Selective Synthesis of Aryl Nitriles and 3-Imino-1-oxoisoindolines via Nickel-Promoted C(sp2)-H Cyanations

Article abstract of DOI:10.1021/acs.orglett.8b01056

An efficient nickel-promoted selective monocyanation of benzamides with TMSCN via 8-aminoquinoline directed ortho C-H activation has been developed. Varieties of functionalized ortho-cyanated (hetero)aryl nitriles can be selectively synthesized in moderate to good yields. These cyanation products can be easily transformed into various 3-imino-1-oxoisoindolines in a one-pot procedure. The mild reaction conditions, use of cheap and commercially available reagents, wide functional group tolerance, and operational convenience make this protocol practical to the synthetic community.

Full text of DOI:10.1021/acs.orglett.8b01056

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selective Synthesis of Aryl Nitriles and 3‑Imino-1-oxoisoindolines via
Nickel-Promoted C(sp2)−H Cyanations
Lin Yu,†,§ Xiang Chen,†,§ Ze-Nan Song,† Da Liu,† Liang Hu,† Yongqi Yu,† Ze Tan,*,†
and Qingwen Gui*,‡
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P. R. China
‡College of Science, Hunan Agricultural University, Changsha 410128, P. R. China
S
* Supporting Information
ABSTRACT: An efficient nickel-promoted selective monocyanation of benzamides with TMSCN via 8-aminoquinoline directed
ortho C−H activation has been developed. Varieties of functionalized ortho-cyanated (hetero)aryl nitriles can be selectively
synthesized in moderate to good yields. These cyanation products can be easily transformed into various 3-imino-1-
oxoisoindolines in a one-pot procedure. The mild reaction conditions, use of cheap and commercially available reagents, wide
functional group tolerance, and operational convenience make this protocol practical to the synthetic community.
nitromethane.7 Since then, great progress has been made by the
ryl nitriles not only are prevalent in natural products,
Aagricultural chemicals, dyes materials, and pharmaceut- groups of Cheng,8 Murahashi,9 Anbarasan,10 Ackermann,11
Chang,12 Zhu,13 and others,14 who independently developed
Pd-,8a,b,12a,14a,b Ru-,9a−c,11a Rh-,10a−c,13d,14g,h Co-,11b,12b
Cu-,8c,13c,14c−f Mn-,11c Re-,13a and Au-13b catalyzed cyanation
protocols using different monodentate or bidentate directing
groups. Despite these advances, most of these methods still
suffer from either needing to use expensive noble metal
complexes or a limited substrate scope. To the best of our
knowledge, direct synthesis aryl nitriles via nickel-catalyzed or
promoted C−H cyanation is unprecedented. As a continuation
of our efforts on the development of new reactions based on
C−H activations,15 we herein present a novel route for an
efficient and direct synthesis of aryl nitriles via nickel-promoted
C−H cyanation using TMSCN, a cheap and commercially
available material, as the cyanide source under mild conditions.
The reaction exhibits high regio- and monoselectivity in
forming various aryl nitrile products, which can be easily
converted into anthranilic acids, a critical scaffold in perfumes,
agrochemicals, and medicinal chemistry.16
icals1 but also can serve as key precursors for the synthesis of
various compounds such as amines, amides, amidines,
aldehydes, tetrazoles, and carboxylic acids.2 Therefore, develop-
ment of efficient strategies toward this high-value building
block is a longstanding goal in organic synthesis. Traditionally,
aryl nitriles can be synthesized through regular functional group
transformations from their corresponding aryl acids, amides,
and aldehydes.3 Alternatively, they can also be prepared via the
classical method of Sandmeyer reaction4 or Rosenmund−von
Braun reaction5 using anilines as the starting materials. In
addition, aryl nitriles can also be obtained through transition-
metal-catalyzed cyanation of aryl halides, pseudo halides, and
arylboronic acids using various cyanide sources.6 Even though
all these methods do provide convenient access to aryl nitriles,
one common problem associated with all the above-mentioned
methods is that a functional group such as an acyl derivative,
halide, or amine must be present at the exact location where the
nitrile is going to be placed. In other words, prefunctionalized
arenes are required and this makes these methods less desirable.
On the other hand, it would be more efficient if one can
synthesize aryl nitriles through direct cyanation of arene
C(sp2)−H bonds, because, in principle, fewer steps would be
needed and higher atom economy would be achieved.
