Iron(II)-Based Metalloradical Activation: Switch from Traditional Click Chemistry to Denitrogenative Annulation

Article abstract of DOI:10.1002/anie.201904702

A unique concept for the intermolecular denitrogenative annulation of 1,2,3,4-tetrazoles and alkynes was discovered by using a catalytic amount of Fe(TPP)Cl and Zn dust. The reaction precludes the traditional, more favored click reaction between an organic azide and alkynes, and instead proceeds by an unprecedented metalloradical activation. The method is anticipated to advance access to the construction of important basic nitrogen heterocycles, which will in turn enable discoveries of new drug candidates.

Full text of DOI:10.1002/anie.201904702

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: A Fe(II)-Based Metalloradical Activation Approach: Overriding
Traditional Click Chemistry Towards Denitrogenative Annulation
Authors: Buddhadeb Chattopadhyay, Satyajit Roy, Hillol Khatua, and
Sandip Kumar Das
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904702
Angew. Chem. 10.1002/ange.201904702
Link to VoR: http://dx.doi.org/10.1002/anie.201904702
http://dx.doi.org/10.1002/ange.201904702

10.1002/anie.201904702
Angewandte Chemie International Edition
COMMUNICATION
A Fe(II)-Based Metalloradical Activation Approach: Overriding
Traditional Click Chemistry Towards Denitrogenative Annulation
Satyajit Roy,† Hillol Khatua, † Sandip Kumar Das, and Buddhadeb Chattopadhyay*
Previous work:
Abstract: A unique concept for the intermolecular denitrogenative
(A) α-Metalloaminyl Radical for Amination and Aziridination
annulation of 1,2,3,4-tetrazoles and alkynes is discovered using
catalytic amount of Fe(TPP)Cl and Zn dust. The developed concept
overrides the traditional more favored click reaction between organic
azide and alkynes. It has been proved that the reaction underwent
via an unprecedented metalloradical activation mechanism, which
successfully overturn the ionic click reaction. We anticipate that the
method will advance access for the construction of important basic
nitrogen heterocycles, which will enable to discover new drug
candidates.
R1
R2
R3
R
N
R1
H
R
N
R
R4
R2
R3
NH
M
Aziridination
Amination
R4
α
-
metalloaminyl
radical
(B) Click Reaction of Tetrazole and Alkyne
Ar
N
Click Chemistry
Cu-cat.
+
Ar
N
N
N
N
N
(Tetrazole) azide surrogate
(C) Concept of Intra-molecular Annulation
N
N
alkyne
1,4-
The concept of metalloradical activation for radical cyclization has
recently been demonstrated as one of the most advanced strategies.
The groups of Zhang and de Bruin have given a new dimension of
this concept based on the Co(II)–metalloradical chemistry for
numerous synthetic transformations.[1,2] Moreover, it has also been
shown that the concept of metalloradical activation could efficiently
be employed for the radical C–H amination[ 3 ] and radical olefin
aziridination[4] via the generation of a-metalloaminyl radicals as the
key intermediates derived from the organic azides (Scheme 1A). In
[Ir]-cat.
N2
N
N
H
H
H
N
N
N3
N
N
N
α-carboline
Intra-molecular Annulation
(D) This work: Intermolecular Annulation Overriding Traditional Click Reaction
Ar
N3
N
N
N
Ar
Ar
N
N
N
N
N
N
N
N
N2
Ar
Intermolecular Annulation
Click Chemistry
Azide-Tetrazole Equilibrium
Scheme 1. Previous Overviews and New Challenge
this context, we have reported
a Co(II)-based metalloradical
activation of 2-(diazomethyl)pyridines resulting from the 1,2,3-
triazoles for the denitrogenative radical transannulation and
We started our initial studies selecting tetrazole (1a) and
phenylacetylene (2a) as test substrates and the reactions were
