Picolinamides as effective ligands for copper-catalysed aryl ether formation: Structure-activity relationships, substrate scope and mechanistic investigations

Article abstract of DOI:10.1002/chem.201404275

The use of picolinic acid amide derivatives as an effective family of bidentate ligands for copper-catalysed aryl ether synthesis is reported. A fluorine-substituted ligand gave good results in the synthesis of a wide range of aryl ethers. Even bulky phenols, known to be very challenging substrates, were shown to react with aryl iodides with excellent yields using these ligands. At the end of the reaction, the first examples of end-of-life Cu species were isolated and identified as Cu^II complexes with several of the anionic ligands tested. A preliminary mechanistic investigation is reported that suggests that the substituents on the ligands might have a crucial role in determining the redox properties of the metal centre and, consequently, its efficacy in the coupling process. An understanding of these effects is important for the development of new efficient and tunable ligands for copper-based chemistry.

Full text of DOI:10.1002/chem.201404275

DOI: 10.1002/chem.201404275
Full Paper
&
Copper Catalysis
Picolinamides as Effective Ligands for Copper-Catalysed Aryl
Ether Formation: Structure–Activity Relationships, Substrate
Scope and Mechanistic Investigations
Carlo Sambiagio,[a] Rachel H. Munday,[b] Stephen P. Marsden,[a] A. John Blacker,[a] and
Patrick C. McGowan*[a]
Abstract: The use of picolinic acid amide derivatives as an
effective family of bidentate ligands for copper-catalysed
aryl ether synthesis is reported. A fluorine-substituted ligand
gave good results in the synthesis of a wide range of aryl
ethers. Even bulky phenols, known to be very challenging
substrates, were shown to react with aryl iodides with excel-
lent yields using these ligands. At the end of the reaction,
the first examples of end-of-life Cu species were isolated
and identified as CuII complexes with several of the anionic
ligands tested. A preliminary mechanistic investigation is
reported that suggests that the substituents on the ligands
might have a crucial role in determining the redox proper-
ties of the metal centre and, consequently, its efficacy in the
coupling process. An understanding of these effects is im-
portant for the development of new efficient and tunable
ligands for copper-based chemistry.
Introduction
structure–activity relationship studies have been reported for
specific families of ligands.[17]
The discovery of copper-catalysed couplings between aryl hal-
ides and anilines, phenols and amides by Fritz Ullmann and
Irma Goldberg during the early 1900s[1–4] represents the start-
ing point of a significant amount of research in the field. Ull-
mann–Goldberg couplings could, until the late 1990s–early
2000s, be performed only on electron-poor aryl halides and
under harsh conditions, such as high temperatures (>2008C),
the use of high-boiling polar solvents and stoichiometric or
over-stoichiometric amounts of copper source.[5] At the end of
the 20th century, pioneering research by, among others, Nico-
laou,[6] Liebeskind,[7] Goodbrand,[8] Ma[9] and Buchwald,[10,11] led
to investigations on the use of ligands in copper-catalysed
cross-coupling reactions, allowing for much milder conditions
to be used in these transformations, as well as increased sub-
strate scope and functional group tolerance.[12–16] Ligands most
frequently used nowadays for this type of chemistry are mostly
bidentate ligands, such as phenanthrolines, bipyridines, b-dike-
tones, b-diamines, and amino acids. Despite much investiga-
tion, the role of the structural features of the ligand in the re-
action has not been yet completely understood, and very few
To establish the effect of the ligand structure on the reac-
tion, and to develop new effective ligands for this process, we
sought to perform a screening of commonly used, structurally
diversified ligands in a model aryl ether synthesis reaction.
