Assembly of α-(Hetero)aryl Nitriles via Copper-Catalyzed Coupling Reactions with (Hetero)aryl Chlorides and Bromides

Article abstract of DOI:10.1002/anie.202014638

α-(Hetero)aryl nitriles are important structural motifs for pharmaceutical design. The known methods for direct synthesis of these compounds via coupling with (hetero)aryl halides suffer from narrow reaction scope. Herein, we report that the combination of copper salts and oxalic diamides enables the coupling of a variety of (hetero)aryl halides (Cl, Br) and ethyl cyanoacetate under mild conditions, affording α-(hetero)arylacetonitriles via one-pot decarboxylation. Additionally, the CuBr/oxalic diamide catalyzed coupling of (hetero)aryl bromides with α-alkyl-substituted ethyl cyanoacetates proceeds smoothly at 60 °C, leading to the formation of α-alkyl (hetero)arylacetonitriles after decarboxylation. The method features a general substrate scope and is compatible with various functionalities and heteroaryls.

Full text of DOI:10.1002/anie.202014638

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7082–7086
International Edition:
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Homogeneous Catalysis
Hot Paper
Assembly of a-(Hetero)aryl Nitriles via Copper-Catalyzed Coupling
Reactions with (Hetero)aryl Chlorides and Bromides
Ying Chen, Lanting Xu, Yongwen Jiang, and Dawei Ma*
Abstract: a-(Hetero)aryl nitriles are important structural
motifs for pharmaceutical design. The known methods for
direct synthesis of these compounds via coupling with (hetero)-
aryl halides suffer from narrow reaction scope. Herein, we
report that the combination of copper salts and oxalic diamides
enables the coupling of a variety of (hetero)aryl halides (Cl,
Br) and ethyl cyanoacetate under mild conditions, affording a-
(hetero)arylacetonitriles via one-pot decarboxylation. Addi-
tionally, the CuBr/oxalic diamide catalyzed coupling of
(hetero)aryl bromides with a-alkyl-substituted ethyl cyano-
acetates proceeds smoothly at 608C, leading to the formation of
a-alkyl (hetero)arylacetonitriles after decarboxylation. The
method features a general substrate scope and is compatible
with various functionalities and heteroaryls.
A
considerable number of pharmaceutically important
Figure 1. Assembly of a-(hetero)aryl nitriles via coupling (hetero)aryl
halides with different surrogates of acetonitrile and primary nitriles.
compounds contain a-(hetero)aryl nitriles as a basic struc-
tural motif[1] and they are valuable building blocks in organic
synthesis. In particular, they have been frequently used as
starting materials for preparing a-aryl amides and carboxylic
acids, including manufacturing some non-steroidal anti-
inflammatory drugs (NSAIDs).[2] Over the past two decades,
many excellent methods for preparing a-aryl nitriles,[3–6] a-
aryl carboxyl acids,[7] a-aryl esters[8] and amides[9] have been
developed through different coupling approaches. Among
them, metal-catalyzed coupling of aryl halides with nitriles is
a promising one for large-scale synthesis because both
coupling partners are conveniently available and cost effec-
tive. In this regard, the groups of Hartwig[3a] and Verkade[3b]
have successfully achieved direct arylation of simple nitriles
under the catalysis of palladium salts and sterically hindered
phosphines (Figure 1). However, both mono-arylation and di-
arylation occurred in most cases if primary nitriles were
employed.[3a,b] To overcome this issue, Hartwig and Wu
utilized a-silyl nitriles as the alternative coupling agents to
achieve selective mono-arylation of acetonitrile and primary
nitriles,[3c] while Velcicky and co-workers employed isoxazole
moiety as the precursor of cyanomethylene unit to obtain a-
arylacetonitriles via a domino Suzuki coupling-isoxazole
fragmentation process.[4] Although the reaction scope with
Hartwigꢀs method remains questionable as only one hetero-
aryl bromide was examined,[3c] this reaction attracted imme-
diate applications in drug discovery,[4a,10] implying that more
practical methods for diversely assembling a-(hetero)aryl
nitriles are highly desirable. We envisioned that ethyl
cyanoacetate and its mono-substituted derivatives are more
readily available surrogates of acetonitrile and primary
nitriles, and therefore attempted for assembly of a-(hetero)-
aryl nitriles through Cu-catalyzed arylation. The successful
realization of this concept is disclosed here.
