Silver-Mediated [3 + 2] Cycloaddition of Alkynes and N-Isocyanoiminotriphenylphosphorane: Access to Monosubstituted Pyrazoles

Article abstract of DOI:10.1021/acs.orglett.9b00860

A silver-mediated [3 + 2] cycloaddition of "CNN" and "C≡C" for constructing pyrazoles has been described. The "CNN" building block used is N-isocyanoiminotriphenylphosphorane, which is a stable, safe, easy-to-handle, and odorless solid isocyanide. The reaction is characterized by its mild conditions, broad substrate scope, and excellent functional group tolerance.

Full text of DOI:10.1021/acs.orglett.9b00860

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver-Mediated [3 + 2] Cycloaddition of Alkynes and
N‑Isocyanoiminotriphenylphosphorane: Access to Monosubstituted
Pyrazoles
Fanhua Yi,†,§ Wanjun Zhao,†,§ Zikun Wang,*,† and Xihe Bi*,†,‡
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A silver-mediated [3 + 2] cycloaddition of “CNN”
and “CC” for constructing pyrazoles has been described. The
“CNN” building block used is N-isocyanoiminotriphenylphos-
phorane, which is a stable, safe, easy-to-handle, and odorless solid
isocyanide. The reaction is characterized by its mild conditions,
broad substrate scope, and excellent functional group tolerance.
lkynes1 and isocyanides2 are two classes of commercially
available and versatile starting materials. The reactions of
monosubstituted pyrazoles; such molecules show broad
biological activities, such as analgesic, antipyretic, antibacterial,
antihyperglycemic, and anti-inflammatory.5
A
alkynes and isocyanides are the most powerful and
representative route for the construction of nitrogen-
containing compounds.3 Among these reported protocols, [3
+ 2] cycloadditions of alkynes and isocyanides have attracted
much attention due to their high efficiency and atom-economy.
In the past, substantial advances have been achieved in the use
of this strategy for the synthesis of pyrroles and their
derivatives (Figure 1A).4 However, these processes often rely
NIITP, a functionalized isocyanide, is synthetically attractive
as a stable, safe, easy-to-handle, and odorless solid isocyanide.6
It is a versatile synthetic intermediate with a variety of
applications, serving as a key intermediate in multicomponent
reactions,7 as “NNC” sources in cyclization reactions,8 and as
one-carbon units in insertion reactions.9 Recently, our group
has reported the application of NIITP as a novel and safe
“cyano” source in the cyanation of alkynes.10 In a continuation
of our program, we sought to further explore and expand the
synthetic utility of NIITP. While taking advantage of NIITP as
a “CNN” source, we envisaged that NIITP could be utilized in
the [3 + 2] cycloaddition of alkynes and isocyanides.
To probe the feasibility of our hypothesis, we started our
investigation by reacting 1-ethynyl-4-methylbenzene (1a) and
NIITP (2) in the presence of Ag2CO3 and Mo(CO)6 (Table 1,
entry 1). Gratifyingly, after 12 h, pyrazole 3a was obtained in
54% yield. We then tested a variety of silver salts (entries 1−4).
Ag2CO3 was found to be the most suitable promoter for this
process, giving 3a in 54% yield (entry 1). A control experiment
confirmed the necessity of the silver catalyst in the reaction
(entry 5). In the absence of Mo(CO)6, the yield of 3a sharply
decreased to 18%, which suggests that Mo(CO)6 plays a
critical role in activating the isocyanide and promoting the
cycloaddition of the isocyanide and the alkyne (entry 6).11
A
Figure 1. [3 + 2] cycloaddition of alkynes and isocyanides.
range of other additives, including Cr(CO)6, W(CO)6,
Sc(OTf)3, and CuI were also evaluated instead of Mo(CO)6,
and all of them resulted in inferior yields (entries 7−10).
Among the tested solvents, THF provided the best yield
(entries 11−15). Additionally, a survey of various bases
on isocyanides with an α-acidic hydrogen, as these species
efficiently provide the “CNC” building block. To the best of
our knowledge, there are no examples of [3 + 2] cycloadditions
of alkynes and isocyanides lacking an α-acidic hydrogen.
Herein, we wish to report a novel silver-mediated [3 + 2]
cycloaddition of alkynes and NIITP for the assembly of
Received: March 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00860
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a−c
Table 1. Optimization of the Reaction Conditions
Scheme 1. Substrate Scope of Arylalkynes
b
entry
[Ag]
additive
solvent
base
3a, yield (%)
1
2
3
4
5
6
7
8
Ag2CO3
Ag3PO4
AgNO3
AgOTf
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
dioxane
DMF
PhCl
DME
THF
THF
THF
THF
54
33
<5
<5
0
18
10
23
<5
<5
<5
42
22
8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Cr(CO)6
W(CO)6
Sc(OTf)3
CuI
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
9
10
11
12
13
14
15
16
17
18
19
30
55
51
LiOH
t-BuONa
MeOLi
K2CO3
c
76 (76 )
39
a
Reaction conditions: 1a (0.5 mmol), 2 (1 mmol), [Ag] (0.5 equiv),
Mo(CO)6 (5 mol %), base (2 equiv) in THF (2.5 mL) at 60 °C for
b
12 h under Ar. Determined by 1H NMR spectroscopy using CH2Br2
