Copper(I)/Copper(II)-Assisted Tandem Catalysis: The Case Study of Ullmann/Chan-Evans-Lam N1,N3-Diarylation of 3-Aminopyrazole

Article abstract of DOI:10.1002/cctc.201500510

Unprecedented Cu^I/Cu^II-assisted tandem catalysis allowing an Ullmann/Chan-Evans-Lam sequence was achieved. This three-component, one-pot reaction triggered by a change in the oxidation state of the metal leads to the selective N¹,N³-diarylation of 3-aminopyrazole. This new method should be a valuable tool for small-molecule drug discovery that requires suitable regio- and/or chemoselective strategies for the N-arylation of nitrogen-containing heterocycles. Tandem power: The first assisted tandem copper-catalyzed process, triggered by a change in the oxidation state of the metal, is developed to allow a one-pot Ullman/Chan-Evans-Lam sequence leading to the selective N¹,N³-diarylation of 3-aminopyrazole.

Full text of DOI:10.1002/cctc.201500510

DOI: 10.1002/cctc.201500510
Communications
Copper(I)/Copper(II)-Assisted Tandem Catalysis: The Case
Study of Ullmann/Chan–Evans–Lam N1,N3-Diarylation of 3-
Aminopyrazole
Astrid Beyer, Thomas Castanheiro, Patricia Busca,* and Guillaume Prestat*[a]
Unprecedented CuI/CuII-assisted tandem catalysis allowing an
Ullmann/Chan–Evans–Lam sequence was achieved. This three-
component, one-pot reaction triggered by a change in the oxi-
dation state of the metal leads to the selective N1,N3-diaryla-
tion of 3-aminopyrazole. This new method should be a valuable
tool for small-molecule drug discovery that requires suitable
regio- and/or chemoselective strategies for the N-arylation of
nitrogen-containing heterocycles.
that 3-aminopyrazole would be a unique model substrate to
study this assisted tandem reaction (Scheme 1a). Indeed, from
a synthetic point of view, N-arylation of polynitrogenated het-
erocycles remains highly challenging owing to the possible for-
mation of regioisomers and/or polyarylated products.[11–13] The
selective N,N’-diarylation of such complex substrates was previ-
ously tackled by two groups: Buchwald in 2012 for 2-amino-
benzimidazoles thanks to the complementarity of palladium
and copper catalysts (Scheme 1b),[14] and more recently, Das
for a variety of aminoazoles by two successive CuII CEL cou-
plings (Scheme 1c).[15] However, these reactions were devel-
oped as two-step procedures. We report herein the successful
achievement of our concept: the first example of a CuI/CuII as-
sisted tandem process leading to the one-pot selective diaryla-
tion of 3-aminopyrazole.
Transition-metal-catalyzed domino reactions are powerful syn-
thetic tools for sustainable organic chemistry, as they allow
atom- and step-economical syntheses.[1] Among the various
tandem catalysis methodologies,[2] assisted tandem catalysis
has recently emerged as a potent strategy.[2c,3] This smart pro-
cess relies on modification of the catalyst’s activity during the
course of the process, triggered in most cases by a change in
the oxidation state of the metal. Mechanistically distinct reac-
tions can thereby be mediated by a single metal source. To
date, assisted tandem catalysis has solely been developed with
the use of Ti,[4] Ru,[5] and Pd[6] complexes.
Within the transition-metal family, copper offers many ad-
vantages in that it is nontoxic, environmentally benign, rather
cheap, and easy to handle. Thanks to the development of effi-
cient catalytic systems over the last decade, copper-mediated
cross-coupling reactions are today providing some of the most
useful methods for the formation of aryl CÀN, CÀO, CÀS, and
CÀC bonds.[7] In particular, Ullmann[8] and Chan–Evans–Lam
(CEL)[9] couplings have become increasingly popular to afford
N-arylated (hetero)aromatic amines, which are essential key
building blocks for medicinal chemistry. Although copper-cata-
lyzed domino reactions are receiving more attention these
days,[10] there is, to our surprise, no report on CuI/CuII assisted
tandem catalysis.
Scheme 1. Strategies for the N,N’-diarylation of aminoazoles.
Efficient arylation of pyrazole and/or pyrazole derivatives has
already been described through Ullmann[12] and Chan–Lam[13]
couplings. However, the selective N1-arylation of 3-aminopyra-
zole has received only very little attention, but it has been re-
ported to proceed either under drastic conditions[12c] or to give
products in moderate yields.[12d] We therefore undertook
a screening of the solvent, base, and catalyst loading (see Table
SA, Supporting Information) and found that the use of CuI
(10 mol%), Cs2CO3 (1.0 equiv.), and 4-iodotoluene (1.5 equiv.) in
1-methylpyrrolidin-2-one (NMP) were optimal conditions to
afford the desired N1-arylated pyrazole in excellent yield.
