BF3-Etherate-Promoted Cascade Reaction of 2-Alkynylanilines with Nitriles: One-Pot Assembly of 4-Amido-Cinnolines

Article abstract of DOI:10.1021/acs.orglett.6b01207

A BF₃-etherate-promoted cascade reaction of nitriles with 2-alkynylanilines is described. This method achieves the formation of two new C-N bonds through a reaction sequence of diazotization with t-BuONO, nucleophilic addition of the alkyne to

Full text of DOI:10.1021/acs.orglett.6b01207

Letter
pubs.acs.org/OrgLett
BF3‑Etherate-Promoted Cascade Reaction of 2‑Alkynylanilines with
Nitriles: One-Pot Assembly of 4‑Amido-Cinnolines
Gopal Chandru Senadi,†,§ Babasaheb Sopan Gore,†,§ Wan-Ping Hu,‡ and Jeh-Jeng Wang*,†
‡
†Department of Medicinal and Applied Chemistry and Department of Biotechnology, Kaohsiung Medical University, No. 100,
Shih-Chuan First Road, Sanmin District, Kaohsiung City 807, Taiwan
S
* Supporting Information
ABSTRACT: A BF3-etherate-promoted cascade reaction of
nitriles with 2-alkynylanilines is described. This method
achieves the formation of two new C−N bonds through a
reaction sequence of diazotization with t-BuONO, nucleophilic
addition of the alkyne to the BF3-coordinated diazonium ion,
followed by nitrile addition to the intermediary vinyl cation
and hydrolysis. The method provides efficient and general access to a variety of 4-amido-cinnolines. Notable features of the
method include its broad functional group tolerance and avoidance of transition metals.
innolines and their derivatives are a pivotal class of aza-
heterocycles with multifarious applications as bioactive
electrophiles to form N-nitrilium ions followed by a cascade
reaction is still an unexplored area of research.12 In this context,
and as part of our research into metal-free reactions,13 herein
we report an alternative method for cinnoline synthesis via BF3-
etherate-promoted cascade cyclization of o-alkynylanilines with
nitriles in the presence of tert-butyl nitrite. The method allows
for the construction of 4-amido-cinnolines via dual C−N bond
formation for the first time (Scheme 1). We envision that the
C
cores (Figure 1).1 They also play a role in organic synthesis2
Scheme 1. Our Approach for 4-Amido-cinnolines
Figure 1. Biologically active cinnoline derivatives.
and electrochemistry,3 and they have useful optical4a and
luminescent properties.4b Despite this, the synthesis of
cinnolines has been less frequently investigated.
Traditional methods for the synthesis of cinnolines utilize the
ring-closure of in situ-generated phenyldiazonium ions onto
ortho functionality.5 In the case of the Ritcher cinnoline
synthesis, the reaction proceeds via an intramolecular
cyclization of the ortho-alkyne functionality in the presence of
a hydrohalic acid, such as HBr or HCl and NaNO2, to afford a
mixture of halocinnolines and cinnolinones.6 However,
restricted substrate scope, activated alkynes, and strongly acidic
conditions limit their application.5,6 Aiming to improve the
efficiency of substrate scope and mild reaction conditions,
recently a few methodologies based on metals7 and metal-free8
strategies have been developed for the synthesis of cinnolines.
Although these methods provide fruitful access to cinnoline
derivatives, hitherto there has been no literature precedent for
the straightforward construction of 4-amido/amino-cinnoline-
s.2a,9
reaction proceeds via diazotization,14 the intramolecular
nucleophilic addition of the alkyne to the diazonium ion to
form a vinyl cation followed by nitrile addition to the vinyl
cation and hydrolysis.