conducted using a variety of transition metal catalysts (Table 1, see
SI, for detail). To our surprise, metal catalysts such as Rh, Ir (that
are known[ 11 ] to produce metal-nitrene), Pd, Zn, Fe, In and Ru
remain completely ineffective towards forming either the click
product or the annulation product. For this extreme ineffectiveness of
the tetrazole, we reasoned that strong coordination[12] of these metal
catalysts with both azide and pyridine nitrogen atoms shut down the
catalytic process for the formation of the metal-nitrene intermediate.
5
]
cyclopropanation.[
Nevertheless, synthetic utility of these
approaches is far from being fully investigated.
On the other hand, metalloradical activation of 1,2,3,4-tetrazoles
(surrogates of organic azides) for radical annulation with terminal
alkynes is entirely underdeveloped till date. Owing to the high
reactivity of the 2-azidopyridine (1,2,3,4-tetrazole), it readily
undergoes the traditional click reaction with alkyne in presence of
transition metal catalysts (Scheme 1B).[ 6 ] As a result, it was
impossible to think about other types of synthetic transformations
between the reaction of 2-azidopyridines (1,2,3,4-tetrazoles) and
alkynes. Moreover, over the past forty years, the chemistry of
1,2,3,4-tetrazole was mainly explored as denitrogenative
photochemical and thermal nitrene-nitrene rearrangement pioneered
by the Wentrup group.[ 7 ] Furthermore, while 1,2,3-triazoles are
known[8] to undergo denitrogenative annulation with metal catalysts,
1,2,3,4-tetrazoles proved entirely inactive for annulation, except our
recently developed intramolecular annulation via metal-nitrene
formation (Scheme 1C).[9] Thus, it would be highly interesting to
design a concept for the intermolecular denitrogenative annulation,
which would override the traditional click reaction. Herein, we report
a novel concept for the denitrogenative intermolecular annulation
between 1,2,3,4-tetrazole (an azide surrogate) and alkyne via a
Fe(II)–based metalloradical activation mechanism, which completely
overturn the traditional click reaction (Scheme 1D).[10]
Table 1. Initial Screening of Denitrogenative Annulation[a]
1.2 eq. Ph(2a)
2-20 mol% [M]-cat.
N
N
N
Ph
N
N
N
N
0-20 mol% additive
solvent, T oC, 24 h
N
N
N
N
N
N
Ph
Ph
N
1a
3a
3a’
3a”
Initial Screening Results:
Rh-cat. (31 conditions)
Ru-cat. (11 conditions)
Ir-cat. (7 conditions)
outcomes:
3a/3a’/3a’’ = 0/0/0
outcomes:
3a/3a’/3a’’ = 0/0/0
outcomes:
3a/3a’/3a’’ = 0/0/0
In-cat. (5 conditions)
Zn-cat. (7 conditions)
Fe-cat. (6 conditions)
outcomes:
3a/3a’/3a’’ = 0/0/0
outcomes:
3a/3a’/3a’’ = 0/0/0
outcomes:
3a/3a’/3a’’ = 0/0/0
Pd-cat. (6 conditions)
Ag-cat. (2 conditions)
Cu-cat. (37 conditions)
outcomes:
3a/3a’/3a’’ = 0/0/0
outcomes:
3a/3a’/3a’’ = 0/100/0
outcomes:
3a/3a’/3a’’ = 0/70/30
Screening Results with Metal-porphyrin Catalysts:
T o
C
ratio, 3a/3a’/3a”
0/100/0
[M(TPP)-cat]
Cu(TPP)
solvent
PhH
conv. (%)
>99
#
1
2
3
150
130
130
0/20/80
Fe(TPP)Cl
Co(TPP)
PhH
>99
26/37/37
PhH
>99
[a] Reactions were conducted with 0.5 mmol scale and GC/MS ratios were
determined using dodecane as internal standard, for details reaction
conditions, see: SI.
Mr. S. Roy, Mr. H. Khatua, Mr. S. K. Das, 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
Homepage: http://www.buddhacbmr.org/
†SR and HK contributed equally to this work.
On the other hand, most of the Cu- and Ag-catalysts resulted
only the regular click chemistry product. Thus, we turned our
attention towards metalloporphyrin-based catalytic systems,
which are well-known[3] to activate organic azide for C–H
This article is protected by copyright. All rights reserved.

