Dual Reactivity of 1,2,3,4-Tetrazole: Manganese-Catalyzed Click Reaction and Denitrogenative Annulation

Article abstract of DOI:10.1002/anie.202009078

A general catalytic method using a Mn-porphyrin-based catalytic system is reported that enables two different reactions (click reaction and denitrogenative annulation) and affords two different classes of nitrogen heterocycles, 1,5-disubstituted 1,2,3-triazoles (with a pyridyl motif) and 1,2,4-triazolo-pyridines. Mechanistic investigations suggest that although the click reaction likely proceeds through an ionic mechanism, which is different from the traditional click reaction, the denitrogenative annulation reaction likely proceeds via an electrophilic metallonitrene intermediate rather than a metalloradical intermediate. Collectively, this method is highly efficient and offers several advantages over other methods. For example, this method excludes a multi-step synthesis of the N-heterocyclic molecules described and produces only environmentally benign N₂ gas a by-product.

Full text of DOI:10.1002/anie.202009078

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Dual Reactivity of 1,2,3,4-Tetrazole: Manganese-Catalyzed Click
Reaction and Denitrogenative Annulation
Authors: Buddhadeb Chattopadhyay, Hillol Khatua, Sandip Kumar
Das, and Satyajit Roy
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009078
Link to VoR: https://doi.org/10.1002/anie.202009078

10.1002/anie.202009078
Angewandte Chemie International Edition
RESEARCH ARTICLE
Dual Reactivity of 1,2,3,4-Tetrazole: Manganese-Catalyzed Click
Reaction and Denitrogenative Annulation
Hillol Khatua, Sandip Kumar Das, Satyajit Roy, and Buddhadeb Chattopadhyay*
Abstract: A general catalytic method using Mn-porphyrin-based
catalytic system is discovered that enables two different reactions
(click reaction and denitrogenative annulation) affording two different
classes of nitrogen heterocycles, such as 1,5-disubstituted 1,2,3-
Thus, considering this challenge, we initiated an investigation to
capture the N-pyridyl metal-nitrene from this 1,2,3,4-tetrazole
hypothesizing that the N-pyridyl metal-nitrene would be applied for
the construction of various N-heterocyclic scaffolds. To our delight,
we discovered a new method to access N-pyridyl metal nitrenes
using an Cp*Ir(III) cation through an electrocyclization to construct
aza-carbazoles and aza-indoles (Figure 1C).[10] Although, this was
the first catalytic method of capturing productively a N-pyridyl nitrene
from a 1,2,3,4-tetrazole, where the presence of the pyridine changes
the fragmentation to produce a nitrene instead of the metal carbene
as reported earlier by Murakami and co-workers,[ 11 ] the method
suffer from many shortcomings, such as, highly expensive Cp*Ir
catalyst, high catalyst loadings, high reaction temperature, only
applicable for the intramolecular amination/annulation and limited
scope for other synthetic transformations. Using that developed
method, we attempted to make many important and valuable N-
heterocyclic molecules, for example, 1,5-disubstituted-1,2,3-triazoles
(bearing the pyridyl handle in one side of the triazole for the
medicinal applications), although, we did not get any success.
Moreover, attempted synthesis of the 1,2,4-triazoles that are the
main API of many scaffolds were unsuccessful (Figure 1D).[12] To
overcome these shortcomings, we also developed a method using
Fe-based metalloradical strategy,[3] where we have demonstrated a
complete switch from the traditional click reaction towards the
triazoles (with
a
pyridyl motif) and 1,2,4-triazolo-pyridines.
Mechanistic investigations suggest that while click reaction likely
proceeds through an ionic mechanism, which is different from the
traditional click reaction, denitrogenative annulation undergoes likely
via an electrophilic metallonitrene intermediate rather than the
metalloradical intermediate. Collectively, the discovered method is
highly efficient that offer obvious advantages over other methods, as
it excludes multi-step synthesis of these classes of N-heterocyclic
molecules and produces only environmentally benign N2 gas by-
product.
Introduction
I
n the chemical community, organic azide is considered as one of
the most intriguing and versatile synthetic intermediates[1] that have a
profound role in diverse fields of research. These are the key
components for the construction of complex N-heterocycles[2,3] owing
to the high reactivity, easy availability, empowerment of exhibiting
different kinds of synthetic transformations via either click reaction
(1,3-cycloaddition) or the formation of metal-nitrene with transition
metal catalysts.[4] Similarly, it has also been demonstrated that 1,2,3-
13
]
intermolecular denitrogenative annulation (Figure 1E).[
The
triazoles could be utilized as an important precursory platform for a
, 6 ]
wide number of useful reactions,[ 5
which undergo via the
reaction underwent via the generation of the metalloradical radical
intermediate. Unfortunately, this method also does not solve the
problems as stated earlier. Here, we report a general Mn-catalyzed
system that enables a highly site selective 1,3-cycloaddition (click
reaction) giving exclusively the 1,5-disubstituted click reaction
product and a denitrogenative annulation for the quick access of
1,2,4-triazoles[ 14 ] (Figure 1F). Importantly, these are the core
structural unit of numerous medicinally important molecules (Figure
1D). The discovered method is highly efficient and offer obvious
advantages over other methods, as it excludes multi-step synthesis
of these classes of N-heterocyclic molecules and produces only
environmentally benign N2 gas by-product.
generation of metal-carbene with transition metal catalysts. In sharp
contrast, whereas the chemistry of organic azides and 1,2,3-triazoles
studied extensively, 1,2,3,4-tetrazole (a surrogate of azide[7] bearing
an important pyridyl unit) remained almost unutilized. In 1969,
Huisgen and Fraunberg for the first time studied[8] the reactivity of
1,2,3,4-tetrazole (Figure 1A) and developed three important
reactions, such as, (i) Cu-powder-catalyzed synthesis of nitrogen
heterocycles at 120 oC, which undergo via a Cu-nitrene intermediate
(ii) cycloaddition reactions with alkynes, and (iii) intermolecular
aminations. While these pioneering results revealed excellent
opportunity for the development of new synthetic methods,
unfortunately, the chemistry was not developed. On the other hand,
since the last four decades, only nitrene-nitrene rearrangement of
1,2,3,4-tetrazole has been investigated using flash vacuum process
at high reaction temperature (>500 oC), pioneered by Wentrup group
(Figure 1B).[9] Thus, these experimental findings by Huisgen and
Fraunberg, and Wentrup led us an important conclusion that the
nitrene generated by the FVT at high reaction temperature, if
trapped by catalytic amount of transition metal, could be utilized as
an important intermediate for the organic synthesis, although
extremely difficult and challenging.