Among other ligands, the use of picolinamide derivatives was
of interest to us for several reasons. Firstly, their precursor pico-
linic acid was shown to be an effective ligand in several
cases.[18,19] Moreover, while a great deal of mechanistic investi-
gation has been performed on neutral ligands such as phenan-
throlines,[20–22] diamines[20,23,24] and iminopyridines,[25] compara-
tively less information is available regarding anionic ligands in
the reaction,[26,27] which can potentially influence the copper
species involved. Furthermore, picolinamide derivatives contain
several coordination sites, and different coordination modes
with a metal centre are therefore available,[28] making them
flexible and useful ligands in catalytic reactions. These ligands
have been used in different transition metal-catalysed reac-
tions.[29–35] Also, picolinamide-derived substrates are nowadays
widely used as coordinating substrates in group-directed CÀH
bond activation, due to their favourable coordination to the
metal centre.[36–38] Reports recently appeared on the use of pi-
colinamides as ligands in Cu-catalysed synthesis of biphen-
yls,[39] and as chiral ligands in asymmetric Mannich-type reac-
tions.[40] To our knowledge, however, no reports have appeared
in the literature on the use of such ligands for Cu-catalysed CÀ
O bond formation. Herein we report the use of N-arylpicolina-
mide ligands for the synthesis of aryl ethers. A structure–activi-
ty relationship study has led to the discovery of a very effective
ligand, even under aerobic conditions. Bulky phenols, normally
very challenging substrates for Cu-catalysed couplings, proved
[a] C. Sambiagio, Prof. S. P. Marsden, Prof. A. J. Blacker, Dr. P. C. McGowan
iPRD, School of Chemistry, University of Leeds
Woodhouse Lane, Leeds, LS2 9JT (UK)
E-mail: P.C.McGowan@leeds.ac.uk
[b] Dr. R. H. Munday
Pharmaceutical Development, AstraZeneca UK
Hulley Road, Macclesfield, SK10 2NA
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404275.
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to be effective coupling partners, allowing for the synthesis of
ortho-substituted aryl ethers, which have several applications
in medicinal chemistry[41–43] and can be found in naturally oc-
curring compounds.[44] The recovery of end-of-life CuII species
and preliminary mechanistic investigation revealed the crucial
role of the ligand in altering the redox behaviour of the metal
centre, thus considerably influencing the reaction outcome.
alysis was reported by Denmark and co-workers.[47] In their
studies, non-anhydrous base led to considerably better results
than the corresponding dry one for the coupling between aryl
halides and aryl silanols.[47] On the basis of these observations,
we investigated the use of three different reaction conditions
for each ligand in a preliminary screening (Methods A–C;
Figure 1). Method A refers to reactions performed in air, using
shelf chemicals and non-treated solvent (aerobic, non-anhy-
drous); method B involved reactions in air using dry reaction
components (aerobic, anhydrous); finally, method C involved
reactions under a nitrogen atmosphere, using anhydrous de-
gassed solvent and dry chemicals (anaerobic, anhydrous). The
results of the preliminary ligand screening are shown in
Figure 1. Control experiments without ligand and with neither
ligand nor copper were also performed, leading to maximum
yields of 3 of 25% and 0%, respectively (see the Supporting
Information, Table S1).
Results and Discussion
Ligand screening, effect of conditions, and structure–activity
relationships
The model reaction between 3,5-dimethylphenol (1) and 4-io-
doanisole (2), leading to aryl ether 3, was carried out in aceto-
nitrile using CuI and Cs2CO3 as base (Scheme 1). In order to
build a comparison of ligand structures for this reaction, we
tested a diverse range of bidentate ligands (Figure 1, L1–L11).
Typically, Ullmann-type reactions are performed under nitrogen
or argon atmosphere, but several reactions under air have also
been reported.[45,46] Moreover, the hygroscopicity of the chemi-
cals used can influence considerably the outcome of the reac-
tion. An example of this effect for caesium carbonate in Pd cat-
From the results, it is clear that the effect of the reaction
conditions strongly depends on the ligand used. The use of
anhydrous chemicals (method B) did not generally influence
the reaction outcome, with respect to method A, and only in
some cases was a significant (>10%) increase (L10) or de-
crease (L5) in yield observed. The improvement obtained
under nitrogen atmosphere (method C) is more remarkable, al-
though only a few ligands (L4–L6, L9, L11) were positively af-
fected. All of the other ligands seem to be relatively insensitive
to the different conditions. Under air-free conditions a slightly
higher amount of anisole, obtained as a side product from
reductive dehalogenation of 2, was generally formed (see the
Supporting Information, Tables S2 and S4).
Scheme 1. Model reaction between phenol 1 and iodoanisole 2.
