Efficient and Mild Ullmann-Type N-Arylation of Amides, Carbamates, and Azoles in Water

Article abstract of DOI:10.1002/chem.201700832

A simple, sustainable, efficient, mild, and low-cost protocol was developed for d-glucose-assisted Cu-catalyzed Ullmann reactions in water for amides, carbamates, and nitrogen-containing heterocycles. The reaction was compatible with diverse aryl/heteroaryl iodides, giving highly substituted pyridine, indole, or indazole rings. This method offers an attractive alternative to existing protocols, because the reaction proceeds in aqueous media, occurs at or near ambient temperature, and provides the N-arylated products in good to high yields.

Full text of DOI:10.1002/chem.201700832

A Journal of
Accepted Article
Title: Efficient and mild Ullmann-type N-arylation of amides,
carbamates, and azoles in water.
Authors: Maud Bollenbach, Pedro G. V. Aquino, Joao Xavier de
Araujo-Junior, Jean-Jacques Bourguignon, Frédéric Bihel,
Christophe Salome, Patrick Wagner, and Martine Schmitt
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201700832
Link to VoR: http://dx.doi.org/10.1002/chem.201700832
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10.1002/chem.201700832
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Efficient and mild Ullmann-type N-arylation of amides,
carbamates, and azoles in water.
Maud Bollenbach,[a]# Pedro G. V. Aquino,[a,b]# João Xavier de Araújo-Júnior,[b] Jean-Jacques
Bourguignon,[a] Frédéric Bihel,[a] Christophe Salomé,[a,c] Patrick Wagner[a] and Martine Schmitt*[a]
Abstract:
A
simple, sustainable, efficient, mild, and low-cost
accelerating the reaction rate owing to the aggregation of
reactants in the unique micellar environment.[10] Very recently,
our group highlighted the efficiency of D-glucose to generate
Cu(I) species from a Cu(II) source for conducting the N-arylation
of primary amines in water at 25 C.[11] However, this new
catalytic system (Cu(OTf)2/D-glucose, dipivaloylmethane, NaOt-
Bu) failed when other classes of amines were used. N-
arylamides represent an important class of compounds found in
numerous bioactive products[13] such as top-selling medicines
(e.g., Lipitor®, Liloderm®, and Vyvanse®)[14] as well as biological
and synthetic polymers (e.g., proteins and nylons);[15,16] they also
serve as versatile building blocks in the preparation of
pharmaceuticals, agrochemicals, polymers, etc.[17] Therefore, we
continued our efforts to develop Cu-catalyzed cross-couplings in
aqueous media for that class of amine.[12] Herein, we report a
simple, practical, and efficient D-glucose-assisted Cu-catalyzed
N-arylation of amides, carbamates, and nitrogen-containing
heterocycles. Our approach includes i) use of an inexpensive
Cu(II) catalyst, ii) presence of renewable feedstocks (D-glucose
protocol was developed for D-glucose-assisted Cu-catalyzed
Ullmann reactions in water for amides, carbamates, and nitrogen-
containing heterocycles. The reaction was compatible with diverse
aryl/heteroaryl iodides, giving highly substituted pyridine, indole, or
indazole rings. This method offers an attractive alternative to the
existing protocols, because the reaction proceeds in aqueous media,
occurs at or near ambient temperature, and provides the N-arylated
products in good-to-high yields.
Introduction
The formation of transition-metal-catalyzed C–N bonds via
cross-coupling reactions plays an important role in the
preparation of numerous important products in biological,
pharmaceutical, and material sciences.[1] Formation of C–N
bonds by Ullmann and Goldberg coupling reactions provides a
powerful tool to prepare these nitrogen-containing compounds
on both laboratory and industrial scales.[2] However, the classic
Ullmann and Goldberg coupling reactions suffer from drawbacks
such as harsh reaction conditions, including high reaction
temperatures (160–200 C), extended reaction times, and the
use of large amounts of Cu, and low tolerance of functional
groups.[3] In 2001, an important breakthrough was achieved by
two research groups with the discovery of efficient and versatile
Cu/ligand systems that enable these cross-coupling reactions to
occur under much milder conditions (90–110 C).[4,5] Since the
last decade, the formation of C–N bonds by Cu-mediated cross-
coupling approaches has led to a spectacular resurgence of
interest.[6-8]
100
80
60
40
20
From economic and environmental point of view, water as a
solvent is a good alternative to organic solvents;[9] wide
applications of N-arylated compounds in many fields have
stimulated the development of new strategies for their synthesis
in water. However, reactions in water suffer from the poor
solubility of organic reagents in aqueous media. A micellar
system can improve the solubility of components, thereby
0
L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 W/L
Ligands
NaAsc
D-Glucose
[a]
M. Bollenbach, P. G. V. Aquino, Dr. J.-J. Bourguignon, Dr. F. Bihel,
Dr. C. Salomé, P. Wagner, Dr. M. Schmitt
Université de Strasbourg, CNRS, LIT UMR 7200 F-67000
Strasbourg France
E-mail: mschmitt@unistra.fr
[b]
[c]