Result and Discussion
At the outset of this investigation, we first attempted the proposed
click reaction between the tetrazole (1a) and phenylacetylene (2a)
using the reported reaction conditions.[13] However, what we
observed is either no reactions or a traditional click reaction for the
preparation of 1,4-disubstituted 1,2,3-triazoles and in some cases a
mixture of 1,4- and 1,5-disubstituted-1,2,3-triazoles (Table 1, entries
1-3, see SI for details). Since, Ru complexes are known[4h] to
produce the 1,5-click product from simple organic azides, thus we
were curious whether the Ru-catalyzed conditions would be
applicable for this complex tetrazole system. Accordingly, we tested
various Ru-based catalytic systems. Unfortunately, none of them
exhibited their catalytic activity towards the formation of the trace
amount of the products (entries 4-5).
Mr. H. Khatua, Mr. S. K. Das, Mr. S. Roy, Prof. Dr. B. Chattopadhyay
Division of Molecular Synthesis & Drug Discovery, Centre of Bio-Medical
Research (CBMR), SGPGIMS Campus, Raebareli Road, Lucknow 226014,
U.P., India.
E-mail: buddhadeb.c@cbmr.res.in, buddhachem12@gmail.com
Homepage: http://www.buddhacbmr.org/
This article is protected by copyright. All rights reserved.

10.1002/anie.202009078
Angewandte Chemie International Edition
RESEARCH ARTICLE
(C) Our Previous Work: Intramolecular Denitrogenative Annulation
(B) Wentrup’s Pioneering FVT Studies of 1,2,3,4-Tetrazole
••
••
•
N
•
•
R
•
•
•
Iridium-nitrene derived from tetrazole
Reaction type: Intramolecular denitrogenative annulation
Reaction mechanism: Electrocyclization
N
•
N
N
•
•
N
N
R
R
> 500 o
C
R1 = H
R1
Ph
R
R
N
[Ir]
N
N
cat. IrCp*
N2
N2
N
NC
CN
N
N
N
N
N
R
N
H
H
R = H
H
(A) Huisgen & Fraunberg’s Pioneering Studies of 1,2,3,4-Tetrazole
Highly important
scaffold
R3
high temp.
R2
N
N
Ar
NH
Ph
applications: rare
N
N
N
N
N
N
with PhCN
(via Cu-nitrene)
with arene
(amination)
with alkyne
(cycloaddition)
(D) Representative Examples of Pyridyl-Bearing 1,5-Disubstituted 1,2,3-Triazoles & 1,2,4-Pyridotriazoles
Cl
HO
B
F
O
Me
O
N
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
N
N
N
N
H
F
Agrochemical
for treating Parasitic infections
ASK1 inhibitors
COOH
ASK1 inhibitors
Cl
N
N
N
Me
N
NH
NH2
N
N
N
N
N
N
N
Me
Me
N
N Me
Me
N
N
O
N
N
Me
SO2NHtBu
Anti-inflamatory
SO2Me
Anti-diabetic
Anticancer
used for CNS disorders
(E) Our Previous Work: Intermolecular Denitrogenative Annulation
Radical Mechanism (Previous Work)
(F) This Work: Click Reaction & Denitrogenative Annulation
Ionic Mechanism
No Annulation
Reaction
Ar
N
Intermolecular
Annulation
N
(This Work)
•
N2
N
Ar
N
N
X
N
N
III
Mn
N
N
only by-product
N2 gas
N
-N2
N
N
II N
Fe
N
cat. Zn
Fe(TPP)Cl
Ar
Metalloradical
Intermediate
(Mn-NR-Int-1)
N
N
Metal-bound
Complex
(Fe-MBC-1)
No Click
Reaction
X
•
N2
N
Ar
N
N
N
N2
cat. Zn
Mn(TPP)Cl
Click
Reaction
N
N
N
N
Ar
N
N
III
N
N
N
N
II N
Fe
N
X
-N2
Mn
N
X
N
N
N
N
Ar
N
3
N2
Tetrazole
Metalloradical
Intermediate
(Fe-NR-Int-1)
Metal-bound
Complex
(Mn-MBC-1)
Tetrazole
N
N
N
Intermolecular
Annulation
No Annulation
Reaction
N
CuI
N
Ar
N
N
Ar
N
N
IV
N
N
IV
Mn
N
N
N
N
Ar
X
Fe
N
N
6
Metal-Nitrene
Intermediate
Metal-Nitrene
Intermediate (Fe-N-Int-1)
(Mn-N-Int-1)
Figure 1. (A), Huisgen and Fraunberg’s pioneering work of 1,2,3,4-tetrazole. (B), Wentrup’s pioneering work for nitrene-nitrene
rearrangement of 1,2,3,4-tetrazoles via FVT process. (C), First report of pyridyl-bearing Ir-nitrene intermediate derived from 1,2,3,4-tetrazoles
for organic synthesis. (D), Representative examples of important molecules pyridyl-bearing 1,5-disubstituted-1,2,3-triazoles and 1,2,4-
pyridotriazoles. (E), Previous report of metalloradical activation of 1,2,3,4-tetrazoles for intermolecular denitrogenative annulation. (F),
Proposed design principle for the present work of 1,3-cycloaddition (click reaction) and denitrogenative annulation with nitriles.
the proposed blueprint is based on two important considerations.
For the ineffectiveness of these catalysts, we reasoned that the
Firstly, requirement of a similar type of porphyrin-based catalytic
azide coordinated Ru-catalyst is deactivated[15] by the chelation with
system that would be different from our previous design principle
the nitrogen atom of the pyridine ring. Next, considering our prior
that would enforce the reaction through an ionic mechanism
working hypothesis using Fe-nitrene radical intermediate (Fe-NR-Int-
generating a metal-bound nitrene type of intermediate instead of the
1) and the importance of the Mn-catalytic systems for various
Fe-nitrene radical intermediate. For that reason, we considered to
synthetic transformations,[16] we made a blueprint. The foundation of
design Mn-based porphyrin systems. The logic behind the selection
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10.1002/anie.202009078
Angewandte Chemie International Edition
RESEARCH ARTICLE
of the porphyrin is that due to the relatively bulkiness of the metal-
porphyrin system, which would prevent the additional coordination of
the metal with the pyridine ring and will facilitate the reaction.
Secondly, replacement of Fe to Mn system that would switch the
radical activation mechanism towards the ionic mechanism.
Table 1. Screening and Optimization of the Click Reactiona
Ph
2.0 equiv.