Attracted by the high value of aryl nitriles, we sought to
efficiently install a cyanide group on the aromatic ring through
cheap-metal-catalyzed C(sp2)−H activations assisted by 8-
aminoquinoline. We began our experiment with the reaction of
N-(quinolin-8-yl)benzamide 1a with 2 equiv of TMSCN, 2
equiv of NiCl2 in the presence of 2 equiv of K2CO3 in DMSO
Indeed, transition-metal-catalyzed C−H cyanation with the
help of a directing group has attracted widespread attention. In
2006, Yu and co-workers reported the first Cu-mediated
cyanation of 2-phenylpyridine with trimethylsilyl cyanide or
Received: April 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01056
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Letter
at 100 °C for 6 h under a nitrogen atmosphere. Gratifyingly, we
found that N-(quinolin-8-yl)benzamide 1a could be cyanated
with TMSCN and the ortho-cyanated product 3a could be
isolated in 15% yield under the conditions shown in Table 1,
due to the fact these ammonium salts can increase the
homogeneity of the reaction mixture. It should be mentioned
that no dicyanated product was formed and the reaction was
highly monoselective. However, experiments showed that 2
equiv of the Ni-promoter were necessary for the reaction to
reach completion and no reaction occurred when the loading of
nickel salts was reduced to a catalytic amount (5 mol %) while
using O2, para-benzoquinone, or Ag2CO3 as an oxidant at the
same time.
a b
,
Table 1. Screening of Reaction Conditions
With the optimized conditions in hand (Table 1, entry 16),
we then examined the scope of benzamides. As shown in
Scheme 1, various functional groups including electron-
b
entry
nickel salt
NiCl2
base
solvent
additive yield (%)
a b
,
1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
NaHCO3
t-BuOLi
−
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
−
−
−
−
−
−
15
trace
17
12
36
0
Scheme 1. Scope of Amides 1
2
NiCl2·6H2O
Ni(OTf)2
3
4
Ni(dppp)Cl2
5
Ni(OAc)2·4H2O
−
6
7
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
−
−
−
−
15
23
25
0
8
9
10
11
12
13
14
15
16
17
18
−
−
−
32
10
0
MeCN
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
KF
trace
12
79
56
62
61
79
0
CsF
TBAA
TBAI
TBAB
TBAA
TBAA
TBAA
TBAA
TBAA
c
19
d
20
e
21
f
22
0
g
23
0
a
Reaction conditions: amide 1a (0.2 mmol), 2 (0.4 mmol), Ni salt
(0.4 mmol), base (0.4 mmol), solvent (2.0 mL), 100 °C under N2 for
b
c
d
e
6 h. Isolated yield. Ni salt (0.2 mmol). Ni salt (0.6 mmol). Ni salt
f
(0.05 mmol) and under O2. Ni salt (0.05 mmol), para-benzoquinone
(0.4 mmol). Ni salt (0.05 mmol), Ag2CO3 (0.4 mmol).
g
entry 1. Encouraged by this result, we then compared the
performance of different nickel salts. As the results listed in
Table 1, entries 2−5 show, Ni(OAc)2·4H2O was found to
possess the highest catalytic activity when compared with other
nickel catalysts. Control experiments showed that no desired
product was observed in the absence of nickel salts (Table 1,
entry 6). Other bases such as K3PO4, NaHCO3, and t-BuOLi
were subsequently examined and we found that they all
performed less satisfactorily than K2CO3 (Table 1, entries 7−
9). In addition to DMSO, other solvents including DMF,
MeCN, and toluene were also tested, and the results indicated
that DMSO was the best choice (Table 1, entries 11−13).
Next, we screened the additives, and the results showed that
neither KF nor CsF were effective (Table 1, entries 14−15).
Satisfyingly, employing tetrabutylammonium acetate (TBAA)
as an addittive, which was found to be beneficial in our previous
works,15g dramatically increased the yield to 79% (Table 1,
entry 16). Meanwhile, the addition of tetrabutylammonium
iodide (TBAI) and tetrabutylammonium bromide (TBAB) also
showed some improvement (Table 1, entries 17−18). The
beneficial effect observed with TBAA, TBAB, and TBAI may be
a
Reaction conditions: amide 1 (0.2 mmol), 2 (0.4 mmol), Ni salt (0.4
mmol), base (0.4 mmol), solvent (2.0 mL), 100 °C under N2 for 1−12
b
h. Isolated yield.