P. G. V. Aquino, Dr. J. X. de Araújo Jr.
Laboratório de Pesquisa em Recursos Naturais, UFAL, Maceió,
Brazil
Dr. C. Salomé
Figure 1. Copper catalyzed amidation of 3-iodotoluene in TPGS-750-M at
50 °C: Impact of various ligands in presence of NaAsc or D-Glucose.
aReaction conditions: CuSO4. 5H2O (10 mol%), ligands (20 mol%), NaOt-Bu (2
equiv.), 3-iodotoluene (1 equiv.), 4-methoxybenzamide (1.2 equiv.), TPGS-
750-M (2 wt%), 50 °C, 20 h. bAverage yield of 2 runs. cYields were determined
by HPLC/UV using benzophenone as an external standard.
SpiroChem AG, c/o ETH-Zürick, Vladimir-Prelog-Weg 3, 8093
Zürich, Switzerland
# These authors contributed equally to this work
Supporting information for this article is given via a link at the end of
the document.
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100
80
60
40
20
0
NaAsc
D-Glu
NaAsc
D-Glu
L9
50°C
L10
25°C
Figure 2. Copper catalyzed amidation of 3-iodotoluene in TPGS-750-M at
50 °C: Impact of ligands loading (L8, L9 and L10) in presence of NaAsc or D-
glucose. aReaction conditions: CuSO4. 5H2O (10 mol%), ligands (20 mol% or
10 mol%), NaOt-Bu (2 equiv.), 3-iodotoluene (1 equiv.), 4-methoxybenzamide
(1.2 equiv.), TPGS-750-M (2 wt%), 50 °C, 20 h. bAverage yield of 2 runs.
cYields were determined by HPLC/UV using benzophenone as an external
standard.
Figure 3. Copper catalyzed amidation of 3-iodotoluene in TPGS-750-M at 25
or 50 °C: Impact of ligands (L9, and L10) in presence of NaAsc or D-Glucose.
aReaction conditions: CuSO4. 5H2O (10 mol%), ligands (10 mol%), NaOt-Bu (2
equiv.), 3-iodotoluene (1 equiv.), 4-methoxybenzamide (1.2 equiv.), TPGS-
750-M (2wt%), 25 or 50 °C, 20 h. bAverage yield of 2 runs. cYields were
determined by HPLC/UV using benzophenone as an external standard.
50% and 57% yields, respectively. The replacement of NaAsc
with D-glucose led to a slight increase in the yield. Further
screening with racemic trans-di–methyl 1,2-cyclohexyldiamine
(L10) resulted in a satisfactory yield (75% with NaAsc and 81%
with D-glucose).
and TPGS-750-M composed of vitamin E), iii) absence of
organic solvents, and iv) broad substrate scope of both
nucleophiles and aryl or heteroaryl iodides.
Results and Discussion
First, 3-iodotoluene 1 and 4-methoxybenzamide 2a were used
as the prototypical substrates to establish the most suitable
conditions for our new catalytic system. CuSO4 was selected as
the Cu source as it was successfully used by Wang in
combination with sodium ascorbate (NaAsc) in DMSO at 100 C
in a ligand-free N-arylation.[18] However, the target product was
not observed at 50 C when the reaction was performed in water
supplemented with TPGS-750-M (2 wt%) in combination with
either NaAsc or D-glucose (Figure 1). Different reaction
parameters were investigated to improve this coupling reaction
in water (Figures 1–4). In particular, different commercially
available ligands were tested using 10 mol% CuSO4 as the
Cu(II) catalyst, 10 mol% of NaAsc or D-glucose as the reducing
agent, and 2 equiv of NaOt-Bu as the base in TPGS-750-M (2
wt%) at 50 C. As reported previously, the linear β-keto ester
(THMD) was inactive.[11] Reactions promoted by different
bidentate N, O (L2, L7) or O, O (L3, L5, and L6) chelators gave
only traces of compound (Figure 1). Phenanthroline (L4) did not
effectively help the Cu salts to improve the yield of 3a. However,
bidentate N, N–ligands such as dimethylethylenediamine
(DMEDA, L8) or racemic (L9) showed a promising effect with
100
80
60
40
20
0
Figure 4. Impact of copper(II) salts : aReaction conditions: Copper(II) (10
mol%), L10 (10 mol%), NaOt-Bu (2 equiv.), 3-iodotoluene (1 equiv.), 4-
methoxybenzamide (1.2 equiv.), TPGS-750-M (2wt%), 25 °C, 20 h. bAverage
yield of 2 runs. Yields were determined by HPLC/UV using benzophenone as
an external standard.
c
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Further investigation revealed the nonefficacy of aryl bromide
and triflate (SI Figure S2). Various surfactants were also tested
under the optimized conditions, but none of them showed a
higher performance than TPGS-750-M 2% (Figure 5).