Ph
N
N
[M]-cat., reductant
N
N
N
Ph
N
NH2
N
N
N
C6H6, T oC, 24 h
N
N
N
N
1a
3a"
3a (1,5)
3a'(1,4)
Entry
1
[M]-cat. (mol%)
Cu(OTf)2•C6H6 (20)
CuI (20)
Reductant (mol%)
T oC
3a/3a'/3a"
0/100/0
0/100/0
25/65/10
0/0/0
Conversion (%)
-
130
130
130
100
100
130
130
130
100
100
80
>99
2
-
>99
3
Ag(OAc)/bpy (20)
RuCp(Cl)(PPh3)2 (5)
RuCp*(Cl)(PPh3)2 (5)
Mn(TPP)Cl (5)
Mn(TPFPP)Cl (5)
Mn(pc) (5)
-
>99
4
-
0
5
-
0/0/0
0
6
-
0/0/0
0
7
-
0/0/0
0
8
-
0/0/0
0
9b
10
11
12
13
Fe(TPP)Cl (5)
Zn (10)
Zn (10)
Zn (40)
Zn (40)
Zn (10)
0/0/0
0
>99 (85)c
82 (73)c
42d
Mn(TPP)Cl (5)
Mn(TPP)Cl (20)
Mn(TPP)Cl (20)
Mn(salen)Cl (5)
90/0/10
95/0/05
100/0/0
0/0/0
60
100
0
b
c
d
aReactions were conducted in 0.5 mmol scale. 99% annulated product was observed. In parenthesis isolated yield is reported. Reaction
was run for 90 h.
Following this blueprint, we screened several Mn-based catalysts
(Table 1) and some of them are Mn(TPP)Cl, Mn(TPFPP)Cl,
Mn(TMPP)Cl, but all these catalysts were found to be inactive to
produce the 1,5-triazoles. Moreover, salen and pthalocyanin
framework-based Mn-catalysts, such as Mn(salen)Cl, Mn(pc) and
Mn(pc)SbF6 were also proved to be unsuccessful (see SI for details).
Notably, in our earlier report, we have shown that the in situ
generated Fe(II)(TPP) was effective catalyst for the denitrogenative
annulation with alkyne, although click reaction was completely failed.
Thus, we questioned that what would occur if we replace the Fe by
the Mn in this reaction? Can we develop an active catalytic system
that would follow as per our proposed blueprint to deliver the desired
product? Accordingly, we performed a reaction using Zn as a
presence of Mn(salen)Cl and Zn-dust (entry 13), which gave no
reaction and thus indicating the essential role of the porphyrin unit in
this catalytic reaction. Importantly, since we have noticed 10% amine
(3a”) as by-product during the course of the click reaction, the origin
of the amine might be via the generation of the corresponding Mn-
nitrene intermediate as proposed in the design principle (Figure 1F).
Using these optimal reaction conditions (conditions-A, entry 10,
Table 1 and conditions-B, entry 11, Table 1), we then assessed the
generality of the 1,3-cycloaddition (click reaction) with respect to the
terminal alkynes, alkyne-bearing important biomolecules and various
types of 1,2,3,4-tetrazoles and the results are summarized in Figure
2 (for detailed discussion, see SI). To demonstrate the utility of the
established method, we applied the conditions for the short
synthesis of ASK1 inhibitor (4) in gram scale (Figure 2B).[19] To
expand the repertoire of the Mn-catalyzed click reaction, the
developed reaction was explored to include some selected and
important biomolecule bearing alkynes, such as alkaloids,
carbohydrates and estrones. To our delight, all of these biomolecule
bearing alkynes underwent 1,3-cycloaddition (click) reactions to
afford the desired products in good yields (3ad-3ah). Notably, the
regiochemical assignments were confirmed by the 2D-NMR (see SI
for details) and other spectroscopic data.[20]
o
reductant in presence of Mn(TPP)Cl at 100 C. Remarkably, we got
exclusively the 1,5-disubstituted triazole[ 17 ] (3a) along with 10%
amine (3a") (entry 10).[ 18 ] To suppress the amine (3a"), several
reactions were performed changing catalyst loadings, reductant
loadings and temperature (see SI for details) and we observed that
the amine (3a") can be suppressed in presence of 20 mol% catalyst
and 40 mol% Zn at either 80 oC temperature (entry 11) that 73%
o
isolated pure product (3a) and 5% (3a") or 60 C temperature (entry
12) that afforded only 40% conversion without any amine (3a"). Next,
to verify the role of porphyrin unit, we performed a reaction in
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10.1002/anie.202009078
Angewandte Chemie International Edition
RESEARCH ARTICLE
conditions-A:
R
conditions-B:
R
developed conditions
N
R
5.0 mol% Mn(TPP)Cl,
10 mol% Zn, C6H6,
100 oC, 24 h
20 mol% Mn(TPP)Cl,
40 mol% Zn, C6H6,
80 oC, 24 h
N
N
N
+
N
N
N
N
1
R
2
3
(A)
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
BnO
tBu
Cl
Ph
conditions-A, 3c: 58%
conditions-B, 3c: 53%
conditions-A, 3e: 71%
conditions-B, 3e: 63%
conditions-A, 3f: 70%
conditions-B, 3f: 62%
conditions-A, 3g: 88%
conditions-B, 3g: 79%
conditions-A, 3b: 65%
conditions-B, 3b: 58%
conditions-A, 3d: 90%
conditions-B, 3d: 78%
N
N
N
N
N
N
N
N
N
MeO
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Br
Me
OMe
tBu
Cl
Me
conditions-A, 3k: 80%
conditions-B, 3k: 69%
conditions-A, 3l: 72%
conditions-B, 3l: 61%
conditions-A, 3h: 70%
conditions-B, 3h: 64%
conditions-A, 3i: 67%
conditions-B, 3i: 56%
conditions-A, 3j: 58%
conditions-B, 3j: 49%
conditions-A, 3m: 75%
conditions-B, 3m: 66%
CF3
Me
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
tBu
N
N
MeO2C
N
N
N
tBu
N
tBu
F
tBu
tBu
conditions-A, 3q: 58%
conditions-B, 3q: 57%
conditions-A, 3o: 68%
conditions-B, 3o: 59%
conditions-A, 3p: 65%