The metal-catalyzed coupling of aryl halides with ethyl
cyanoacetate has received considerable attention during the
past decades.[11–13] However, it remains to be developed for
the practical applications in organic synthesis. For example,
Cu-catalyzed arylation only worked well for aryl iodides,[11,12]
while Pd-catalyzed version, albeit using rather expensive
metal and ligands, is still problematic to most heteroaryl
halides and a-alkyl substituted ethyl cyanoacetate.[13,5a] Thus,
our primary goal was to develop a powerful catalytic system
for Cu-catalyzed arylation with ethyl cyanoacetate and its
derivatives. Based on our previous studies on oxalic diamides
promoted Cu-catalyzed coupling reactions,[14] we decided to
screen a series of oxalamide ligands using coupling of 4-
chloroanisole and ethyl cyanoacetate as a model reaction. As
demonstrated in Table 1, N-(2-methyl-naphthalen-1-yl)-N’-
benzyl oxalamide (MNBO, L1), a ligand displayed excellent
activity in amine arylation,[14e] was initially tested (entry 1). It
was found that reaction occurred under the assistance of
[*] Dr. Y. Chen
School of Physical Science and Technology
ShanghaiTech University
393 Middle Huaxia Road, Shanghai 201210 (China)
Dr. L. Xu, Dr. Y. Jiang, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic & Natural Products Chemistry
Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: madw@sioc.ac.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202014638.
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Table 1: Cu-catalyzed coupling of 4-chloroanisole with ethyl cyanoacetate
under the assistance of different ligands.[a]
implied that the better performance of L2 might result from
relatively poor electron-donating ability of pyridin-2-yl
methyl group, but not from the additional coordination to
copper. Further evaluation revealed that changing the left
part of the ligand L2 to anthracenyl (L5, AMPO) and pyridin-
2-ylmethyl (L6) also gave 3a in reasonably high yields
(entries 10 and 11), while ligands such as proline and 1,10-
phenanthroline previously reported led to no conversion
(entries 12 and 13).
In view of the above encouraging result, we examined
whether the newly developed catalytic system is applicable
for coupling of aryl bromides at low catalytic loading.
Gratifyingly, under the catalysis of 0.5 mol% CuBr and
1 mol% L2, coupling of 4-bromoanisole and ethyl cyanoace-
tate proceeded smoothly at 808C to afford 3a in 70% yield
(entry 14). Changing the copper salt to CuCl led to the
formation of 3a in a better yield (entry 15). Further attempt
indicated that combination of K3PO4 and ethanol gave a best
result (compare entries 16–18).
We next examined the established conditions with a vari-
ety of (hetero)aryl chlorides and bromides. As summarized in
Table 2, a series of aryl halides (Cl, Br) bearing either
electron-donating or electron-withdrawing groups at the para
and meta-position worked well, producing the corresponding
a-aryl acetonitriles 3b–3j in 70–89% yields. In case of ethyl 4-
bromobenzoate as a substrate, the decarboxylation step
should be carried out under acidic conditions to preserve
the ester group in the structure (3g). Coupling with 2-
chloroanisole gave 3k in a poor yield, although a good result
was observed in case of 2-bromoanisole as a coupling partner.
This result indicated that the steric hindrance significantly
influenced the coupling reaction with aryl chlorides. Further
evidence was observed from the difference in coupling with 2-
chloronathphlene (3p) and 1-chloronathphlene (3o). Addi-
tionally, three trisubstituted and two heterocycle-substituted
aryl halides were applicable, delivering a-aryl acetonitriles
3l–3n and 3q in good yields.