As shown in Table 1, our preliminary investigation began
with easily accessible 2-(phenylethynyl)aniline 1a and acetoni-
trile 2a as model substrates. To our surprise, 4-amido-cinnoline
3aa was obtained in 30% yield when these substrates were
treated with BF3·Et2O (1.0 equiv), t-BuONO (2.0 equiv), and
CH3CN (0.5 mL) at room temperature for 18 h (Table 1, entry
1). The structure of compound 3aa was confirmed
unambiguously by X-ray analysis.15 Subsequent work (Table
1, entries 2−4) eventually revealed that 4.0 equiv of BF3·Et2O
and 7 h gave 3aa in 90% yield (Table 1, entry 4). Other acids
such as AcOH, benzoic acid, TFA, TfOH, TsOH, PivOH, and
HCl resulted in low yields when evaluated in this process
In recent decades, transition-metal-free reactions have
become indispensable tools in organic synthesis.10 The
utilization of nitrile derivatives for the construction of
heterocyclic rings is particularly well-established.11 However,
the addition of weak nucleophiles like nitriles onto π-
Received: April 25, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01207
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Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of o-Alkynylanilines with Acetonitrile
b
entry
acid (equiv)
“N” source
solvent
neat
time, h yield (%)
1
2
3
4
5
BF3·Et2O (1)
BF3·Et2O (2)
BF3·Et2O (4)
BF3·Et2O (4)
BF3·Et2O (5)
BF3·Et2O (4)
AcOH (4)
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
TBN
amyl nitrite
NaNO2
NaNO2
TBN
TBN
TBN
18
18
14
7
30
48
neat
neat
64
neat
neat
90
7
73
c
6
neat
7
71
7
neat
7
trace
0
8
PhCOOH (4)
TFA (4)
neat
24
7
9
neat
36
10
11
12
13
TfOH (4)
neat
7
65
TsOH (4)
neat
7
trace
0
PivOH (4)
neat
7
HCl (4)
neat
7
<20
trace
trace
45
d
14
BF3·Et2O (4)
BF3·Et2O (4)
BF3·Et2O (4)
BF3·Et2O (4)
BF3·Et2O (4)
BF3·Et2O (4)
BF3·Et2O (4)
BF3·Et2O (4)
HCl (4)
toluene
dioxane
DCE
PhCl
CH3NO2
THF
neat
7
d
15
7
d
16
7
d
17
d
7
32
18
7
<10
<10
76
d
19
7
20
21
22
7
neat
7
<10
trace
73
neat
7
e
23
f
BF3·Et2O (4)
BF3·Et2O (4)
neat
7
24
neat
7
30
25
neat
7
0
a
All reactions were carried out using 1a (0.51 mmol), 2a (0.5 mL),
acid, and “N” source (2.0 equiv) at room temperature (25 °C) unless
otherwise noted. TBN = tert-butyl nitrite. PhCl = chlorobenzene.
Entry in bold represents the optimized reaction conditions. Neat
represents acetonitrile (0.5 mL) as reagent and solvent. TFA =
trifluoroacetic acid. TfOH = trifluoromethanesulfonic acid. TsOH = p-
toluenesulfonic acid. PivOH = pivalic acid. HCl = hydrochloric acid.
a
Reaction conditions: Compounds (1a-r, 0.51 mmol), acetonitrile (2a,
0.5 mL), t-BuONO (1.02 mmol) and BF3·Et2O (2.04 mmol) at rt for
indicated time. Isolated yields.
b
c
d
Isolated yields. At 60 °C. Used 2.0 equiv of acetonitrile and solvent
e
f
(2.0 mL). Added 2.0 equiv of H2O. Used 1.0 equiv of TBN.
Ph (1e), and p-COOMe-Ph (1f), worked well to afford the 4-
amido-cinnoline derivatives 3ba−fa in 42−75% yields. The
reaction also proceeded smoothly for the alkyl (1g) derivative
of the R1 group to afford 3ga in 73% yield. We next evaluated
the scope of the R group with electron-donating and
-withdrawing substituents like p-Me (1h), p-Et (1i) p-F (1j),
p-Cl (1k), p-Br (1l), p-CF3 (1m), p-COOMe (1n), and 2,4-di-
Me (1o). The reaction proceeded well to give compounds
3ha−3oa in 52−84% yields. In general, the reaction rate was
comparatively slower when electron-withdrawing substituents
were present in the R or R1 group. However, terminal alkyne
(1p) or p-NO2 (1q) on R and o-F-Ph (1r) on the R1 group
gave trace amounts or no product at all.
In light of our success with o-alkynylaniline derivatives, we
next envisioned the synthesis of 4-amido-cinnolines with
various nitrile derivatives, as shown in Scheme 3. The reaction
worked well with aromatic nitriles such as benzonitrile (2b) and
3-methoxybenzonitrile (2c) to afford the corresponding 4-
amido-cinnoline derivatives 3ab and 3ac in 71−86% yields.