Among those tested, the picolinamide ligand L11 proved
one of the most effective ligands. The yield of 3 obtained in air
(method A) is comparable with those observed with ligands
L5, L9, and L10, while in anaerobic conditions (method C),
only with ligands L5 and L9. Encouraged by these results, we
sought to modify the parent ligand L11 to assess a structure–
activity relationship. To investigate the role of the heteroaro-
matic group we compared picolinic acid L10 and picolinamide
L11 with a series of other heterocyclic carboxylic acids
(Figure 2, L12, L14, L16, with heterocycles furan, thiophene,
and quinoline, respectively) and the corresponding N-phenyla-
mides (L13, L15, L17) with method A. The use of ligands L12–
L17, however, resulted in much lower yields than with L10 and
L11 (Figure 2), thus confirming the primarily important role of
the pyridine ring in the ligand.
Next, we synthesised a series of N-phenylpicolinamide
ligands with electron-donating and electron-withdrawing sub-
stituents on the phenyl ring (Figure 3a, L18–L26), and tested
them in the catalytic reaction in air (method A). The trends re-
ported in Figure 3a show the remarkable effect of the substitu-
ent on the ligand. The addition of electron donating groups
on picolinamide ligands (L18–L20) led to lower yields of 3
than the unsubstituted L11, while the presence of electron
withdrawing groups (L21–L26) generally increased the activity
of the ligand (Figure 3a). The importance of electronic effects
on the ligand can be clearly observed by comparing ligands
L20 and L21; the substitution of the second methoxy group in
Figure 1. Effect of reaction conditions for several common ligands (GC
yields).
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Figure 2. Effect of the heterocycle in carboxylic acid and amide ligands
(method A, GC yields).
L20 with a nitro group in L21 led to a 15% increase in the
yield of aryl ether 3 (Figure 3a).
Ligand L22, functionalised with a chlorine atom (2-Cl-6-Me),
led to the best yield among the ligands tested (74% of ether
3). This prompted us to investigate halogen substituents on
the ring, and a series of ligands substituted with F, Cl, Br and I
in different positions (Figure 3b, L27–L44) were prepared and
tested in the reaction with method A. Some of the halogenat-
ed ligands were more effective than the other electron-poor li-
gands (Figure 3b), in particular N-(2-fluorophenyl)picolinamide
L27 led to an excellent yield of 3 (84%) in air. The best ligand
in each series (L27, L32, L36, L40 and L43) was further tested
with methods B and C for comparison. As expected, the use of
method B did not particularly influence the reaction outcome;
interestingly, even anaerobic conditions (method C) furnished
little or no improvement, showing a much lower sensitivity to
atmospheric oxygen than the parent L11. It is interesting to
note that a trend is recognisable in the activity of differently
substituted ligands. For ligands substituted in the ortho posi-
tion (L27–L30), the activity decreased from fluorine to iodine;
this trend may be due to the possibility of intramolecular cou-
pling within the ligand, which has been previously ob-
served.[48,49] The decrease in yield when using ortho-brominat-
ed ligands L41 and L44, in comparison with L33 and L37
(meta- and para-substituted), may be due to the same reason.
The yield decreases from ortho- to para-substituted ligands
with fluorine, but increases again when a second fluorine atom
is inserted in the ortho position (L39 and L42), which confirms
the importance of the ortho fluorine atom. A complete list of
yields with these ligands is reported in Table S4 (see the
Supporting Information).
Figure 3. Screening of substituted picolinamide ligands (GC yields).
sults are reported in Table 1. The use of other polar solvents
led to moderate yields (43–61%; Table 1, entries 2–5), whereas
the use of toluene led to 17% yield (entry 6). DMSO, being
a very common solvent for Ullmann arylations, was also used
with ligands L1–L11, but no better results were obtained (see
the Supporting Information, Table S5). The use of potassium
and sodium carbonate as bases gave respectively 32% and 8%
yield (Table 1, entries 7 and 8). The use of potassium phos-
phate led to 70% yield (entry 9), whereas potassium tert-but-
oxide only furnished 3 in 22% yield (entry 10). Different Cu
sources, either metallic copper, CuI or CuII (Table 1, entries 11–
14), all led to yields above 70%, showing the relative unimpor-
tance of the copper source in the reaction.