In the absence of surfactant, no reaction was observed. Only
moderate yields were obtained when Brij 30 (45% yield), tween
(53% yield), triton (57% yield), and TPGS 1000 (65% yield) were
used. Surprisingly, the third-generation sterol-based surfactant
Nok[19] was inefficient under those conditions. This may be
explained by the difference in the geometry of the micelles
obtained using Nok (worm-like micelles) compared to those
obtained using TPGS-750-M (spherical particles).
100
80
84
65
57
53
60
40
20
0
45
1
1
1
0
Lastly, it is important to notice that NaOt-Bu can be replaced by
NaOH with only a slight decrease of yields (5-10%) for the N-
arylation of 3a and 3k (see Table S1). However, in order to get
the best yield, we choose to run the reaction in presence of
NaOt-Bu.
Figure 5. Impact of the surfactants aReaction conditions: CuBr2 (10 mol%),
L10 (10 mol%), NaOt-Bu (2 equiv.), 3-iodotoluene (1 equiv.), 4-
methoxybenzamide (1.2 equiv.), TPGS-750-M (2 wt%), 25 °C, 20 h. bAverage
Scope and limitations
Under the optimized set of conditions (10 mol% CuBr2, 10 mol%
racemic trans-dimethyl 1,2-cyclohexyldiamine (L10), 10 mol% D-
glucose, 2 equiv. NaOt-Bu in TPGS-750-M (2 wt%, 1 M
substrate concentration) at 25 C), the scope and versatility of
the reaction were investigated using variously substituted aryl
iodides 1 and acetanilides 2 to prepare the corresponding
benzanilides 3 at 25 or 50 C depending on the solubility of the
reactant. The results are shown in Table 1. Acetanilides
substituted with electron-withdrawing as well as electron-
donating groups such as MeO, SMe, Cl, Br, CF3, NH2, and NO2
were well tolerated in the reaction, giving the corresponding
benzanilides 3 in good yields. We were particularly pleased to
find that 3l could be efficiently prepared by this protocol as
trifluoromethyl-substituted amides serve as important building
blocks in the preparation of diverse agrochemicals and
pharmaceuticals.[20] Finally, the reaction of 2-aminobenzamide
with 3-iodotoluene proceeded in an excellent yield and with
complete selectivity for the reaction of the amide group (3r). This
N-arylation was also amenable to diverse iodoaryl coupling
partners including different electronic and steric substituents.
The reaction tolerated diverse functional groups such as ester
(3t), ketone (3l), trifluoromethyl (3n), and nitrile (3f and 3k).
Moreover, the use of an unprotected hydroxymethyl group
enabled the arylation (3q, 63%). Particularly noteworthy is the
reactivity difference exhibited by arylbromide versus aryliodide
towards oxidative addition. The reaction of benzamide with 4-
bromoiodobenzene at 50 C occurred on the iodine moiety with
complete regioselectivity (3m, 79%). To further expand the
scope of substrates, alkyl (3s, 3u) and aralkyl (3v, 3w)
acetanilides were subjected to the standard reaction conditions;
the target products were obtained in satisfactory yields (54–
79%). Starting from the highly soluble acetamide, an excess of
the amide was needed (5 equiv) to achieve a yield of 60% at
50 C (3s). The reaction was also successfully extended to
c
yield of 2 runs. Yields were determined by HPLC/UV using benzophenone as
an external standard.
Next, we evaluated the lower limit of ligand/catalyst ratio
compatible with high yields. This ratio significantly affected the
amidation cross-coupling reaction (Figure 2). In presence of
NaAsc, reducing the catalyst/ligand ratio from 1:2 to 1:1
improved the formation of 3a with either ligand L9 or L10. D-
glucose was found to be independent of the ligand/metal ratio as
comparable yields were obtained in both the cases. In contrast
to L8, a significant decrease in the catalytic activity was
observed in the presence of both the reducing agents. Finally, a
decrease in the amount of CuSO4 to 5% led to an incomplete
consumption of 3-iodotoluene, or the reaction was inefficient (SI
Figure S1).