In this context, we sought to develop a one-pot N,N’-diaryla-
tion process relying on CuI-mediated Ullmann and CuII-cata-
lyzed CEL reactions by using a single Cu source as the catalyst
precursor and an oxidant as the in situ trigger. We envisioned
[a] Dr. A. Beyer, T. Castanheiro, Dr. P. Busca, Prof. Dr. G. Prestat
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques
UMR CNRS 8601
UniversitØ Paris Descartes
45 rue des Saints-P›res, 75006 Paris (France)
E-mail: patricia.busca@parisdescartes.fr
guillaume.prestat@parisdescartes.fr
We next explored the substrate scope with a variety of func-
tionalized aryl iodides and iodo-substituted heterocycles
(Table 1). Our optimized conditions proved to be efficient with
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201500510.
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Table 1. Scope of the first N-arylation under Ullmann conditions.[a]
Table 2. Scope of the second N-arylation under CEL conditions.[a]
[a] Reaction conditions: 2a (0.5 mmol), arylboronic acid (1.15 mmol),
Cu(OAc)2 (0.05 mmol), pyridine (0.055 mmol), NMP (4 mL), RT, air, 16 h;
yields refer to isolated products.
[a] Reaction conditions:
1
(1 mmol), aryl iodide (1.5 mmol), CuI
(0.1 mmol), Cs2CO3 (1 mmol), NMP (3 mL), 1208C, 24 h; yields refer to iso-
lated products; ratio was determined by 1H NMR spectroscopy. [b] 1,10-
Phenanthroline (20 mol%) was added. [c] 1,1’-Bi-2-naphthol (20 mol%)
was added.
To develop the desired one-pot Ullmann/CEL sequence by
using a single Cu source, we next tackled the feasibility of the
CuII-catalyzed CEL reaction starting with CuI. Replacing
Cu(OAc)2 with CuI under our standard CEL conditions did not
allow the formation of the desired product (Table 3, entry 1 vs.
Table 2, 3a). As oxidation of CuI to CuII by O2 requires a proton
source, the reaction was performed in the presence of AcOH
(0.3 or 0.2 mol% without pyridine), but these conditions led to
poor results (Table 3, entries 2 and 3). CEL coupling starting
with CuI was finally achieved by the addition of PhI(OAc)2
(0.2 mol%), which afforded 3a in a good 74% yield (Table 3,
entry 4).
electron-rich, electron-neutral, and electron-poor aryl iodides,
and desired monoarylated pyrazoles 2a–j were afforded in
good to excellent yields ranging from 64 to 94% with high se-
lectivities. Regioisomers 2 (major) and 2’ (minor) could be sep-
arated by column chromatography. Heteroaromatic coupling
partners were the only ones to require the use of a ligand (see
products 2k–m). Interestingly, ortho-substituted product 2d
was exclusively formed without any trace amount of its 2’d
isomer, which suggests that N1/N2 selectivity is mostly gov-
erned by steric hindrance. Notably, these conditions are per-
fectly chemoselective, as no arylation of the exocyclic amine
was observed.
Table 3. CuI as a precatalyst for CEL coupling.[a]
Entry
[Cu]
Additive [(mol%)]
Yield[b] [%]
1
2
3[c]
4
CuI
CuI
CuI
CuI
–
0
21
21
74
We then focused on the subsequent CEL arylation of the
exocyclic NH2 group. Our objective of a domino process im-
posed to keep NMP as the solvent and to work under catalytic
conditions. Using 2a as the starting material, optimization of
the reaction conditions (see Table SB) demonstrated that the
use of Cu(OAc)2 (10 mol%) with pyridine (11 mol%) afforded
desired pyrazole 3a in 87% yield. The substrate scope was
next investigated with various boronic acids as coupling part-
ners (Table 2). The reaction proved to be efficient with elec-
tron-rich and electron-neutral boronic acids, as well as with
a para-iodo-derivative to afford diarylated products 3a–g in
good yields ranging from 55 to 88%. As expected, a few limita-
tions were encountered for ortho-Me derivative 3c (33%), as
a result of steric hindrance, and for para-CF3 derivative 3h
(34%) and para-NO2 product 3i (0%), as a result of a lack of re-
activity.
AcOH (0.3)
AcOH (0.2)
PhI(OAc)2 (0.2)
[a] Reaction conditions: 2a (0.5 mmol), 4-TolB(OH)2 (1.15 mmol), [Cu]
(0.05 mmol), pyridine (0.055 mmol), NMP (4 mL), RT, air, 22 h. [b] Yields
refer to isolated products. [c] Without pyridine.
A first attempt at the one-pot sequence was next undertak-
en by submitting 1 to our Ullmann conditions before 4-tolyl-
boronic acid [4-TolB(OH)2], PhI(OAc)2, and pyridine were added
(Scheme 2). After 22 h of stirring, the formation of 3a could
not be observed, whereas Ullmann adduct 2a was isolated in
86% yield (see Table 1), which demonstrates thereby a com-
plete inhibition of the CEL step.