conditions-B, 3p: 57%
conditions-A, 3s: 62%
conditions-B, 3s: 60%
conditions-A, 3r: 55%
conditions-B, 3r: 51%
conditions-A, 3n: 73%
conditions-B, 3n: 65%
Me
Cl
Br
CF3
Ph
EtO2C
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
tBu
tBu
tBu
tBu
tBu
tBu
conditions-A, 3t: 55%
conditions-B, 3t: 49%
conditions-A, 3u: 65%
conditions-B, 3u: 52%
conditions-A, 3v: 55%
conditions-B, 3v: 48%
Me
conditions-A, 3w: 58%
conditions-A, 3x: 69%
conditions-B, 3x: 68%a
conditions-A, 3y: 51%
conditions-B, 3y: 75%a
conditions-B, 3w: 55%a
Et2NOC
Ph
(B)
Me
Br
one step
N
N
N
N
N
N
Br
N
N
N
N
N
N
N
N
N
N
N
N
N
N
tBu
O
tBu
N
tBu
Gram scale synthesis
ASK1 Inhibitor
4: 70%
conditions-A, 3aa: 49%
conditions-B, 3aa: 38%
conditions-A, 3ab: 67%
conditions-B, 3ab: 59%
conditions-A, 3ac: 50%
conditions-B, 3ac: 61%
conditions-A, 3z: 57%
conditions-B, 3z: 73%a
(C)
Me
N
N
N
N
N
N
O
N
N
O
N
N
N
N
MeO
N
N
O
N
N
N
N
N
O
N
Me
Me
O
N
Me
Me
Me
Me
Me
Me
Me
H
O
H
O
Cl
Cl
H
H
Me
Me
Me
O
Me
conditions-A, 3ad: 71%
conditions-B, 3ad: 63%
conditions-A, 3af: 75%
conditions-B, 3af: 58%
conditions-A, 3ag: 70%
conditions-B, 3ag: 66%
conditions-A, 3ah: 65%
conditions-B, 3ah: 50%
conditions-A, 3ae: 68%
conditions-B, 3ae: 64%
MeO
Figure 2. Substrates Scope for the 1,3-Cycloaddition Reaction. (A), General scope of the reaction with different tetrazoles and
alkynes. Reactions were conducted using conditions-A and conditions-B with 0.5 mmol tetrazoles (1) and 2.0 equiv. alkynes (2);
aReaction temperature is 60 oC. (B), ASK1 inhibitor (4) was prepared in gram scale from 3ac. (C), Bioactive molecule-bearing alkynes
were tested with tetrazole for the 1,3-cycloaddition reaction.
developed Mn-catalyzed reaction conditions could solve this
After developing a new catalytic system for the 1,3-cycloaddition
long-standing problem or not. For that, we choose tetrazole (1a)
and benzonitrile (5a) as the model substrates. As per our design
principle (Figure 1F), we anticipated that the metal-bound
complex (Mn-MBC-1) would generate the Mn-nitrene complex
(Mn-N-Int-1) if a reaction was performed between tetrazole (1a)
and benzonitrile (5a) upon loss of the dinitrogen molecule.
(click) reaction using Mn-porphyrin catalyst, we then became
interested to develop the denitrogenative annulation between
tetrazole and nitrile, which was failed under our previously
developed
electrocyclization[10]
and
radical
activation
mechanism.[13] Thus, we wondered whether our newly
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10.1002/anie.202009078
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RESEARCH ARTICLE
Accordingly we performed a denitrogenative annulation reaction
using Mn(TPP)Cl (5.0 mol%) and reductant Zn-dust (10.0
mol%) in benzene solvent at 100 oC (Table 2, entry 5), but to our
surprise, we did not see any product in the crude reaction
mixture. Increasing the reaction temperature from 100 oC to 140
oC, we saw minor amount of desired product along with the
reduced amine product (entry 6). Conducting annulation using
Mn(TPFPP)Cl at 100 oC resulted in no reaction (entry 7).
Table 2. Screening and Optimization of the Denitrogenative Annulation Reactiona
N
N
N
[M]-cat., reductant
additive, C6H6, T oC, 24 h
–N2
N
Ph
Ph
N
+
+
N
N
N
N
NH2
1a: 0.5 mmol
5a: 0.6 mmol
6a
3a"
Entry
1
[M]-cat. (mol%)
[Cp*IrCl2]2 (5)
[Cp*IrCl2]2 (5)
Fe(TPP)Cl (5)
Mn(TPP)Cl (5)
Mn(TPP)Cl (5)
Mn(TPP)Cl (5)
Mn(TPFPP)Cl (5)
Mn(TPP)Cl (5)
Mn(TPP)Cl (5)
Mn(TPP)Cl (5)
Mn(TPP)Cl (5)
Mn(TPP)Cl (5)
Mn(TPP)Cl (5)
-
Reductant (mol%)
Additive (mol%)
T oC
6a/3a"
0/0
-
-
130
130
100
100
100
140
100
100
100
100
100
100
100
100
100
120
100
80
2
-
AgSbF6 (20)
-
0/0
3
Zn (10)
-
0/5
4
0/0
5
Zn (10)
Zn (10)
Zn (10)
Zn (10)
Zn (10)
Zn (10)
Zn (10)
Zn (10)
Zn (10)
-
-
-
0/10
23/20
0/10
0/15
0/15
0/12
0/10
0/10
95(92)b/5
0/0
6
7
-
8
InCl3 (5)
In(OTf)3 (5)
AgBF4 (5)
AgSbF6 (5)
AgNTf2 (5)
CuI (5)
9
10
11
12
13
14
15
16c
17
18d
CuI (5)
-
-
Cu-powder (20)
Cu-powder (100)
Cu-powder (5)
CuI (5)
0/0
-
-
65/0
0/10
77(62)b/7
Mn(TPP)Cl (5)
Mn(TPP)Cl (20)
Zn (10)
Zn (40)
aReactions were conducted in 0.5 mmol scale. bIn parenthesis isolated yield is reported. cThe reaction was run for 3 h. dReaction was
run for 36 h.
Thus, we realized that perhaps benzonitrile is not that much
reactive relative to the alkyne, as we seen in the denitrogenative
annulation between tetrazole and alkyne. In order to activate the
nitrile, we decided to see the effects of additives in the same
reaction conditions. Hence, the reactions were performed using
various additives such as InCl3, In(OTf)3 and different Ag-salts
(AgBF4, AgSbF6, AgNTf2) however, no reaction occurred (entries
8-12). Remarkably, when we used 5.0 mol% CuI as an additive
in our annulation reaction, we observed 95% product conversion
(6a, 92% isolated yield, entry 13) based on crude GC-MS
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10.1002/anie.202009078
Angewandte Chemie International Edition
RESEARCH ARTICLE
analysis along with 5% reduced product 2-amino pyridine (3a").