Optimization and substrate scope for ligand L27 in air
After the identification of the 2-fluoro-substituted picolinamide
L27 as the best ligand for the model reaction in air, we sought
to investigate the effect of other parameters. A screening of
solvents, bases and copper sources was performed, and the re-
We then investigated the remaining parameters in the catal-
ysis, such as amount of base, copper source and ligand, time
and temperature (Table 2). An increase in the amount of caesi-
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tron-rich) aryl iodides led to very good isolated yields (com-
pounds 3 and 4, 80%, 76% yield). Similar results were ob-
tained with more reactive electron-poor aryl iodides (5, yield
78%). The same effect was observed for compounds 6 and 7,
obtained with comparable yields (54–58%). The sensitivity to
the electronics on the aryl halide increases when more elec-
tron-poor phenols are used. A comparison between 3–5, 8–10,
11, and 12 highlights this effect.[50] A similar trend can be ob-
served for the phenol. When electron-withdrawing aryl halides
are used, the reaction is relatively insensitive to the electronics
on this moiety (compounds 5, 10), but using electron-rich hal-
ides the reaction becomes considerably dependent on the
substituent (compounds 3, 4, 8, 11). b-Naphthol reacted with
iodobenzene giving 15 in 71% yield, whereas electron-rich or
unsubstituted phenols coupled with novel N-phenylindazole
substrates to furnish products 16–19 in good yields (63–89%);
no coupling with the chlorinated ring was observed for com-
pounds 17–19. This type of indazolic nucleus is of importance
because of their applications in medicinal chemistry, for exam-
ple in glucocorticoid receptor modulators.[51–54] Reactions using
2-hydroxypyridine and 8-hydroxyquinoline as nucleophiles
were also investigated. Unfortunately, no reaction was ob-
served under the optimised conditions. However, the use of
6-methyl-2-pyridone resulted in selective arylation of the hy-
droxy group, with moderate to low yields (compounds 20 and
21). 8-Hydroxyquinaldine was more reactive, leading to com-
pounds 22 and 23 with 37 and 65% yields, respectively. O-ary-
lation of 2-pyridones is known to be a challenging process,
with most of the literature data showing a strong preference
for the N-arylation.[55–58] However, substitution at the 6-position
proved to inhibit N-arylation,[56,58] facilitating O-arylation in-
stead,[59] as observed in our case. The latter selectivity can also
be favoured by hindered aryl halides, as demonstrated by
Buchwald.[56] In the case of 8-hydroxyquinoline, taking into ac-
count the stabilisation of its CuII complexes (see below), the
failure of the coupling is not entirely surprising,[56] although
this substrate can react at higher temperature or by using mi-
crowave techniques.[56,60,61] In 8-hydroxyquinaldine, the methyl
group might act as a destabilising agent for its copper com-
plex, thus making the substrate more available for the
coupling. Due to their ligating ability, these substrates would
probably require different reaction conditions to react
properly.
Table 1. Screening of solvent, base and Cu source.[a]
Entry
Solvent
Base
Cu source
Yield [%][b]
1
2
3
4
5
6
7
8
MeCN
DMSO
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Cu0 powder
CuBr
CuCl
84
43
61
48
59
17
32
8
70
22
76
78
72 (70)[c]
81
NMP
dioxane
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Na2CO3
K3PO4
9
10
11
12
13
14
tBuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
[d]
CuCl2
[a] Conditions: 3,5-dimethylphenol (1.2 mmol), 4-iodoanisole (1.0 mmol),
base (2.0 mmol), Cu source, (0.1 mmol), ligand L27 (0.1 mmol), solvent
(2 mL); 908C, 24 h, under air; [b] GC yields using p-cymene as internal
standard; [c] 4 mL of solvent were used; [d] anhydrous.