We hypothesized that byproducts formed during the first ar-
ylation step or unreacted starting materials were responsible
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Scheme 3. One-pot N1,N3-diarylation.
Scheme 2. First one-pot N1,N3-diarylation attempt.
Table 4. Inhibition of the second arylation step.[a]
A final set of experiments was undertaken to refine the one-
pot reaction conditions by varying the “antidotes” sources and
amounts (see Table SC). PhI(OAc)2 was found to be unnecessa-
ry in the presence of AgBF4, with an optimal amount of
1.4 equivalents, and AcOH (1 equiv.) proved to be the best acid
additive. Hence, 1 was submitted to our Ullman conditions for
24 h before 4-TolB(OH)2, AcOH, and AgBF4 were added to
afford desired diarylated product 3a in a good 63% yield
(Scheme 3). The scope of the one-pot diarylation was finally
examined (Scheme 3, Table 5). To our delight, a variety of sub-
stituted aryl iodides and boronic acids proved to be suitable
coupling partners for 3-aminopyrazole (1). In a first set of ex-
periments, the boronic acid was varied while keeping 4-iodoto-
luene as the partner for the Ullmann step. Yields of the
domino sequence typically ranged from 45 to 63% for com-
pounds 3a, 3b, 3d–f, and 3j, except for 4-iodo derivative 3g
(36% yield). Next, the aryl iodide was varied while keeping 4-
TolB(OH)2 as the partner for the CEL step. In this series, elec-
tron-neutral, electron-rich, and electron-poor aryl iodides also
reacted smoothly to deliver 3k–p in yields of 48–62%, except
for the meta-nitro coupling partner (i.e., 3q, 14% yield). Inter-
Entry
Additive [(equiv.)]
Yield[b] [%]
1
2
3
4
5
6
7[c]
8
1 (0.1)
4-iodotoluene (0.5)
Cs2CO3 (0.1)
CsHCO3 (1.0)
CsI (1.0)
CsHCO3 (1.0)/PhCO2H (1.0)
CsHCO3 (1.0)/PhCO2H (1.0)
CsI (1.0)/AgBF4 (1.2)
CsI (1.0)/AgBF4 (2.0)
CsI (1.0)/AgBF4 (1.0)
CsHCO3 (1.0)/CsI (1.0)
PhCO2H (1.0)/AgBF4 (1.2)
84
85
72
43
0
15
84
59
9
9
10
11[c]
29
73
[a] Reaction conditions: 2a (0.5 mmol), 4-TolB(OH)2 (1.15 mmol), Cu(OAc)2
(0.05 mmol), pyridine (0.055 mmol), additive, NMP (4 mL), RT, air, 22 h.
[b] Yields refer to isolated products. [c] Without pyridine, reaction temper-
ature: 808C.
for the inhibition of the CEL reaction. Various control experi-
ments were thus performed by separately adding each poten-
tial inhibitor to the second aryla-
tion reaction (Table 4). The addi-
tion of 1 or 4-iodotoluene had
Table 5. Scope of the one-pot N1,N3-diarylation.[a]
little impact on the reaction
yield (Table 4, entries 1 and 2 vs.
88%, Table 2, 3a). In contrast,
the addition of Cs2CO3, CsHCO3,
and, unexpectedly, CsI was
found to be deleterious to the
reaction (Table 4, entries 3–5).
Neutralization of CsHCO3 was
performed with PhCO2H in the
absence of pyridine at 808C
(Table 4, entries 6 and 7). The ad-
dition of a silver salt (AgBF4,
1.2 equiv.) allowed the effect of
CsI to be counteracted (Table 4,
entries 8–10). Finally, running the
reaction in the presence of both
inhibitors (CsHCO3, CsI) and both
“antidotes” (PhCO2H, AgBF4) in
the absence of pyridine at 808C
allowed the catalytic activity to
be recovered and smoothly af-
forded 3a in 73% yield (Table 4,
entry 11).
[a] Reaction conditions: 1 (0.5 mmol), aryl iodide (0.75 mmol), CuI (0.05 mmol), CsCO3 (0.5 mmol), NMP (1.5 mL),
1208C, 24 h; then, AgBF4 (0.7 mmol), acetic acid (0.5 mmol), arylboronic acid (1.15 mmol), 3 Š molecular
sieves,[16] 808C, 23 h; yields refer to isolated products. [b] Without molecular sieves.
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In summary, we demonstrated that two successive CuI- and
CuII-catalyzed CÀN bond-formation events could be performed
within a one-pot procedure by using a unique copper source.
This is the first report of CuI/CuII assisted tandem catalysis trig-
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Acknowledgements
We gratefully acknowledge the French Agence Nationale pour la
Recherche (ANR) for funding (grant ANR-12-BSV1-0026-02), the
UMR 8601 mass spectrometry service for HRMS analyses, and Vic-
toria N’Doyom for early contributions to this project.
Keywords: aminoazoles · C–N coupling · copper · domino
reactions · N-arylation
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Received: May 7, 2015
Published online on July 14, 2015
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