as an internal standard. Isolated yield.
c
revealed that the nature of the counterion has a significant
impact on the reaction, and the utilization of MeOLi
substantially improved the yield of the pyrazole (entries 16−
19). We thus selected the conditions illustrated in entry 18 as
the optimal conditions for further evaluation of the substrate
scope.
a
Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), [Ag] (0.5 equiv),
Mo(CO)6 (5 mol %), base (2 equiv) in THF (2.5 mL) at 60 °C for
b
12 h under Ar. The yields were determined by 1H NMR
spectroscopy using CH2Br2 as an internal standard. The yields in
parentheses are isolated yields.
c
a−c
With the optimal conditions in hand, we then explored the
scope of this cycloaddition reaction first with respect to
arylalkynes (1), and the results are shown in Scheme 1. The
results revealed that the electronic effect of the substituent on
the aryl acetylene had little effect on the reaction. However, the
position of the substituents and the associated steric hindrance
had a significant impact on the yield of the desired product.
The ortho-substituted arylalkyne (1c) gave the corresponding
products in a lower yield than the meta- (1d−g) or para-
substituted arylalkynes (1h−p). In addition, arylalkynes with
less steric hindrance would readily undergo the cycloaddition.
Disubstituted aryl- (1q and 1r) and naphthylalkynes (1s) were
also smoothly converted to the corresponding products in
good yields. Notably, alkynes bearing heterocycles, including
pyridyl (1t) and thienyl (1u) moieties, gave the desired
products in good yields. Several pyridyl pyrazoles have been
used in pharmaceutical chemistry; for example: LY-36494712 is
an ATP-competitive and tight-binding inhibitor, 4-(1H-
pyrazol-3-yl)pyridine13 is a kinase inhibitor, and morpholino-
(3-(pyridin-3-yl)-1H-pyrazol-1-yl)methanone14 is an FAAH
inhibitor.
Scheme 2. Substrate Scope of Alkyl- and Alkynylalkynes
a
Reaction conditions: 4 (0.5 mmol), 2 (1 mmol), [Ag] (0.5 equiv),
Mo(CO)6 (5 mol %), base (2 equiv) in THF (2.5 mL) at 60 °C for
b
12 h under Ar. The yields were determined by 1H NMR
Next, we examined a variety of alkyl- and alkenylalkynes (4)
with NIITP under the optimal conditions (Scheme 2). A series
of alkynes bearing alkyl (4a), benzyl (4b), phenylethyl (4c),
and cycloalkyl (4d−f) substituents exhibited good reactivities
c
spectroscopy using CH2Br2 as an internal standard. The yields in
parentheses are isolated yields.
B
DOI: 10.1021/acs.orglett.9b00860
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Organic Letters
Letter
but afforded the corresponding alkylpyrazoles in lower yields
than those obtained from aryl-substituted substrates. Interest-
ingly, eneynes, including a cycloeneyne (4g) and linear eneyne
(4h), were also acceptable substrates for this cycloaddition
reaction. Moreover, functionalized pyrazoles (5j, k) could also
be prepared by this protocol.
“CC” sources are alkynes which are commercially available
and versatile staring materials, and the “NNC” source is
NIITP, which is a safe, easy-to-handle, and odorless solid
isocyanide. Mechanistic investigations revealed that the silver
acetylide derived from ion exchange between the alkyne and
Ag2CO3 was the key intermediate for the cycloaddition.
Further studies on the utilization of NIITP are ongoing in our
group.
To elucidate the reaction mechanism, two control experi-
ments were carried out (Scheme 3). First, the reaction of silver
ASSOCIATED CONTENT
* Supporting Information
Scheme 3. Mechanistic Investigations
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00860.
Experimental procedures along with characterization
data and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
acetylide (6) and NIITP (2) was performed under the
standard conditions, but in the absence of Ag2CO3. As
expected, pyrazole 3a was obtained in 79% yield (eq 1). Next,
substrate 1a and NIITP (2) were subjected to the standard
reaction conditions, except H2O was replaced by D2O.
Deuterium labeling at both C3 (86%) and C4 (83%) was
observed by 1H NMR spectroscopy (eq 2). Both results
demonstrated that the activation of the alkyne by the silver is
vital in this cycloaddition, and silver acetylide was the key
intermediate.
*E-mail: wangzk076@nenu.edu.cn.
*E-mail: bixh507@nenu.edu.cn.
ORCID
Zikun Wang: 0000-0002-8672-4311
Xihe Bi: 0000-0002-6694-6742
Author Contributions
§F.Y. and W.Z. contributed equally to this work.
Notes
On the basis of previous studies15 and the above-described
experimental results, we developed a plausible mechanism for
the [3 + 2] cycloaddition of alkynes and NIITP (Figure 2).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21871043, 21522202, 21502017,
21604082) and the Department of Science and Technology
of Jilin Province (20180101185JC, 20190701012GH) is
acknowledged.
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C
DOI: 10.1021/acs.orglett.9b00860
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DOI: 10.1021/acs.orglett.9b00860
Org. Lett. XXXX, XXX, XXX−XXX