Table 2. Optimisation of the reaction for ligand L27.[a]
Entry
Equiv Cs2CO3
CuI/L27 [mol%]
t [h]
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
9
3.0
1.5
1.0
2.0
2.0
2.0
2.0
2.0
2.0
10/10
10/10
10/10
5/5
24
24
24
24
24
24
18
12
24
90
90
90
90
90
90
90
90
80
77
73
52
66
71
78
77
62
68
5/10
10/20
10/10
10/10
10/10
[a] Conditions: 3,5-dimethylphenol (1.2 mmol), 4-iodoanisole (1.0 mmol),
Cs2CO3, CuI, ligand L27, MeCN (2 mL), under air; [b] GC yields using p-
cymene as internal standard.
Ortho-substituted, hindered aryl ethers are found in many
natural products and biologically active molecules. For exam-
ple, polyhalogenated (thyroid hormone thyroxin, antibacterial
triclosan) or polyphenol derivatives (vancomycin and related
macrocyclic compounds) are common naturally-occurring com-
pounds and have different biological effects.[44] Aryl ethers
bearing carbonaceous side chains in the ortho position have
also shown biological activity, for example triclosan derivatives
showing antimalarial effects[62,63] and thyroid receptor antago-
nists derived from thyroxin.[64] Other examples can be found of
various medicinal applications of substituted aryl ethers.[41–43]
The formation of such hindered aryl ethers in Ullmann chemis-
try is rare, especially in intermolecular reactions, and only
a few examples have been reported.[10,19,65–69] Interesting results
um carbonate did not lead to any improvement, but decreas-
ing the amount of base led to a decrease in yield (Table 2, en-
tries 1–3). The use of 5 mol% of copper iodide also led to de-
creased yields (Table 2, entries 4 and 5), and higher amounts of
ligand did not have any beneficial effect (entry 6), so the initial
ratio 1:1 (10 mol% each) was considered optimal. Finally, either
reducing the reaction time or lowering the temperature
resulted in lower yields (Table 2, entries 7–9).
With the optimised conditions in hand, the scope of the re-
action was investigated. The results are reported in Scheme 2.
The reaction between activated phenols and deactivated (elec-
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Scheme 2. Substrate scope, isolated yields (X=I if not specified otherwise).
were obtained with bulky substrates in our system (Scheme 2).
A comparison of the yields for compounds 3 and 4 with those
of 24 and 25 shows how just the presence of the substituent
on the electron-rich aryl halide in the ortho position, instead of
the para, reduces the yields by 40–50%, although the yields
remain remarkable for such substrates. Compound 26, bearing
steric hindrance on both substrates, was obtained in 42%
yield, comparable with 24 and 25. The similar results suggest
insensitivity to the steric hindrance on the phenol. When the
reaction was performed using o-cresol as a nucleophile (com-
pounds 27 and 28), high yields were obtained, comparable
with those obtained for non-hindered compounds 3–5. This
effect was further demonstrated by the synthesis of com-
pounds 30–33, bearing increasingly bulky ortho substituents,
obtained in 52–81% yields. Strong sensitivity to the steric hin-
drance on the aryl iodide (see also compound 38, Scheme 3a),
but not (or to a much lesser extent) to that on the phenol, was
also observed by Hsieh and Ma using different systems.[67,69]
Couplings with hindered phenols and deactivated iodoanisole,
or with indazole precursors, were also accomplished in very
Scheme 3. Radical clock experiments.
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good yields (34–36; see also compound 41, Scheme 3b). Inter-
estingly, the use of 2,6-dimethylphenol in the reaction led to
considerably lower yields than other phenols (compounds 30,
57% and 34, 53%). Even lower yields for the use of 2,6-dime-
thylphenol were reported by Buchwald, Wu and Qian.[10,66,68]
Better results with this substrate were later reported by Buch-
wald using a different ligand.[19] Very hindered groups, such as
tert-butyl and tert-amyl are rarely found in Ullmann ether syn-
thesis, and, to our knowledge, only a single example of the
use of o-tert-butylphenol in the coupling with iodobenzene
was reported by Hsieh.[67]
a very fast reaction,[78,79] some authors have argued that the
coupling with the nucleophile might be faster than the radical
closure, thus invalidating the test.[72,80] To rule out this possibili-
ty, we performed the same reaction in the absence of phenol
1, but 81% (L27) and 72% (L11) of unreacted iodide 37 was
isolated at the end of the reaction (Scheme 3a). No other com-
pounds were detected in the reaction mixture.