Furthermore, the feasibility of the reaction was investigated
with alkyl nitriles such as 4-phenylbutyronitrile (2d),
propionitrile (2e), and isobutyronitrile (2f). The reaction
(Table 1, entries 7−13). The effect of solvents was tested by
using CH3CN (2.0 equiv) with toluene, 1,4-dioxane, 1,2-
dichloroethane, chlorobenzene, nitromethane, and THF (Table
1, entries 14−19). However, none of them gave a better yield
than entry 4. By replacing t-BuONO with amyl nitrite, 3aa was
formed in 76% yield (Table 1, entry 20). The reaction gave
complex mixtures with NaNO2 and HCl (Table 1, entries 21
and 22). For nitrilium hydrolysis, we presumed that the
addition of water (2.0 equiv) could facilitate the reaction.
However, we found no positive observation (Table 1, entry 23).
Reducing the quantity of t-BuONO (1.0 equiv) led to a low
yield (Table 1, entry 24). The reaction also failed to yield
compound 3aa in the absence of BF3·Et2O (Table 1, entry 25).
Thus, the reaction conditions mentioned in Table 1, entry 4
were chosen as the optimum conditions.
As shown in Scheme 2, the scope and limitations of this
method were investigated by systematic variation of the o-
alkynylanilines (1a−r) with acetonitrile 2a under standard
conditions. A series of substituents on the R1 functionality, such
as p-Me-Ph (1b), m-OMe-Ph (1c), 3,4-di-F-Ph (1d), m-NO2−
B
DOI: 10.1021/acs.orglett.6b01207
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Organic Letters
Letter
a
Scheme 3. Scope of nitriles with 2-(phenylethynyl)aniline
Scheme 5. Control Experiments
enamide 6aa with a second nitrile via an addition−elimination
sequence.16 Similar results were observed with propionitrile, as
shown in eq 4. Next, we examined the reaction of 1a without a
nitrile source and isolated diphenyl acetylene 5a in 42% yield
(eq 5). The reason for the low yield of diphenylacetylene 5a
formation can be attributed to the lower stability of in situ-
generated o-alkynylphenyldiazoniums in the absence of a nitrile.
These results suggest that the reaction proceeds through
diazotization followed by nucleophilic addition of the alkynes to
the diazonium ions. A plausible mechanism is shown in Scheme
6.
a
Reaction conditions: Compound (1a, 0.51 mmol), nitriles (2b-k, 0.5
mL), t-BuONO (1.02 mmol) and BF3·Et2O (2.04 mmol) at rt for
indicated time. Isolated yields.
smoothly afforded 3ad−af in 72−76% yields. Interestingly, the
reaction also worked well with acrylonitrile (2g) and
cinnamonitrile (2h) to generate the corresponding acrylamide
(3ag) and cinnamamide (3ah) derivatives, respectively, in 47−
82% yields. However, the reactions of 3-oxo-3-phenylpropane-
nitrile (2i), bromoacetonitrile (2j), and trichloroacetonitrile
(2k) gave traces or no product.
Scheme 6. Plausible Reaction Mechanism
The practicality of this reaction has been investigated on a
2.0 g scale for the synthesis of compound 3aa, as shown in
Scheme 4. The reaction went smoothly, affording N-(3-
Scheme 4. Gram Scale and Deacylation Reaction
In conclusion, we have developed a one-pot cascade reaction
strategy for the construction of 4-amido-cinnoline derivatives.
The process involves two C−N bond formations under
transition-metal-free conditions. The notable advantages are
broad functional group tolerance, ambient reaction temper-
ature, and moderate to good reaction yields alongside the
introduction of an amide functional group.
phenylcinnolin-4-yl)acetamide in 79% yield (eq 1). Further-
more, we also hydrolyzed the N-acetyl group under acidic
conditions to afford the amine for possible library work (eq 2).
For some preliminary understanding of the reaction
mechanism to be obtained, a few control experiments were
carried out as shown in Scheme 5. The reaction of
diphenylacetylene 5a with acetonitrile 2a under the standard
conditions, without t-BuONO, gave enamide 6aa as the major
product and pyrimidine 7aa as a minor product (eq 3). We
presume that compound 7aa was obtained by the reaction of
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.6b01207.
Experimental procedures, spectroscopic data and copies
of NMR spectra for all new compounds (PDF)
X-ray crystallographic data for 3aa (CIF)
C
DOI: 10.1021/acs.orglett.6b01207
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jjwang@kmu.edu.tw.
Author Contributions
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§G.C.S. and B.S.G. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge funding from the ministry
of science and technology (MOST), Taiwan, and the Centre
for Research and Development of Kaohsiung Medical
University (KMU) for 400 MHz NMR analyses. The authors
thank Ms. Chyi-Jia Wang (KMU) for her NMR experimental
assistance.
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