Entry
X
[Cu]
L
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
CuI
CuI
CuI
L1
L2
L2
L2
L2
L2
L2
L3
L4
L5
L6
L7
L8
L2
L2
L2
L2
L2
K3PO4
K3PO4
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
EtOH
7
17
50
80
61
28
0
30
58
75
62
0
t-BuONa
t-BuONa
t-BuONa
t-BuONa
NaOH
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
K3PO4
CuBr
CuCl
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
CuCl
CuCl
CuCl
EtOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
EtOH
9
10
11
12
13
14
15
16
17
18
0
70
84
71
87
56
K3PO4
K3PO4
dioxane
Heteroaryl halides are recognized as difficult substrates
under previous Pd- or Cu-catalyzed coupling conditions.[11–13]
Fortunately, our new catalytic system addressed this long-
standing problem. Under the standard conditions, coupling
reaction of a range of heteroaryl halides (Cl, Br) proceeded
smoothly, leading to the formation of a-heteroaryl acetoni-
triles 3r–3ad in good to excellent yields. Noteworthy was that
the common heterocycles such as pyridine (3r, 3s), quinoline
(3t, 3u), isoquinoline (3v), benzothiophene (3w–3y), indole
(3z), benzothizole (3aa), carbazole (3ab), dibenzothiophene
(3ac) and pyrrole (3ad) were conveniently introduced by
employing the corresponding heteroaryl halides. When 2-
bromothiophene was used, coupling reaction took place to
afford ester 4 in 53% yield. After its decarboxylation, we
failed to isolate 2-(thiophen-2-yl)acetonitrile, mainly because
of its low boiling point.
[a] Reaction conditions: for entries 1–13: 1 (1.0 mmol), 2 (1.5 mmol),
[Cu] (0.05 mmol), ligand (0.1 mmol), base (2.5 mmol), solvent (1.5 mL),
1058C, 24 h; then water, 1058C; For entries 14–18: 1 (4.0 mmol), 2
(8.0 mmol), [Cu] (0.5 mol%), ligand (1.0 mol%), base (12.0 mmol),
solvent (4.0 mL), 808C, 24 h, then H2O (1.0 mL), 808C, 12 h. [b] The
1
yield was determined by H NMR analysis of crude products.
K3PO4 in 2-propanol at 1058C. However, low conversion was
observed and the desired a-aryl nitrile 3a was obtained in 7%
yield after decarboxylation. Changing the ligand to N-(2-
methylnaphthalen-1-yl)- N’-(pyridin-2-ylmethyl)oxalamide
(MNPMO, L2) gave an improved result (entry 2). Using this
ligand we further screened several bases, copper salts and
solvents, and found that t-BuONa was the best base (compare
entries 2, 3 and 7), CuBr was the best catalyst precursor
(compare entries 3–5), and 2-propanol was the better solvent
than ethanol. Since L2 showed better activity than L1, we
wondered if its pyridine moiety can provide the additional
coordination to copper, and thereby facilitating the catalytic
cycle. Consequently, L3 and L4, two simple analogues of L2,
were also examined (entries 8 and 9). Their activity trend
Furthermore, we found that the present method could be
utilized for direct functionalization of known drugs bearing an
aryl chloride unit. For example, coupling reaction with
chlorpheniramine and clomipramine afforded 3ae and 3af,
respectively. Additionally, an ester-embodied aryl chloride
was applicable to afford 3ag in 68% yield, while 1-(4-
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Table 2: Coupling of (hetero)aryl halides with ethyl cyanoacetate.[a,b]
ethyl cyanoacetates as the nucleophiles. As illustrated in
Table 3, reaction of 2-bromoanisole and ethyl 2-cyanopropa-
noate under the catalysis of 3 mol% CuBr and 6 mol% L2
occurred at 608C to afford 5a in 50% yield. A quick screening
revealed that using L5 (APMO) as a ligand significantly
improved the yield (77%). The combination of CuBr and
APMO was then tested for the reactions of a series of
(hetero)aryl bromides and ethyl a-alkyl cyanoacetates. In
general, decarboxylation took place spontaneously after
coupling reaction occurred. However, incomplete decarbox-
ylation was observed, particularly for those substrates pos-
sessing an electron-donating group. In such case, adding 5%
NaOH and prolonging the heating gave the desired products
in better yields. The generality of this reaction was quite
Table 3: Coupling of (hetero)aryl bromides with ethyl a-alkyl cyanoace-
tates.[a,b]
[a] Reaction conditions: for chlorides: 1 (1.0 mmol), 2 (1.5 mmol), CuBr
(0.05 mmol), L2 (0.1 mmol), t-BuONa (2.5 mmol), i-PrOH (1.5 mL),
1058C, 24 h; then H2O (1 mL), 1058C, 12 h; for bromides: 1 (4.0 mmol),
2 (8 mmol), CuCl (0.02 mmol), L2 (0.04 mmol), K3PO4 (12.0 mmol),
EtOH (4.0 mL), 808C, 24 h; then H2O (4 mL), 808C, 6–12 h. [b] Isolated
yield. [c] Decarboxylation was conducted with 5 mL 2 N HCl, 808C, 12–
36 h.