In this context, it deserves mentioning that a reaction between
1,2,3,4-tetrazole (1a) and benzonitrile (5a) was reported[8c] in
presence of the Cu-powder catalyst, which afforded the product
(6a) in 62% yield (Figure 3). The reaction likely underwent via a
Cu-nitrene intermediate. Thus, we were curious whether our
annulation reaction would occur in presence of CuI only or not.
Accordingly, we performed few reactions without Mn(TPP)Cl and
found that use of CuI catalyst (entry 14) was not effective for the
reaction (see SI for details).
denitrogenative annulation might proceed by the in situ
generation of the Mn-nitrene complex (Figure 4B, Mn-N-Int-1),
which takes protons from either the reaction solvent or reacting
substrate through a HAT mechanism.[16d]
Table 3. Substrates Scope of Denitrogenative Annulationa
N
N
N
N
developed conditions
N
Ar
R
R
N
Ar
N
+
N
N
1
5
6
N
N
N
N
N
N
N
N
N
Cu-powder
120 oC, 3 h
N
N
N
N
Ph
Ph
N
+
N
N
OMe
F
Br
1a
5
6a: 62%
conditions-A, 6c: 86%
conditions-B, 6c: 64%
conditions-A, 6b: 74%
conditions-B, 6b: 56%
conditions-A, 6d: 75%
conditions-B, 6d: 51%
Figure 3. Fraunberg and Huisgen’s Report in 1969.
N
N
N
F
OMe
Br
Inspiring by Fraunberg and Huisgen’s reaction, we also were
curious to see the effect of the reaction using catalytic amount of
Cu-powder and performed a reaction using 20 mol% Cu-powder
(entry 15) at 100 oC, which resulted in no reaction. Repeating
the same reaction using 100 mol% Cu-powder at 120 oC, it
afforded 65% desired product based on GC/MS analysis (entry
16). Moreover, to see the effect of catalytic amount of Cu-
powder instead of the catalytic amount of CuI for our developed
reaction conditions (as described in entry 13), accordingly we
performed a reaction (entry 17). To our surprise, the reaction did
not occur to give even a trace amount of the desired product,
which clearly indicates the different reactivity of the Cu-powder
and CuI in the same reaction. To this end, we studied the same
reaction varying catalyst loading, reductant loading and
temperature. After extensive optimizations (see SI for details) we
found that employment of 20 mol% Mn(TPP)Cl, 40 mol% Zn and
5 mol% CuI at lower temperature (80 oC) gave the desired
product 77% conversion that was isolated in 62% pure product
(entry 18).
We next examined the scope of this reaction with respect to
various nitriles using our developed reaction conditions
(conditions-A, entry 13, Table 2 and conditions-B, entry 18,
Table 2). We found that different substituted nitriles (such as
halogen, pyridine, thiophene) were well tolerated under the
developed conditions. Moreover, bioactive phenol-derived
nitriles (5k-5l) also participates in our annulation reaction. On
the other hand, conjugated nitriles (5j, 5m) also produced
annulated product in excellent yields.[21] Next, we tested our
annulation reaction with various substituted tetrazoles. As shown
in Table 3, tetrazole with different substituents (such as methyl,
amide, ester, trifluoromethyl and chloro) were found to be
compatible as well.
N
N
N
N
N
N
conditions-A, 6e: 76%
conditions-B, 6e: 54%
conditions-A, 6f: 89%
conditions-B, 6f: 69%
conditions-A, 6g: 78%
conditions-B, 6g: 58%
N
N
N
N
N
N
N
N
N
S
N
Ph
conditions-A, 6h: 90%
conditions-B, 6h: 65%
conditions-A, 6i: 87%
conditions-B, 6i: 51%
conditions-A, 6j: 87%
conditions-B, 6j: 66%
O
O
Cl
Ph
N
N
N
O
O
N
N
N
conditions-A, 6k: 70%
conditions-B, 6k: 53%
conditions-A, 6l: 70%
conditions-B, 6l: 49%
Ph
Me
N
EtO2C
N
N
Ph
N
N
Ph
Ph
N
N
N
N
conditions-A, 6n: 83%
conditions-B, 6n: 62%
conditions-A, 6o: 80%
conditions-B, 6o: 67%
conditions-A, 6m: 90%
conditions-B, 6m: 68%
O
CF3
N
N
N
N
Ph
Ph
Ph
N
N
N
N
N
N
CF3
conditions-A, 6p: 81%
conditions-B, 6p: 65%
conditions-A, 6q: 85%
conditions-B, 6q: 71%
conditions-A, 6r: 80%
conditions-B, 6r: 73%
N
N
N
Ph
Ph
Ph
N
N
N
N
N
N
Cl
Et2NOC
EtO2C
conditions-A, 6s: 72%
conditions-B, 6s: 54%
conditions-A, 6t: 82%
conditions-B, 6t: 65%
conditions-A, 6u: 80%
conditions-B, 6u: 71%
aReactions were conducted in 0.5 mmol scale using conditions-A
and conditions-B. Isolated yields are reported. conditions-A: 5
mol% Mn(TPP)Cl, 10 mol% Zn, 5 mol% CuI, C6H6, 100 oC, 24 h,
conditions-B: 20 mol% Mn(TPP)Cl, 40 mol% Zn, 5 mol% CuI,
C6H6, 80 oC, 36 h.
To understand the mechanism of Mn(II)-catalyzed click reaction
and denitrogenative annulation, we performed several control
experiments (Figure 4). First, we carried out a deuterium
labelling experiment, which resulted in almost complete
preservation of the d-atom in the desired click product (Figure
4A, eq. 1). This experiment indicates that our click reaction does
not follow the traditional metal acetylide complex formation
(which is common for Cu-catalyzed click reaction[22]). Since we
observed minor amount of the competitive amine by-product (2-
aminopyridine) in the click reaction, we hypothesized that the
However, we cannot completely overrule the formation of the
Cu-nitrene intermediate (Figure 4B, Cu-N-Int-1), as proposed
by the Fraunberg and Huisgen, since our reaction also involves
the employment of catalytic amount of CuI. Thus, to get the
detailed information whether the denitrogenative annulation
undergoes via either a Mn-nitrene intermediate or a Cu-nitrene
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10.1002/anie.202009078
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RESEARCH ARTICLE
intermediate (Figure 4B), we conducted several experiments.