Early research demonstrated that CuII species could be re-
duced during the reaction, thus leading to the active CuI.[81,82]
This reduction process in the presence of phenols would lead
to the formation of phenoxy radicals, as occurs in copper-
based oxidase enzymes.[83] The high yields obtained with hin-
dered phenols, together with their ability to stabilise phenoxy
radicals,[84] prompted us to investigate this possibility. Although
phenoxy radicals typically isomerise to carbon-centred radicals,
leading to the formation of CÀC or CÀO dimers,[84] which were
not observed during the reaction, we reasoned that, if the O-
centred radical was stabilised through copper coordination,
the use of a cyclisation radical clock experiment may be envis-
aged, as a similar process occurs for corresponding aliphatic
alkoxy radicals.[85] Thus, we used 2-allylphenol (40) in coupling
reactions with 4-iodoanisole (2). However, the reaction with
either L11 or L27 led to the coupling product 41 with high iso-
lated yields, without trace of the cyclisation product 42 or
other side products (Scheme 3b). To be sure of the non-in-
volvement of a radical intermediate, we also carried out the re-
action of 4-iodoanisole (2) without phenol using both ligands,
with and without TEMPO (1 equiv). In all cases, >99% of 2
was unreacted after 24 h. Leaving either phenol 1 or 40 under
the reaction conditions in the absence of aryl iodide, resulted
in about 30% (40) or 50–60% (1) of phenol left in the crude
reaction, with both ligands.[86] Similar results were obtained
with 1 equivalent of TEMPO added to the reaction. Again, no
side products or TEMPO-trapped compounds were detected in
solution.
Despite their lower reactivity toward SNAr reactions than
bromides and chlorides, strongly electron-poor aryl iodides
have been reported to react even in the absence of copper
catalyst.[70] To verify this, we performed the synthesis of com-
pounds 13, 14, 21, 23 and 29 without Cu or ligand. Products
13, 14 and 29 were obtained with similar yields, thus demon-
strating a non-catalytic SNAr process in these cases. However,
compound 21 was not obtained under these experimental
conditions, and compound 23 was obtained only in 16% yield
(Scheme 2).
The use of aryl bromides in the reaction, in particular the
electron-rich bromoanisole, for the synthesis of 3, 8, 11, 27, 34
and 35 did not furnish high yields under our catalytic condi-
tions. However, reaction was still observed even with electron-
poor phenols (11, 10%) and 2,6-dimethylphenol (34, 22%),
which suggests that improvements are possible.
Radical trap experiments
The mechanism of Cu-catalysed couplings is still not certain,
and several authors have reported different possible mecha-
nisms for these reactions. In particular, oxidative addition/re-
ductive elimination cycles involving CuI/III species and single
electron transfer (SET) mechanisms involving CuI/II species are
the mechanisms on which much debate has arisen.[71–74] The
large difference in catalytic activity of ligands L11 and L27 in
air, although being quite similar under anaerobic conditions
(Figure 3b), prompted us to perform some mechanistic investi-
gations, aiming to gain an explanation for such a difference
and an understanding of the role of the substituents on the
ligand.
Recovery of end-of-life CuII species: the role of the ligand
Although no evidence was obtained for a radical mechanism
(furnishing or derived from CuII species), the presence of CuII
species was proven by the isolation of CuII complexes of the
type [Cu(ligand)2] at the end of the reaction, with several of
the anionic ligands tested. Single crystals suitable for X-ray dif-
fraction were obtained with ligands L5 and L9 directly by slow
evaporation of the crude filtrate and successive washing with
water and diethyl ether. CuII complexes with picolinamide li-
gands were obtained as powders and, following recrystallisa-
tion, led to single crystals of [Cu(L24)2] (vapour diffusion, DCM/
Et2O), [Cu(L26)2(H2O)] (evaporation of acetone solution) and
[Cu(L32)2] (vapour diffusion, DCM/Et2O). X-ray crystal structures
for these complexes are depicted in Figure 4; a discussion on
the crystal structures and selected bond lengths and angles for
Cu-picolinamide complexes are reported in the Supporting In-
formation. It is worth noting that the recovered complexes are
formed with ligands that performed well in the catalysis. To
our knowledge, this is the first example of end-of-life copper
species recovered from Ullmann-type reactions.