donating and -withdrawing substituents on the aryl ring of 1
were well tolerated to provide the corresponding cyanation
products in moderate to good yields. From the Scheme 1 we
can see that the yields for benzamides bearing electron-
donating groups such as OMe and tBu on the para- position of
the aryl ring are slightly higher than those with electron-
withdrawing groups including the Br, Cl, COOMe, and Ph
group. Notably, a benzamide containing a vinyl group at the
para-position could also deliver the desired product 3g in 68%
yield. With regard to the meta-substituted benzamides,
activation of C−H bonds occurred predominantly at the
sterically less congested side to afford monocyanated products
3j, 3k, 3l, and 3m in yields ranging from 68% to 73%. We also
found that ortho-substituted benzamides were compatible with
the reaction conditions (3n−3p). We were surprised to find
that an ortho-nitro-substituted benzamide exhibited high
B
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Letter
reactivity in our reaction (entry 3p), which means the electron
density on the aryl ring may not have a significant effect on the
reaction. It should be noted that 1-naphthoic acid or 2-
naphthoic acid derived amides were also applicable under the
standard conditions as well and their reactions afforded the
mono-cyanated product 3s in 60% yield or 3t in 74% yield,
respectively. Gratifyingly, a 2-thiophenecarboxylic acid derived
amide, a heteroaromatic substrate, was smoothly converted to
the corresponding cyanated product 3u in 83% yield. We were
disappointed to find that a 1-cyclohexene-1-carboxylic acid
derived amide failed to deliver the desired product when it was
subjected to the optimized conditions (not shown in Scheme
1).
promoted cyanation/cyclization tandem processes in a one-pot
procedure, regardless of the electronic nature of the
substituents on the starting materials. Halogen atoms such as
F, Br, and Cl were well compatible, which may be utilized for
further transformation (4h−4j, 4m, and 4o). One general trend
could be observed for the cyclization step is that arenes bearing
electron-withdrawing groups tend to react faster than electron-
rich benzamides. However, we failed to obtain the desired
product 4t in the reaction with 2-thiophenecarboxylic acid
derived amide, and only the product 3u was obtained in 83%
yield.
In order to highlight the synthetic utility of this protocol,
transformations of two products were performed (see Scheme
3 and the Supporting Information). Phthalic acid 5 can be
During the investigation of the scope of amide 1, we found
an interesting phenomenon. After the termination of the
cyanation step, DCM was added to the crude reaction mixture
and the reaction flask was opened to air for a period of time.
Surprisingly, the cyanated product 3a was transformed into 3-
imino-1-oxoisoindoline 4a in 62% yield. It should be pointed
out that 3-imino-1-oxoisoindolines are an important class of
heterocyclic compounds that can be found in medicines.17
Clearly the formation of 4a was due to base catalyzed
intramolecular cyclization. Then, we examined the scope and
limitations of this nickel-promoted cyanation and cyclization
tandem reaction (Scheme 2). Under the above-mentioned
reaction conditions, a variety of 3-imino-1-oxoisoindolines
could be synthesized in moderate to good yields via the nickel-
Scheme 3. Removal of the Directing Group and
Derivatization of the Obtained Products
obtained in 81% yield through basic hydrolysis of 3a (Scheme
3, eq 1). Meanwhile, the directing group was removed and
recovered in 91% yield. Furthermore, when 4i was treated with
sulfuric acid in tetrahydrofuran, the imine group could be
hydrolyzed to give dicarboximide 7 in 66% yield (Scheme 3, eq
2). Unfortunately, detachment of the directing group from 4 so
far has not been successful.
ab
,
Scheme 2. Scope of Cyclization of 3
Preliminary experiments were carried out to gain some
mechanistic insight (Scheme 4, eq 3). First, radical inhibition
Scheme 4. Preliminary Mechanistic Studies
experiments were performed. The reaction was not affected by
radical scavengers such as 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), 1,1-diphenylethylene (DPE), and butylated hydrox-
ytoluene (BHT). These results indicated that the reaction may
not involve radical processes. We next conducted several
experiments to measure the kinetic isotopic effect. The
competition reaction of a mixture of 1a and 1a-d5 with 2a
gave an intermolecular kinetic isotopic effect (KIE) value of 1.4,
a
Reaction conditions: amide 1 (0.2 mmol), 2 (0.4 mmol), Ni salt (0.4
mmol), base (0.4 mmol), solvent (2.0 mL), 100 °C under N2 for 1−6
h. After the cyanide reaction, add 10 mL of DCM and put it in the air
b
for 1−2 days. Isolated yield.
C
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Letter
Notes
whereas the parallel reaction provided a KIE of 1.5 (Scheme 4,
eq 4). These results indicated that the C−H activation step may
not be involved in the rate-limiting step.
The authors declare no competing financial interest.
On the basis of the above-mentioned experimental results
and previous reports,18 a plausible mechanism is proposed for
this nickel-promoted cyanation reaction (Scheme 5). Initially,
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01056.
Experimental procedure, characterization data, and NMR
spectra for all products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ztanze@gmail.com.
*E-mail: gqw1216@163.com.
ORCID
Ze Tan: 0000-0002-7156-5063
Author Contributions
§L.Y. and X.C. contributed equally.
D
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