First, we carried out a control experiment between 1,2,3,4-
tetrazole (1a) and 9,10-dihydroanthracene (7) under the
developed reaction conditions assuming that if the annulation
reaction undergoes via the Mn-nitrene formation, then we would
be able to see the formation of the corresponding oxidized
product, such as anthracene (8) along with the amine product by
the HAT mechanism (Figure 4A, eq. 2). To our delight,
analyzing the crude reaction mixture by the GC/MS analysis, we
observed the formation of 48% oxidized product (8, anthracene)
and 55% 2-aminopyridine (3a"), which indicates the possibility for
the generation of the Mn-nitrene intermediate. We then
performed another control experiment between tetrazole (1a)
and benzonitrile (5a) in presence of 9,10-dihydroanthracene (7)
without CuI under the developed conditions (Figure 4A, eq. 3)
and noticed that while the reaction did not produce even a trace
amount of the annulation product (6a), it resulted a mixture of
anthracene (8) and 2-aminopyridine (3a"), which again indicates
the generation of the Mn-nitrene complex (Mn-N-Int-1) and
revealing the important role of the CuI to activate the benzonitrile
for the denitrogenative annulation.
(A)
(B)
N
N
N
5 mol% Mn(TPP)Cl
10 mol% Zn, 100 oC,
C6H6, 24 h
N
N
2a–d
> 95% d
N
N
N
(IV) N
Mn
D
N
N
[Cu]
Ph
D
Ph
N
(eq. 1)
3a–d, >94% d
7
Proposed Cu-nitrene by
Fraunberg and Huisgen
Proposed Mn-nitrene for
present work
Mn-N-Int-1
Cu-N-Int-1
+
5 mol% Mn(TPP)Cl
NH2
N
10 mol% Zn, 100 oC,
C6H6, 24 h
N
N
N
1.2 equiv. Ph
5.0 mol% Mn(TPP)Cl
10.0 mol% Zn
N
8, 48%
3a", 55%
N
(eq. 2)
N
N
N
N
Ph
(eq. 5)
7
1a
N
N
N
5.0 mol% Cu-powder
C6H6, 100 oC, 24 h
0%
N
Ph
N
N
without CuI
6a
1a
Ph
5 mol% CuI &
8 + 3a",
100%
+
N
PhCN, 100 oC,12 h
5 mol% Mn(TPP)Cl
10 mol% Zn, 100 oC,
C6H6, 24 h
100% by GC/MS
(eq. 3)
6a, 0%
1.0 equiv.
Mn(TPP)Cl
N
N Ph
7
N
2.0 equiv. Zn
C6H6, 100 oC, 6 h
+
IV
Mn
N
N
N
CuI, C6H6, 100 oC,
24 h
N
N
(eq. 7)
Ph
Ph
NH2
N
"
N
N
8, 0%
3a
, 0%
Mn-N-Int-1
Ph
1a: 1.0 equiv.
(eq. 4)
eq. 6
confirmed by HRMS
(C)
C(sp3)–H amination
O
O
N
O
O
Ph
Ph
O
Ph
Ph
N
Ph
Ph
5.0 mol% Mn(TPP)Cl
10.0 mol% Zn-dust
C6H6, 100 oC, 24 h
N
Ph
Ph
N
Ph
N
N
5.0 mol% CuI
C6H6, 100 oC, 24 h
N
N
N
N
Ph
N
IV
N
N
N
N
N
N
H
N
N
H
Mn
N
–N2
N
[Cu]
via Cu–N
via Mn–N
(10): 0%
(9)
(10): 70% (isolated)
Figure 4. Detailed Mechanistic Studies and Control Experiments
Moreover, another control experiment was performed between
the 1,2,3,4-tetrazole (1a) and 9,10-dihydroanthracene (7) in
presence of only catalytic amount of CuI assuming that if the
annulation reaction undergoes via the Cu-nitrene generation,
then it would also produce the corresponding oxidized product
anthracene (8) and amine product by the HAT mechanism
(Figure 4A, eq. 4). However, no reaction occurred that was
generation of the Mn–nitrene intermediate (Mn-N-Int-1) was
confirmed by the HRMS experiment (See SI for details) by the
reaction of 1,2,3,4-tetrazole (1a), Mn(TPP)Cl and Zn without the
presence of CuI (eq. 6). Moreover, when
a mixture of
benzonitrile and CuI in benzene solution was treated with the
(Mn-N-Int-1) intermediate[ 23 ] derived from 1,2,3,4-tetrazole,
Mn(TPP)Cl and Zn, the reaction gave 100% conversion within
12 h, again supporting the proposed hypothesis (eq. 7).
Furthermore, in order to extend the scope of the developed Mn-
nitrene concept, we designed a substrate (9) for the C(sp3)–H
bond amination[ 24 ] and performed the reaction using our
developed conditions, which gave the C(sp3)–H aminated
product in 70% yield that also follows a Mn-nitrene intermediate
(Figure 4C). In sharp contrast, the same reaction does not occur
in presence of catalytic amount of CuI.
1
confirmed by the GC/MS and H-NMR data, which is eliminating
the possibility for the generation of the Cu-nitrene intermediate.
To get additional confirmation for the annulation mechanism via
Mn-nitrene intermediate and the reactivity of the catalytic
amount of CuI versus Cu-powder, we performed a reaction
using our developed conditions in presence of Cu-powder
without CuI (Figure 4B, eq. 5) that resulted in no reaction, which
tells us two important points, such as, (i) the reaction does
proceeds via a Cu-nitrene intermediate and (ii) the essential role
of CuI to activate the nitrile for the annulation. Finally, the
Thus, based on these experimental evidences, we proposed a
possible mechanism for the 1,3-cycloaddition (click) and
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10.1002/anie.202009078
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RESEARCH ARTICLE
annulation reaction (Figure 5). Initially, Mn(TPP)Cl reduced to
Mn(TPP) in presence of a catalytic amount of Zn-dust through a
single electron transfer to form the active catalyst MnII(TPP)
which was confirmed by the UV-visible spectroscopy (See SI for
details). Then MnII(TPP) coordinates with the terminal nitrogen
atom of the tetrazole to form intermediate (B).
catalytic cycle. For the annulation reaction, by the loss of
nitrogen gas, the metal-bound azide complex (B) forms the
metal nitrene intermediate (D). Then copper first promotes a
nucleophilic attack of Mn-N intermediate (D) on the nitrile
providing the amidine[25] type of intermediate (E). Subsequent
Cu-induced oxidative ring closure and reduction of Cu-species
affords the triazolopyridine (6a) with the regeneration of the
catalytic cycle. Notably, the formation of the competitive minor
amount of side product formed may be due to the hydrogen
atom transfer from either reacting substrate or reaction solvent.