Then, the effect of temperature was evaluated. Attempts to
couple the iodohalides with amide 2a at room temperature failed
when L9 was used in combination with either NaAsc or D-
glucose. However, when the reaction was conducted using L10
in the presence of D-glucose, this coupling was achieved even
at room temperature. The use of NaAsc gave a lower yield
under the same conditions.
The reaction was also carried out using different Cu sources as
shown in Figure 3. Among them, CuSO4, CuBr2, CuNO3, and
Cu(OTf)2 were found to have the same efficacy with a yield of
80%. Other Cu salts such as CuO, CuCl2, and Cu(OAc)2
provided slightly lower yields, while a significant drop of 20%
conversion was observed with amorphous CuFe2O4. CuBr2 was
selected for this study because of its cost-effectiveness.
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Table 1 : Scope of amides and carbamates derivatives
Reaction conditions : CuBr2 (10 mol%), L10 (10 mol%), D-glucose (10 mol%), NaOt-Bu (2 equiv.), ArI (1 equiv.), RCONH2 (1.2 equiv.), TPGS-750-M (2 wt%),
25 °C, 24 h. aYields refer to isolated, chromatographically, purified materials. bUnpublished products were fully characterized by NMR and HR-MS data. cReaction
carried out at 50 °C. dUse of TPGS-750-M (5 wt%). eAmide (3 equiv.). fAmide (5 equiv.). gQuenched with NH3. hProduct isolated by precipitation.
heteroaromatic amides. In the case of the reaction with
nicotinamide, only 11% of the target product 4a was observed
under standard conditions. Interestingly, when the reaction was
carried out with 3 equiv of the amide, the yield became 57%.
Under the same conditions, N-aryl pyrazine- (4b) and furan- (4c)
carboxamide derivatives were obtained in 47% and 69% isolated
yields, respectively.
To further evaluate our methodology, we attempted reactions
with heteroaryl iodides. As shown in Table 1, generally the
desired coupling products 5 were obtained in moderate-to-good
yields depending on i) the position of the iodide and ii) the
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Table 2 : Scope of NH heterocycles
Reaction conditions : CuBr2 (10 mol%), L10 (10 mol%), D-glucose (10 mol%), NaOt-Bu (2 equiv.), ArI (1 equiv.), HetNH (1.2 equiv.), TPGS-750-M (5 wt%), 50 °C,
24 h. aYields refer to isolated, chromatographically, purified materials. bUnpublished products were fully characterized by NMR and HR-MS data. cReaction carried
out at 25 °C. dUse of TPGS-750-M (2wt%). eNucleophile (3 equiv.). fNucleophile (5 equiv.). g18% on N2. h12% on N2. iPreformulated.
reaction conditions. N-arylation of 3-iodothiophene was
conducted at 25°C, and the target product 5a was isolated in
89% yield. Similarly, the catalytic system was suitable for the
amidation of 3(4)-iodopyridine derivatives, providing 5d and 5e
in moderate yields (40%). A significant improvement (+20% in
yield) was achieved by quenching the reaction mixture with
ammonia (67% for 5d and 58 % for 5e). The N-arylation of 2-
iodopyridine or thiophene was tedious even at 50 C (5f, 41%,
5c, 59%). The presence of a second halogen in the pyridine
moiety increased the efficiency of the coupling reaction as
and 3-iodotoluene, the N-arylated compound 5l was isolated in
69% yield.
The reaction was affected by the steric hindrance of the
nucleophile, because although cyclic aliphatic secondary amides
such as pyrrolidine-2-one or its homolog (n = 0) afforded the
coupling product 3x in good yields, no reaction was observed
starting from the acyclic N-methylbenzamide.
Of particular interest was the reaction with tert-butylcarbamate, a
protected ammonia equivalent. The reaction of 3-iodotoluene at
room temperature afforded the target compound 3y in 57%
isolated yield. The use of 5 wt% TPGS-750-M at 25 C or 50 C
improved the yield of 3y to 64% and 71%, respectively. Similar
results were obtained starting from 3-iodothiophene 5b. Next,
shown by 5h (71%) and
highly
functionalized
pyridine
derivatives 5j (70%)[21a] and 5k[21b] (63%). Finally, the cross-
coupling reaction was also effective when two heterocyclic
partners were used. In particular, starting from 2-thienylamide
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the N-arylation of oxazolidin-2-one with iodobenzene was
performed. N-aryloxazolidin-2-ones have gained significant
interest in the recent decade as illustrated by the FDA-approved
drugs: Toloxatone®[22] and Rivaroxaban®[23]. Under the micellar
conditions, the five-membered ring cyclic carbamate (3z) was
isolated in 68% yield.
