction through
the use of excess amount of monodentate ligand was discovered.
This new finding may bring further evolution in transition metal
catalyzed synthetic reactions using coordinatively unsaturated
active species. Synthetic studies of some natural compounds with
interesting biological activity utilizing this new etherification
procedure are now in progress.
L
CuCl
L
L
L
L
OPh
1 / 2
Cu OPh
+
Cu
Cu
L
L
L
OPh
NaOPh
Ic
IVc
Acknowledgments
Scheme 1. Hartwig's reported equilibrium between polarized binuclear complex
IVc and tricoordinate alcoxide complex Ic.
This work supported by JSPS for a Grant-in-Aid for scientific
research (C) (Grant No. 25460025).
In addition, independently prepared binuclear complex IVd is
found to be less reactive toward aryl halides in the absence of a
L2 than in the presence of L2 (Scheme 2).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
References and notes
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Evano G, Blanchard N, Toumi M. Chem Rev. 2008;108:3054.
2. Ullmann F. Chem Ber. 1904;37:855.
3. Lindley J. Tetrahedron. 1984;40:1433.
4. Wolter M, Nordman G, Job GE, Buchwald SL. Org Lett. 2002;4: 973.
5. Altman RA, Shafir A, Choi A, Lichtor PA, Buchwald SL. J Org
Chem.2008;73:284.
6. (a) Beletskaya IP, Cheprakov AV. Coord Chem Rev. 2004;248: 2337; (b)
Ley SV, Thomas AW. Angew Chem Int Ed. 2003;42:5400.
7. Uchiro H, Kato R, Arai Y, Hasegawa M, Kobayakawa Y. Org Lett.
2011;13:6268.
8. (a) Jones GO, Liu P, Houk KN, Buchwald SL. J Am Chem Soc.
2010;132:6205; (b) Lefevre G, Franc G, Tlili A, Adamo C, Taillefer M,
Ciofini I, Jutand A. Organometallics. 2012;31:7694; (c) Zhang S, Zhu Z,
Ding Y. Dalton Trans. 2012;41:13832 (also references cited therein).
9. Sambiagio C, Marsden SP, Blacker J, McGowan PC. Chem Soc Rev.
2014;43:3525.
These Hartwig’s observations indicated that coordination of
phen ligand (L2) toward the negatively charged copper atom of
the polarized binuclear complex IVc afford the active species for
the next halide activation, and it should be the three-coordinate
copper alkoxide complex Ic. Putting all this together, excess
amount of monodentate ligands would produce a new fast
equilibrium between three kinds of copper species as shown in
Scheme 3. As a result, the reactive three-coordinate copper
alkoxide complex Ib could be more smoothly provided from the
less reactive polarized binuclear complex IVb through the
equilibrium. 17
10. A 1:1 mixture of copper (I) iodide and L2 is scarcely soluble in the
reaction solvent and less active.
11. Copper catalyzed C-O and C-N coupling reactions by using four-
coordinate cationic copper complexes were also reported, see: (a) Niu J,
Zhou H, Li Z, Xu J, Hu S. J Org Chem. 2008;73:7814; (b) Moriwaki K,
Satoh K, Takada M, Ishino Y, Ohno T. Tetrahedron Lett. 2005;46:7559.
12. Synthesis and interesting properties of five-coordinate copper (I)
complexes were already reported: (a) Gagne RR, Allison JL, Gall RS,
Koval CA. J Am Chem Soc. 1977;99:7170; (b) Gagne RR, Allison JL,
Ingle DM. Inorg Chem. 1979;10:2767; (c) Sakurai T, Kimura M,
Nakahara A. Bull Chem Soc Jpn. 1981;54:2976; (d) Goodwin JA, Wilson
LJ, Stanbury DM, Scott RA. Inorg Chem. 1989;28:42.
13. Wong K-T, Ku S-Y, Yen F-W. Tetrahedron Lett. 2007;48:5051.

14. A cross coupling reaction of alkenyltrifluoroborate salts with carboxylic
acid catalyzed by copper-DMAP complex was also reported, see: Huang F,
Quach TD, Batey RA. Org Lett. 2013;15;3150.
15. Recently, an interesting Chan-Lam cross coupling reaction utilizing
copper-DMAP complex has been reported, see: Roy S, Jyoti S, Kashyap
B, Phukan P. Chem Comm. 2016;52:117.
16. Tye JW, Weng Z, Giri R, Hartwig JF. Angew Chem Int Ed. 2010;49:2185.
17. Hartwig et al. also reported that the equilibrium as shown in Scheme 1
significantly shifted to the polarized binuclear complex IVc by using
polar solvent such as DMSO.16 This observation well agreed with our
described undesirable results on using polar solvents (Table 3, Entry 15-
16).

6
Tetrahedron
Ullmann C-O Coupling of Sterically
Hindered Secondary Alcohols Using
Excess Amount of Strongly Coordinating
Monodentate Ligands
Hayato Sugata a, Tetsu Tsubogo a, Yoshitaka Kino a,
and Hiromi Uchiro a,b,*
a Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641
Yamazaki, Noda, Chiba 278-8510, Japan
b Division of Fusion of Regenerative Medicine with DDS, Research Institute
for Science and Technology (RIST), Tokyo University of Science
HIGHLIGHTS
A new effective copper catalyzed C-O coupling reaction is
successfully developed.
A remarkable acceleration by using excess amount of
monodentate ligands is observed.
Various hindered or acyclic secondary alkyl-aryl ethers are
obtained in high yields.
Advantages on the reaction mechanism by using
excess amount of ligands are discussed.

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Ullmann C-O Coupling of Sterically Hindered
Secondary Alcohols Using Excess Amount of Strongly
Coordinating Monodentate Ligands
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Hayato Sugata a, Tetsu Tsubogo a,b, Yoshitaka Kino a and Hiromi Uchiro a,b,
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