Zn
Mn(TPP)
Mn(TPP)Cl
(A)
1a
N
N
1a
(II)
N
6a
N
N
N
N
Mn
N
1a
Ph
(II)
N
N
N
N
Cu
N
N
N
N
Mn
Conclusion
N
N
Ph
In conclusion, we have developed a Mn-porphyrin based
catalytic method that enables to access two different classes of
nitrogen heterocycles, such as pyridyl-substituted 1,5-
disubstituted 1,2,3-triazoles via 1,3-cycloaddition (click reaction)
and 1,2,4-triazolo-pyridines via denitrogenative annulation.
While the click reaction undergoes directly via the Mn-bound
complex, denitrogenative annulation proceeds through the Mn-N
complex. Further investigations are underway to get the full
details of the Mn-nitrene intermediate. The method is compatible
for a wide range of substrates for both the reactions. We believe
that the method would be useful for pharmaceutical industries,
drug discovery and other fields of medicinal chemistry.
Click Reaction
(II)
N
N
N
(III) N
Annulation
N
N
Mn
N
Mn
N
N
Ph
N
Ph
(E)
N
N
N
(B)
N2
N
N
N
N
N
CuI
+
(II)
Mn
(IV) N
N
N
N
N
N
N
N
Ph
Mn
3a
Ph
N
N
2a
(D)
(C)
3a”
NH2
HAT
Figure 5. Proposed Reaction Mechanism
In case of 1,3-cycloaddition (click) reaction, intermediate (B)
then readily undergoes cycloaddition reaction in presence of
phenyl acetylene (2a) generating the intermediate (C), which
then release the click product (3a) with the regeneration of the
Acknowledgements
Funding Sources
This
work
was
supported
SERB-STAR
and
by
SERB-CRG
AWARD
grant
grant
grant
The authors have filled a patent based on this work (patent
application number: 202011021740).
(CRG/2018/000133),
(STR/2019/000045)
SERB-SUPRA
Keywords: denitrogenative annulation • Mn-nitrene • 1,3-
(SPR/2019/000158). HK, SKD and SR thank CSIR for their SRF.
We also thank CBMR for research facilities.
cycloaddition • catalysis • click reaction
Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2596-2599; e) J. Du Bois,
C. S. Tomooka, J. Hong, E. M. Carreira, Acc. Chem. Res. 1997, 30,
364–372; f) T. G. Driver, Org. Biomol. Chem. 2010, 8, 3831-3846; g) W.
G. Kim, M. E. Kang, J. B. Lee, M. H. Jeon, S. Lee, J. Lee, B. Choi, P. M.
S. D. Cal, S. Kang, J.-M. Kee, G. J. L. Bernardes, J. U. Rohde, W.
Choe, S. Y. Hong, J. Am. Chem. Soc. 2017, 139, 12121–12124; h) B.
C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao, Z. Lin, G.
Jia, V. V. Fokin, J. Am. Chem. Soc. 2008, 130, 8923–8930; i) J. R.
Johansson, T. Beke-Somfai, A. S. Stalsmeden, N. Kann, Chem. Rev.
2016, 116, 14726–14768; j) S. Ding, G. Jia, J. Sun, Angew. Chem., Int.
Ed. 2014, 53, 1877-1880.
[1]
[2]
[3]
a) G. L’abbe, Angew. Chem. Int. Ed. Engl. 1975, 14, 775-782; b) E. F.
V. Scriven, K. Turnbull, Chem. Rev. 1988, 88, 297-368; c) S. Bra se, C.
̈
Gil, K. Knepper, V. Zimmermann, Angew. Chem. Int. Ed. 2005, 44,
5188- 5240.
a) E. T. Hennessy, T. A. Betley, Science 2013, 340, 591-595; b) O.
Villanueva, N. M. Weldy, S. B. Blakey, C. E. MacBeth, Chem. Sci. 2015,
6, 6672-6675; (c) Y. Dong, R. M. Clarke, G. J. Porter, T. A. Betley, J.
Am. Chem. Soc. 2020, 142, 25, 10996–11005.
For pioneering work on metalloradical activation method, see: a) H.
Jiang, K. Lang, H. Lu, L. Wojtas, X. P. Zhang, J. Am. Chem. Soc. 2017,
139, 9164-9167; b) C. Li, K. Lang, H. Lu, Y. Hu, X. Cui, L. Wojtas, X. P.
Zhang, Angew. Chem. Int. Ed. 2018, 57, 16837-16841; c) Y. Hu, K.
Lang, C. Li, J. B. Gill, I. Kim, H. Lu, K. B. Fields, M. Marshall, Q. Cheng,
X. Cui, L. Wojtas, X. P. Zhang, J. Am. Chem. Soc. 2019, 141, 18160-
18169; d) K. Lang, S. Torker, L. Wojtas, X. P. Zhang, J. Am. Chem.
Soc. 2019, 141, 12388-12396; e) H. Jiang, K. Lang, H. Lu, L. Wojtas, X.
P. Zhang, Angew. Chem. Int. Ed. 2016, 55, 11604-11608.
[5]
For denitrogenative annulation via ionic mechanism, see: a) B.
Chattopadhyay, V. Gevorgyan, Angew. Chem. Int. Ed. 2012, 51, 862-
872; b) H. M. L. Davies, J. S. Alford, Chem. Soc. Rev. 2014, 43, 5151-
5162.
[6]
[7]
For denitrogenative annulation via radical activation mechanism, see: S.
Roy, S. K. Das, B. Chattopadhyay, Angew. Chem. Int. Ed. 2018, 57,
2238-2243.
a) B. Chattopadhyay, C. I. Rivera Vera, S. Chuprakov, V. Gevorgyan,
Org. Lett. 2010, 12, 2166–2169; b) R. Sun, H. Wang, J. Hu, J. Zhao, H.
Zhang, Org. Biomol. Chem. 2014, 12, 5954-5963.
[4]
a) J. E. Moses, A. D. Moorhouse, Chem. Soc. Rev. 2007, 36, 1249-
1262; b) M. Meldal, C. W. Tornøe, Chem. Rev. 2008, 108, 2952–3015;
c) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed. 2001,
40, 2004-2021; d) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B.
This article is protected by copyright. All rights reserved.

10.1002/anie.202009078
Angewandte Chemie International Edition
RESEARCH ARTICLE
[8]
a) R. Huisgen, K. von Fraunberg, H. J. Sturm, Tetrahedron Lett. 1969,
30, 2589-2594; b) R. Huisgen, K. von Fraunberg, Tetrahedron Lett.
1969, 30, 2595-2598; c) K. von Fraunberg, R. Huisgen, Tetrahedron
Lett. 1969, 30, 2599-2602.
reagent (Et2Zn) followed by Pd-catalyzed cross-coupling reaction that
resulted in 31% yield of the product. However, our developed
cycloaddition reaction conditions followed by the modified cross-
coupling method afforded 70% isolated yield of the desired product. For
the previous report in details, see, reference, 12a.