Having observed the formation of blue/green compounds in
the reaction tubes,[75]we suspected the formation of CuII spe-
cies during the reaction. Because CuII intermediates were sug-
gested to be formed from CuI during SET radical-chain mecha-
nisms,[76,77] we performed radical clock experiments, with both
ligands L11 and L27, to investigate the presence of radical in-
termediates in the reaction (Scheme 3a). Using ligand L27, the
coupling between 2-(3-butenyl)iodobenzene (37) and 3,5-di-
methylphenol (1) led to the formation of the aryl ether 38 in
40% yield, and a further 40% of unreacted starting material
was recovered. The same reaction with L11 led, as expected,
to a lower yield of 38 (ca. 25%), while approximately 50% of
the starting aryl iodide was recovered. The radical cyclisation
product 39 was not recovered or detected after the reactions.
Although the intramolecular radical cyclisation is known to be
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Figure 4. End of life CuII species (50% probability ellipsoids, hydrogen atoms omitted for clarity).
The formation of these complexes from reactions into which
CuI and ligand were introduced in a 1:1 ratio indicates that
a maximum of 50% of the copper can be present in this form.
A related phenomenon was recently reported by Lei, who pro-
posed the disproportionation of CuI to explain the formation
of CuII species.[27] The same process may thus be suggested for
our system. However, Lei suggested the formation of the CuII
species to be a detrimental off-cycle side reaction, making the
active CuI species labile and low in concentration during the
whole reaction, whereas CuII was considered as a spectator
species not involved in the catalysis.[27] Because of the negative
results of the radical clock experiments, the involvement of the
CuII species may be external to the actual mechanism of the re-
action, but the equilibrium between CuI and CuII species might
also be reversible, in which case the CuII species may play an
important role in the reaction, instead of being merely a spec-
tator species. With this idea in mind, we performed further ex-
periments to try to assess the effect of the ligand on the elec-
tronic properties of the copper atom in the reaction. The syn-
thesis of compound 3 was performed in the presence of
TEMPO, l-ascorbic acid and DDQ, with 10 mol% or 1 equiva-
lent of each, with ligands L11 and L27 (Table 3). Although the
addition of 1 equivalent of TEMPO to the reaction did not
result in any significant difference from the standard condi-
tions (Table 3, entry 3),[87] the addition of only 10 mol% of
TEMPO resulted in the formation of 3 in about half the yield
Table 3. Control experiments with TEMPO, l-ascorbic acid and DDQ.[a]
Entry
Yields [%]
L27[b]
L11[b]
1
2
3
4
5
6
7
Standard conditions
TEMPO (10 mol%)
TEMPO (1 equiv)
l-ascorbic acid (10 mol%)
l-ascorbic acid (1 equiv)
DDQ (10 mol%)
87
51
76
77
85
48
9
40
21
41
77
68
39
2
DDQ (1 equiv)
[a] Conditions: 3,5-dimethylphenol (1.2 mmol), 4-iodoanisole (1.0 mmol),
Cs2CO3, CuI, ligand L27, MeCN (2 mL), under air; [b] GC yields using 1,3,5-
trimethoxybenzene as internal standard.
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with each ligand (entry 2), which is in agreement with the pos-
sibility that an electron transfer occurs during the reaction. The
addition of l-ascorbic acid, a common agent for the reduction
of CuII to CuI, resulted in a significant increase in the reaction
yield with ligand L11, whereas it did not particularly affect the
reaction with ligand L27 (Table 3, entries 4 and 5). In contrast,
the addition of 10 mol% of DDQ, an oxidant species, notably
reduced the yield when using ligand L27, leaving unaltered
the result with L11 (Table 3, entry 6). The use of 1 equivalent of
DDQ resulted in almost complete inhibition with both ligands.
Based on these results, and in the absence of evidence for
radical mechanisms, we suggest the tentative mechanism de-
picted in Scheme 4, whereby an initial CuI species A formed
sensitive to the presence of air, although a more oxidative
environment becomes deleterious (addition of DDQ).