To broaden the scope of our arylation protocol, the efficiency of
our catalyst–ligand systems was evaluated for reactions
involving weak nucleophilic nitrogen atoms such as azoles. The
coupling of azoles is of great importance to the pharmaceutical
industry. Pharmaceuticals incorporating this privileged motif
display diverse biological activities such as anti-inflammatory,
antiviral, antimicrobial, and anticancer activities.[24] Therefore,
the development of efficient methods to access highly
functionalized azole derivatives with respect to sustainable
chemistry is highly desirable.
Scheme 2: Gram-scale experiments
Notably, our method provided
a
straightforward way to
synthesize an advanced intermediate for the preparation of
As shown in Table 2, representative couplings involving pyrrole,
pyrazole, indole, and indazole ring-containing substrates
afforded the desired N-arylated coupling products 6 in moderate-
to-good yields (43–95%) at 25 C or 50 C in TPGS-750-M 5
wt%. Attempts to N-arylate 1,2,4-triazole with 3-iodotoluene
failed at 50 C even with a higher loading of ligand (Cu:L  1:2
and 1:4). The arylating agent was recovered after 20 h heating.
The efficiency of the reaction was affected by the steric
hindrance of an adjacent substituent as no reaction was
observed starting from 2- or 7-substituted indoles and 7-
substituted indazoles. However, displacement of the substituent
from positions 2 to 3, or 7 to 6 restored the efficiency of the
reaction, and 6fa, 6fb and 6rb were obtained in respectively
77%, 90% and 91% isolated yields.
AZD-7594 actually under active development (Phase II) for
chronic
obstructive
pulmonary
diseases
(COPD).[25]
Unfortunately, under our standard conditions, only 54% of the
expected N1-Aryl indazole 6y was isolated after the
purification.Beside the remaining starting materials, we also
observed the formation of a small amount of his regioisomer, the
N2-Aryl indazole 6z with a N1/N2-selectivity of 1:6. Addition of
an organic solvent (THF) to the reaction mixture, as recently
reported by Gallou and coworkers,[26] was the key to success.
The presence of
a
co-solvent channeled the reactive
components of the system between water and the lipophilic
micellar interior, playing both the roles of slightly increasing the
solubility and rate of dissolution. To our pleasure, under these
new conditions the target product 6y was isolated in 87% yield
(6z: 13%).
Azoles bearing both electron-donating and -withdrawing
substituents coupled smoothly, affording the target products 6 in
good yields and with a high tolerance of several functional
groups (CF3, CN, CHO, NO2, F, Cl, Br, and OMOM).
Unfortunately, as shown in Table 2, the methodology is not
compatible with free phenol. However, when the phenol is
protected (6n, OMOM), the desired product was obtained in a
moderate yield of 44%. Notably, halogen substituents such as Cl
and Br were well tolerated (6c, 6h–i, 6q, and 6u–x), thus
providing handles for postcoupling transformations.
To demonstrate the usefulness of this novel N-amidation
protocol, two gram-scale experiments were carried out under the
standard conditions. Using 3-iodobenzonitrile (10 mmol) and
benzamide, the corresponding N-(3-cyano-phenyl)benzamide 3k
was isolated in 78% yield. In addition, the reaction with indole
and 3-iodotoluene also proceeded smoothly, affording product
6e in 76% yield.
All the final compounds 3–6 were purified by flash
chromatography using a step gradient algorithm to i) optimize
the separation of the target compound and ii) use a minimal
amount of solvent. However, to avoid the column
chromatography step, we also developed a greener procedure
to recover the final solid compounds. The strategy was based on
a convenient purification procedure based on precipitation upon
the addition of water. The micellar media was first extracted with
isopropyl acetate and then passed through a cotton-wool filter to
remove traces of Cu. The filtrate was concentrated under
vacuum and then diluted with isopropanol. After the precipitation
from cold water and filtration, this procedure allowed the
isolation of 3a and 5l in 67% and 60% yields (Table 1),
respectively, and the purity was higher than 98% (determined by
HPLC). For these two examples, the reaction was run on a small
Scheme 1: Synthesis of an advances intermediate for the preparation of AZD
7594.
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2 equiv.), CuBr2 (10 mol%), trans-N,N’-dimethylcyclohexane-1,2-diamine
(10 mol%) and D-glucose (10 mol%) were added and the resulting
mixture was stirred (at 1200 rpm) at 25 °C or 50 °C (20 h). The mixture
was extracted twice with 3 mL of isopropyl acetate. The combined
organic layers were evaporated and the crude residue was purified by
chromatographic column on silica gel using n-heptane and ethyl acetate
as eluent.