chlorophenyl)ethan-1-one gave the product 3ah in rather low
yield. Taken together, we concluded that our method could be
used for assembling a wide range of a-(hetero)aryl acetoni-
triles.
Considering that a-alkyl (hetero)arylacetonitriles are
more important building blocks for drug synthesis, we next
attempted the coupling reaction using a-alkyl substituted
[a] Reaction conditions: 1 (2.0 mmol), 4 (4.0 mmol), CuBr (0.06 mmol),
APMO (0.12 mmol), t-BuONa (4.0 mmol), i-PrOH (6.0 mL), 608C, 24 h;
then 5% NaOH (2 mL), 608C, 4 h. [b] Isolated yield. [c] Using L2 as the
ligand. [d] Absence of 5% NaOH. [e] i-PrOH (2.0 mL). [f] i-PrOH
(7.0 mL), 708C. [g] 4 (6.0 mmol), 808C, 24 h; then 5% NaOH (3.0 mL),
808C, 4 h.
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[5] For selected references on Pd-catalyzed coupling of aryl halides
satisfactory, as a number of functionalized aryl bromides and
heteroaryl bromides were applicable for preparing a-methyl
(hetero)arylacetonitriles 5a–5v. Besides ethyl 2-cyanopropa-
noate, other more bulky analogues also worked well, afford-
ing 5w–5ad in 43–81% yields. The olefin (5z, 5aa) and amine
(5ab) groups in the side chain did not alter the reaction
process. Remarkably, some of our products were applicable
for preparing non-steroidal anti-inflammatory drugs
(NSAIDs),[15] which include Ibuprofen (from 5c), Fenoprofen
(from 5g), Ketoprofen (from 5h), Flurbiprofen (from 5i),
Naproxen (from 5j), Cicloprofen (from 5m), Indoprofen
(from 5e), Araprofen (from 5e) and Alminoprofen (from
5e). Thus, our method provided a facile and alternative entry
to these known drugs and their analogues.
In conclusion, we have revealed that two pyridine-
embodied oxalic diamides are powerful ligands for promoting
Cu-catalyzed coupling reaction of (hetero)aryl halides with
ethyl cyanoacetate and its a-mono-alkylated derivatives.
Under the present conditions, readily available and inex-
pensive (hetero)aryl chlorides and bromides could be
employed as the coupling partners for the first time. More
importantly, a wide range of functionalized aryl and hetero-
aryl halides are applicable, thereby providing a convenient
approach for preparing a-(hetero)aryl nitriles in a concise and
diverse manner. Further application of these ligands in other
coupling reactions are being explored in our laboratory, and
the results will be disclosed in due course.
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Acknowledgements
Financial support of this research from Chinese Academy of
Sciences (supported by the Strategic Priority Research
Program, grant XDB20020200 & QYZDJ-SSW-SLH029)
and the National Natural Science Foundation of China
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Conflict of interest
The authors declare no conflict of interest.
À
Keywords: anti-inflammatory drugs · C C cross-coupling ·
copper · oxalamide ligands · a-(hetero)aryl nitriles
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Manuscript received: November 2, 2020
Accepted manuscript online: December 28, 2020
Version of record online: February 17, 2021
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