[9]
For pioneering FVT studies on 1,2,3,4-tetrazoles, see: a) C. Wentrup,
Tetrahedron 1971, 27, 367-374; b) R. Harder, C. Wentrup, J. Am.
Chem. Soc. 1976, 98, 1259-1260; c) C. Wentrup, H. W. Winter, J. Am.
Chem. Soc. 1980, 102, 6159–6161; d) R. A. Evans, M. W. Wong, C.
Wentrup, J. Am. Chem. Soc. 1996, 118, 4009-4017; e) C. Wentrup, M.
Kuzaj, H. Lüerssen. Angew. Chem. Int. Ed. 1986, 25, 480- 482; f) D.
Kvaskoff, M. Vosswinkel, C. Wentrup, J. Am. Chem. Soc. 2011, 133,
5413–5424.
[20] X. Creary, A. Anderson, C. Brophy, F. Crowell, Z. Funk, J. Org. Chem.
2012, 77, 8756–8761.
[21] Notably, employment of aliphatic nitriles resulted in no product
formation under the developed reaction conditions.
[22] B. T. Worell, J. A. Malik, V. V. Fokin, Science 2013, 340, 457-460.
[23] The Mn-nitrene intermediate was confirmed by the HRMS, however,
failed to isolate this intermediate due to stability issue.
[10] S. K. Das, S. Roy, H. Khatua, B. Chattopadhyay, J. Am. Chem. Soc.
2018, 140, 8429-8433.
[24] An iron-catalyzed method for the strong aliphatic C(sp3)–H bond
amination of suitably designed 1,2,3,4-tetrazole substrate has been
developed. For details, see: S. K. Das, S. Roy, H. Khatua, B.
[11] T. Nakamuro, K. Hagiwara, T. Miura, M. Murakami, Angew. Chem. Int.
Ed. 2018, 57, 5497-5500.
Chattopadhyay,
J.
Am.
Chem.
Soc.
2020,
142,
[12] a) B. S. David, PCT Int. Appl. 2018, WO 2018187506 A1; b)J. Bohan, D.
Qing, H. Gene, PCT Int. Appl. 2018, WO 2018151830 A1; c) U. C. John,
V. J. Elizabeth, J. Linda, B. Effi, M. O. J. Stephen, PCT Int. Appl. 2019,
WO 2019141972 A1; d) J. R. Toms, L. Yang, J.S. Richard, PCT Int.
Appl. 2018, WO 2018160845 A1; e) C. Hamdouchi, P. Maiti, A. M.
Warshawsky, A. C. DeBaillie, K. A. Otto, K. L. Wilbur, S. D. Kahl, A.
doi.org/10.1021/jacs.0c07810.
[25] V. Y. Kukushkin, A. J. L. Pombeiro, Chem. Rev. 2002, 102, 1771–1802.
Graphical Abstract
Patel Lewis, G. R. Cardona,
R. W. Zink, K. Chen, S. Cr, J. P.
Denitrogenative Annulation
1,3-Cycloaddition (Click Reaction)
Lineswala, G. L. Neathery, C. Bouaichi, B. A. Diseroad, A. N. Campbell,
S. A. Sweetana, L. A. Adams, O. Cabrera, X. Ma, N. P. Yumibe, C.
Montrose-Rafizadeh, Y. Chen, A. R. Miller, J. Med. Chem. 2018, 61,
934–945; f) C. J. Menet, S. R. Fletcher, G. Van Lommen, R. Geney, J.
Blanc, K. Smits, N. Jouannigot, P. Deprez, R. M. van der Aar, P.
ClementLacroix, L. Lepescheux, R. Galien, B. Vayssiere, L. Nelles, T.
Christophe, R. Brys, M. Uhring, F. Ciesielski, L. Van Rompaey, J. Med.
Chem. 2014, 57, 9323–9342.
N
N2
N
R
CuI
N
N
Ar
R
N
N
II N
N
Ar
N
Mn
N
N
N
N
N
N2
Metal-bound
Complex
21 examples
34 examples
[13] S. Roy, H. Khatua, S. K. Das, B. Chattopadhyay, Angew. Chem. Int. Ed.
2019, 58, 11439-11443.
Dual Reactivity
[14] For a leading report towards facile synthesis of 1,2,4-triazole using Cu-
catalyst at 130 oC, see: a) S. Ueda, H. Nagasawa, J. Am. Chem. Soc.
2009, 131, 15080-15081; For a recent report, see: b) A. Bhatt, R. K.
Singh, R. Kant, B. K. Sarma, Synthesis 2019, 51, 3883-3890.
[15] H. M. L. Davies, R. J. Townsend, J. Org. Chem. 2001, 66, 6595–6603.
[16] a) X. Huang, T. M. Bergsten, J. T. Groves, J. Am. Chem. Soc. 2015,
137, 5300–5303; b) S. M. Paradine, J. R. Griffin, J. Zhao, A. L.
Petronico, S. M. Miller, M. C. White, Nat. Chem. 2015, 7, 987–994; c) J.
R. Clark, K. Feng, A. Sookezian, M. C. White, Nat. Chem. 2018, 10,
583–591; d) M. M. Abu-Omar, Dalton Trans. 2011, 40, 3435- 3444; e) X.
Huang, T. Zhuang, P. A. Kates, H. Gao, X. Chen, J. T. Groves, J. Am.
Chem. Soc. 2017, 139, 15407–15413.
[17] We hypothesized that the origin of 1,5-selectivity over 1,4-isomer is due
to the following particular orientation between the azide and alkyne that
minimizes the steric interaction between alkyne and the bulky TPP
ligand as shown in the following TSs.
origin of 1,5-selectivity
origin of 1,4-selectivity
N
N
N
N
N
(II)
N
N
N
(II)
N
N
N
N
N
N
Mn
Mn
N
N
dis-favoured
TS-2
favoured
TS-1
For terminal coordination with azide nitrogen and metal catalyst, see: a)
M. G. Fickes, W. M. Davis, C. C. Cummins, J. Am. Chem. Soc.1995,
117, 6384-6385. b) H. V. R. Dias, S. A. Polach, S.-K. Goh, D. F.
Archibong, D. S. Marynick, Inorg. Chem. 2000, 39, 3894-3901.
[18] In all cases for the click reaction, 2.0 equivalent of alkynes were
employed. Lowering the amount of alkyne, we observed slightly less
conversion of the click product.
[19] Notably, the preparation of ASK1 inhibitor (4) was reported earlier from
the same starting material via two-step method using pyrophoric
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