4-Methoxy-N-(3-methylphenyl)benzamide 3a
Cycle
1
2
3
Prepared following the general procedure, using CuBr2 (11.2 mg, 0.050
mmol), trans-N,N’-dimethylcyclohexane-1,2-diamine (7.9 µL, 0.050
mmol), D-Glucose (9.0 mg, 0.050 mmol), 3-iodotoluene (64.2 µL, 0.500
mmol), 4-methoxybenzamide (90.7 mg, 0.600 mmol) and NaOt-Bu (99
mg, 1.000 mmol) in aqueous TPGS-750-M (2 wt %, 0.50 mL), followed
by purification using column chromatography (SiO2) and n-heptane/ethyl
acetate (7:3), yielded 3a as a white solid (98 mg, 0.405 mmol, 81%). mp
= 117-119 °C; 1H NMR (400 MHz, CDCl3) δ ppm 2.34 (s, 3H), 3.87 (s,
3H), 6.95-6.97 (m, 3H), 7.25 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H),
7.51 (s, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.87 (br s, 1H); 13C NMR (101 MHz,
CDCl3) δ ppm 21.5, 55.4, 113.9, 117.2, 120.8, 125.1, 127.2, 128.8, 128.9,
138.0, 138.9, 162.4, 165.2.
Yield [%]
95
88
79
Figure 6. Recycling of the copper catalyst and the micellar phase
scale (see SI). Scale-up of the synthesis from laboratory scale to
pilot scale will probably maximize the precipitation of the
expected final compounds and in fact improve the product yields.
In order to investigate the greener and economical aspects of
the developed catalytic system, a recyclability study was carried
out for the N-arylation of indole with 3-iodotoluene. As illustrated
in Figure 6 the yield drops from 95% to 88% for the second cycle
and to 79% for the third cycle. These results validated the
possibility to recycle CuBr2. After each cycle, the aqueous
reaction mixture was extracted using diethyl ether to remove all
traces of the product or reactants. The resulting aqueous
solution containing the CuBr2 catalyst was directly used for the
next catalytic cycle.
Acknowledgements
We thank Dr Frédéric Leroux for the gift of 4-Iodo pyridine
trifluoromethyl ether derivative. Financial supports from MNERT
(M.B.) and CAPES-Br (P.G.V. A) are gratefully acknowledged
with thanks. We thanks Dr Gallou (Novartis) for the gift of TPGS-
750-M and ind(az)ols derivatives and Isochem for the gift of
TPGS-1000.
Conclusions
Keywords: amination • amides • NH heterocycle • copper •
We developed a facile, convenient and mild protocol for
aqueous Ullmann cross-coupling catalysis. We successfully
demonstrated that the catalytic system (CuBr2, D-glucose, L10,
and NaOt-Bu) allowed the high-yielding arylation of diverse
nitrogen nucleophiles at relatively low temperatures (25–50 C).
Diverse substituted aryl or heteroaryl iodides were readily
coupled with several amides, carbamates, and azoles. With
respect to azoles, the catalytic system was particularly efficient
for condensations with substituted 3-, 4-, 5- and 6-indazole and
indole derivatives. The method enables the selective conversion
of polyhalogenated aromatics and provides access to
differentially substituted pharmacologically relevant motifs.
Mildness, low-cost, experimental simplicity, and ability to use
water and D-glucose as the reducing agent are the features of
the developed methodology that make it particularly well suited
for industrial-scale syntheses.
micelles
[1]
a) I. P. Beletskaya, A. V. Cheprakov, Coor. Chem. Rev. 2004, 248,
2337-2364; b) E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocomola,
Chem. Rev. 2007, 107, 5318-5365; c) S. V. Ley, A. W. Thomas, Angew.
Chem. Int. Ed. 2003, 42, 5400-5449; d) J. P. Corbert, G. Mignani,
Chem. Rev. 2006, 106, 2651-2710.
[2]
[3]
a) D. S Surry, S. L. Buchwald, Chem. Sci. 2010, 1, 13-31; b) F. Monnier,
M. Taillefer, Angew. Chem. Int Ed. 2009, 48, 6954-6971 ; c) D. W. Ma,
Q. Cai, Acc. Chem. Res. 2008, 41, 1450-1460; d) A. Casitas, X. Ribas,
Chem. Sci. 2013, 4, 2301-2318.
a) K. Kunz, U. Scholz, D. Ganzer, Synlett 2003, 15, 2428–2439, b) E.
J. Hennessy, S. L. Buchwald, Org. Lett. 2002, 4, 269–272, c) J. Lindley,
Tetrahedron 1984, 40, 1433–1456, d) K. Moriwaki, K. Satoh, M. Takada,
Y. Ishio, T. Ohno, Tetrahedron Lett. 2005, 46, 7559–7562.
A. Klapars, J. C. Antilla, X. H. Huang, S. L. Buchwald, J. Am. Chem.
Soc. 2001, 123, 7727–7729.