Due to the small amounts of CuII complexes recovered from
the reactions, these could not be used in the catalysis without
changing drastically the reaction conditions, but ongoing in-
vestigation shows that preformed complexes of this type are
effective in the catalytic reaction in the same conditions, and
different reduction potentials (CuII to CuI) are actually observed
for these complexes, thus supporting the theory that these
compounds are not just spectator or decomposition species.[88]
Conclusion
During a comparative study of a model coupling reaction, N-
phenylpicolinamide ligands were discovered to be an effective
ligand family for Cu-catalysed aryl ether formation. Electron-
withdrawing substitutents on the phenyl ring of the ligand
proved to lead to the most active catalysts. In particular, ligand
L27 (N-(2-fluorophenyl)picolinamide), was effective in catalys-
ing the coupling between a broad range of substrates in air
and under relatively mild conditions. Excellent results were ob-
tained with sterically hindered phenols, and even tert-butyl
and tert-amyl substituents in the ortho position were well toler-
ated. Ortho-substituted phenols are known to be challenging
coupling partners in Cu-catalysed reactions, and only few ex-
amples have previously been reported. Aryl bromides are not
very reactive under these conditions, although some product
is still formed even with ortho-substituted phenols. Further
modification of the ligand and the conditions might be neces-
sary to increase their reactivity. The first examples of end-of-life
CuII complexes were isolated with several effective ligands,
which we consider fundamental in understanding the mecha-
nism of the reaction. Results from radical trapping experiments
strongly suggest that the reaction does not proceed through
free-radical mechanisms, thus the CuII species observed may
be involved as off-cycle species, which can, nonetheless, be in
equilibrium with an active CuI species. Control reactions using
two different ligands showed that the reaction outcome can
be altered by the addition of an oxidant or reductant species,
with different results for the two ligands. This suggests that
the ligand plays an important part in altering the redox prop-
erties of the metal centre, thus inhibiting or favouring the reac-
tion, and explaining the different results obtained in aerobic or
anaerobic conditions.
Scheme 4. Suggested reaction mechanism.
from CuI undergoes coordination with the nucleophile, fol-
lowed by oxidative addition and reductive elimination to form
the aryl ether. The identity of the active CuI species A is uncer-
tain, and it might be a neutral (L=MeCN) or an anionic species
(L=I). The coordination of the nucleophile may occur before
(B, path i) or after deprotonation (C, path ii), depending on its
electronic properties. This step is followed by an oxidative ad-
dition (D) and a reductive elimination to release the product
and reform A.
CuII species such as those reported above might be in equi-
librium with the active species A; the substituent on the
ligand affects the redox properties of the copper atom, altering
the equilibrium and stabilising the CuII or CuI state to different
extents (Scheme 4). The low yields obtained with the addition
of TEMPO may be due to the inhibition of this redox process,
in one direction or the other. The different effect that air plays
on the two ligands (Figure 3b) can be explained in that ligand
L11 requires a more reductive environment to be efficient (ad-
dition of ascorbic acid), which favours the formation of the
active copper species from CuII, whereas L27, already facilitat-
ing the formation of the active CuI species, is not particularly
Acknowledgements
We are thankful to AstraZeneca UK for funding, and to Drs.
Helena J. Shepherd and Christopher M. Pask for help with the
crystallographic data.
Keywords: aryl ethers · copper · cross-coupling · N ligands ·
structure–activity relationships
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Published online on && &&, 0000
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FULL PAPER
&
Copper Catalysis
C. Sambiagio, R. H. Munday,
S. P. Marsden, A. J. Blacker,
P. C. McGowan*
&& – &&
Picolinamides as Effective Ligands for
Copper-Catalysed Aryl Ether
Formation: Structure–Activity
Relationships, Substrate Scope and
Mechanistic Investigations
Picolinamides for Ullmann coupling: A
structure–activity relationship study
using picolinamide ligands for Cu-cata-
lysed aryl ether synthesis is reported.
Electron-withdrawing substituents on
the ligand allow the coupling of a broad
range of substrates in air, including ster-
ically hindered compounds, normally
challenging substrates. Preliminary
mechanistic investigation shows how
the substituents on the ligand might
influence the redox properties of the
metal centre.
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