[4]
[5]
[6]
M. Taillefer, H. J. Cristau, P. Cellier, J. F. Spindler, WO Patent 053,885-
A, 20 December 2002.
a) A. Klapars, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124,
7421–7428; b) D. Audisio, S. Messaoudi, J. B. Peyrat, J. D. Brion, M.
Alami, J. Org. Chem. 2011, 76, 4995–5005; c) F. T. Zhou, J. J. Guo, J.
G. Liu, K. Ding, S. Y. Yu, Q. Cai, J. Am. Chem. Soc. 2012, 134, 14326–
14329.
Experimental Section
General procedure
[7]
a) G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054–
3131; b) G. Evano, N. Blanchard, Copper-Mediated Cross-Coupling
Reactions, John Wiley & Sons, New Jersey, 2014.
Nucleophile (1.2 equiv.) and aryl or heteroaryl halide (1 equiv.) were
added to an aqueous solution of TPGS-750-M (2 wt %, 1 mL/mmol). The
mixture was degassed by bubbling Argon (5 min). NaOt-Bu (97% purity,
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[8]
a) C. Sambiagio, S. P. Marsden, A. J. Blacker and P. C. McGowan,
Chem. Soc. Rev. 2014, 43, 3525–3550; b) F. Monnier, M. Taillefer,
Amination and Formation of sp2 C-N Bonds, (Eds. M. Taillefer and D.
Ma), Springer Berlin Heidelberg, 2013, pp. 173–204.
Breneman, J. F. Liebman, The amide linkage: Structural Significance in
Chemistry, Biochemistry and Material Sciences, John Wiley &sons:
New York, NY 2000; e) T. J. Deming, Prog. Polym. Sci. 2007, 32, 858-
875; f) J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Biomol.
Chem. 2006, 4, 2337-2347.
[9]
a) K. H. Shaughnessy, Chem. Rev. 2009, 109, 643-710; b) A. Chanda,
V. V. Fokin, Chem. Rev. 2009, 109, 725-748; c) K. Bahrami, M. M.
Khodaei, A. Nejati, Green Chem. 2010, 12, 1237-1241; d) X. Li, D.
Yang., Y. Jiang, H. Fu, Green Chem. 2010, 12, 1097-1105; e) O. Saidi,
A. J. Blaker, M. M. Farah, S. P. Marsden, J. M. Williams, Chem.
Commun. 2010, 46, 1541-1543; f) G.-L. Li, K. K.-Y. Kung, L. Zou, H.–C.
Chong, Y.-C. Leung, K. H. Wong, M.–K. Wong, Chem. Commun. 2012,
48, 3527-3529 ; g) J. Feng, G. Lu, M. Lv, C. Cai, J. Org. Chem. 2014,
79, 10561-10567; h) A. Kumar, A. K. Bishnoi, RSC Adv. 2015, 5,
20516-20520.
[17] a) G. W. Wang, T. T. Yuan, D. D. Li, Angew. Chem. 2011, 123, 1416 –
1419; Angew. Chem. Int. Ed. 2011, 50, 1380– 1383; b) X. X. Zhang, W.
T. Teo, P. W. H. Chan, J. Organomet. Chem. 2011, 696, 331- 337.
[18] Z. J. Quan, H. D. Xia, Z. Zhang, Y. X. Da, X. C. Wang, Tetrahedron
2013, 69, 8368-8374.
[19] P. Klumphu, B. H. Lipshutz, J. Org. Chem. 2014, 79, 888-890.
[20] a) F. Lerou, P. Jeschke, M. Schlosser, Chem. Rev. 2005, 105, 827-856;
b) K. Mueller, C. Faeh, F. Dietrich, Science 2007, 317, 1881-1886; c) M.
Shimizu, T. Hiyama, Angew. Chem. Int. Ed. 2005, 44, 214-231; d) P.
Jeschke, ChemBioChem 2004, 5, 570-589.
[10] a) T. Dwars, E. Paetzold, G. Oehme, Angew. Chem. Int. Ed. 2005, 44,
7144–7199; b) K. Ahlford, J. Lind, L. Maler, H. Adolfsson, Green Chem.
2008, 10, 832–835; c) M. Srivastava, J. Singh, S. B. Singh, K. Tiwari, V.
K. Pathak, J. Singh, Green Chem. 2012, 14, 901–905; d) R. D. Shukla,
A. Kumar, Green Chem. 2015, 17, 848-851; e) G. L. Sorella, G. Strukul,
A. Scarso, Green Chem. 2015, 17, 644–683; f) N. Singh, Y. Karpichev,
R. Sharma, B. Gupta, A. K. Sahu, M. L. Satnami, K. K. Ghosh, Org.
Biomol. Chem. 2015, 13, 2827–2848; g) B. H. Lipshutz, F. Gallou, S.
Handa, ACS Sustainable Chem. Eng. 2016, 4, 5838-5849.
[21] Preparation of starting materials : a) C. Doebelin, P. Wagner, F. Bihel,
N. Humbert, C. A. Kenfack, Y. Mely, J. -J. Bourguignon, M. Schmitt M.,
J. Org. Chem. 2014, 79, 908-918; b) B. Manteau, P. Genix, L. Brelot, J.
P. Vors, S. Pazenok, F. Giornal, C. Leuenberger, F. R. Leroux, Eur. J.
Org. Chem. 2010, 31, 6043-6066.
[22] a) F. Moureau, J. Wouters, D. P. Vercauteren, S. Collin, G. Evrad, F.
Durant, F. Ducrey, J. J. Koenig, F. X. Jarreau, Eur. J. Med. Chem. 1994,
29, 269-277; b) D. S. Goldstein, Y. Jinsmaa, P. Sullivan, C. Holmes, I. J.
Kopin, Y. Sharabi, J. Pharmacol Exp. Ther. 2016, 356, 483-492.
[23] a) H. Oberpichler-Schweng, Med. Monatsschr. Pharm. 2008, 31, 412-
416; b) D. Kubitza, M. Becka, M. Zuehlsdorf, W. Mueck, J. Clin.
Pharmacol. 2008, 48, 1366-1367.
[11] M. Bollenbach, P. Wagner, A. G. V. Aquino, J.-J. Bourguignon, F. Bihel,
C. Salomé, M. Schmitt, ChemSusChem 2016, 9, 3244-3249.
[12] a) C. Salomé, P. Wagner, M. Bollenbach, F. Bihel, J.-J. Bourguignon, M.
Schmitt, Tetrahedron 2014, 70, 3413; (b) P. Wagner, M. Bollenbach, C.
Doebelin, F. Bihel, J.-J. Bourguignon, C. Salomé, M. Schmitt, Green
Chem. 2014, 16, 4170–4178.
[24] a) I. P. Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004, 248,
2337–2364; b) E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola,
Chem. Rev. 2007, 107, 5318-5365; c) M. Newer, Organic-Chemical
Drugs and their Synonyms: An International Survey, 7th ed., Akademic
Verlag GmbH, Berlin, 1994; d) H. Montgomery, Agrochemicals Desk
Reference: Environmental Data, Lewis Publishers, Chelsea, MI, 1993;
e) J. P. Corbert, G. Mignani, Chem. Rev. 2006, 106, 2651–2710; f) S. V.
Ley , A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42, 5400 –5449.
[25] E. Carbo Tutusaus, D. Chan, Drugs Fut. 2016, 41, 267.
[26] F. Gallou, P. Guo, M. Parmentier, J. Zhou, Org. Process Res. Dev.
2016, 1388-1391.
[13] P. P. Kung, B. W. Huang, G. Zhang, J. Z. Zhou, J. Wang, J. A.Digits, J.
Skaptason, S. Yamazaki, D. Neul, M. Zientek, J. Elleraas, P. Mehta, M.
J. Yin, M. J. Hickey, K. S. Gajiwala, C. Rodgers, J. F. Davies, M. R.
Gehring, J. Med. Chem. 2010, 53, 499 – 503.
[14] C. W. Lindsley, Curr. Top. Med. Chem. 2008, 8, 12.
[15] V. R., Pattabiraman, J. W. Bode, Nature 2011, 480, 471e479
[16] a) E. Armelin, L. Franco, A. Rodriguez-Galan, J. Puiggali, Macromol.
Chem. Phys. 2002, 203, 48 – 58; b) M. A. Glomb, C. Pfahler, J. Biol.
Chem. 2001, 276, 41638–41647; c) J. Zabicky, The chemistry of
Amides, Wiley-Intersciences, New York, 1970; d) A. Greenberg, C. M.
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Entry for the Table of Contents
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Naturally efficient! A protocol for the
smooth N-arylation of amides,
M. Bollenbach, P. G. V. Aquino, J.
X. De Araújo Jr., J.-J.
carbamates and azoles is described in
water at almost rt with the help of cheap
and commercial catalysts.The method
enables the selective conversion of
polyhalogenated aromatics and
provides access to pharmacologyrelevant
motifs.
Bourguignon, F. Bihel, C. Salomé,
P. Wagner, M. Schmitt*
Page No. – Page No.
Title
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