10.1002/anie.201904702
Angewandte Chemie International Edition
COMMUNICATION
amination via metal-nitrene generation. Thus, we first conducted
a reaction employing Cu(TPP) at high temperature, which
afforded energetically more favored click chemistry product
quantitatively (Table 1, entry 1). Likewise, performing the same
reaction using Fe(TPP)Cl, we did not see even a trace amount
of the desired annulation product, instead, it afforded the 1,5-
disubstituted click product as the major isomer (entry 2). To our
delight, initial breakthrough was observed when the reaction was
repeated with Co(TPP) as a metalloradical catalyst, which
resulted the annulation product as minor and click chemistry
product as the major one (entry 3).
reaction at relatively high temperature (130 oC), we observed
complete switching to the click reaction with moderate
conversion (entry 6).[15]
Table 2. Optimization of the Intermolecular Annulation[a]
1.2 eq.
5 mol% [M]-cat.
Ph(2a)
N
N
N
Ph
N
N
N
N
10 mol% additive
PhH, T oC, 24 h
N
N
N
N
N
N
Ph
Ph
T o
N
1a
3a
3a’
3a”
ratio
conv. (%)
#
reducing agent
C
[M]-cat.
0/0/0
0/0/0
0
1
2
3
4
5
6
NaBH4
LiAlH4
Zn
100
100
100
100
100
130
Fe(TPP)Cl
Fe(TPP)Cl
Fe(TPP)Cl
Fe(TPP)Cl
no catalyst
no catalyst
0
100/0/0
0/0/0
>99 (95)[b]
Thus, inspired by these initial results using the metalloradical
activation concept by Zhang and de Bruin,[1,2,3,4] and considering
a pioneering work by Arnold and co-workers[ 13 ] using Fe(III)
heme-enzyme (cytochrome-P411) biocatalyst to form nitrene
intermediate from azide precursor in presence of NADPH
0
0
Mn
0/0/0
Zn
0/100/0
>65
Zn
[a] Reactions were conducted with 0.5 mmol scale and GC/MS ratios were
determined using dodecane as internal standard. [b] In parentheses, isolated
yield is given.
reductant, we designed
a blueprint (Scheme 2) for the
intermolecular annulation, which might override the traditional
click chemistry. Based on this blueprint, we hypothesized the
following two important considerations, i) requirement of a
metalloradical activation manifold, which would overpower the
click chemistry enforcing the intermolecular annulation, and ii)
replication of Arnold’s Fe-heme enzyme/NADPH biocatalytic
system by easily redox switchable Fe(TPP)Cl system in
presence of a reductant, which could reduce the ferric state of
the catalyst to the ferrous state overturning the ionic click
chemistry towards the metalloradical activation strategy.
Table 3. Scope of Reaction with Diverse Alkynes[a]
5.0 mol% Fe(TPP)Cl
10 mol% Zn dust, PhH
100 oC, 24 h
– N2 gas
N
N
N
N
R
+
N
N
1
2
3
R
N
N
N
N
N
N
N
N
Me
3b: 93%
3c: 88% tBu
3d: 83% OMe
3e: 73% Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
Ar
N
N
III
II
N
Fe
Cl
Fe
N
MeO
Cl
N
N
N
N
N
N2
reducing
agent
N
N
F
NO2
3f: 85%
3g: 93%
3h: 91%
3i: 90%
Ar
Metalloradical Pathway
Annulation
Ionic Pathway
N
N
N
N
N
N
III
Fe
III
III
N
N
N
N
Click-Chemistry
Fe
Cl
Fe
Ar
N
Cl
Ar
N
MeO
3j: 73%
N
MeO2C
3k: 81%
Br
3l: 90%
NC
3m: 87%
FeIII
Ar
N
N
N
N
N
N
N
N
N
Ar
N
N
N
N
Me
Cl
Cl
Scheme 2. Blueprint for Annulation Versus Click Chemistry Using Fe-
Porphyrin Catalytic System
tBu
tBu
MeO
3q: 91%
Accordingly, we performed a reaction using NaBH4 as reductant
in presence of Fe(TPP)Cl at 100 oC and found no reaction
occurred (Table 2, entry 1). Employment of LiAlH4 as reducing
agent was also unsuccessful (entry 2). Remarkably, when the
same reaction was carried out in presence of Fe(TPP)Cl in
combination with a catalytic amount of Zn dust, we observed
complete overturn of the reaction from click reaction to the
intermolecular annulation affording quantitative conversion into
the desired product (entry 3), which is in line with our proposed
blueprint.[ 14 ] To verify the possibility of other reductant, we
performed the same reaction using Mn dust, which resulted no
reaction (entry 4). Moreover, for better understanding the role of
the Zn dust, a control experiment was conducted without the
Fe(TPP)Cl catalyst and observed that neither a annulation nor a
click reaction occurred (entry 5). However, repeating the same
Me
OMe
3n: 85%
N
3o: 88%
3p: 80%
N
N
N
N
N
N
N
Br
OMe
Br
3u: 97%
F
3t: 86%
3r: 83%
N
3s: 96%
N
N
N
N
N
N
N
N
Cl
N
N
S
3x: 74%
3y: 81%
3v: 87%
3w: 92%
[a] Reactions were conducted with 0.5 mmol scale; isolated yields were
reported after purification.
This article is protected by copyright. All rights reserved.

10.1002/anie.201904702
Angewandte Chemie International Edition
COMMUNICATION
With these optimized conditions, Fe(II)-based metalloradical
activation of the intermolecular denitrogenative annulation were
performed for a series of terminal alkynes (Table 3), different
tetrazoles and conjugated alkynes (Table 4). To our delight, this
newly developed Fe(II)-based metalloradical approach appeared
to be very general irrespective of the substituents present in the
alkynes (such as halogen, alkyl, alkoxy, nitro, ester, nitrile etc.)
producing diversely substituted imidazopyridines with excellent
yields (see SI for details). In this context, it deserves mentioning
that in all cases, we did not see even a trace amount of the click
chemistry products. Finally, to highlight the utility of our newly
discovered method, we have synthesized anxiolytic drug TP003
(5) and an important molecule which is GABAA agonist (7) with
excellent yield from the corresponding tetrazoles (Scheme 3).
mechanism, we performed a reaction in presence of TEMPO,
which shut down the reaction completely (Scheme 4C). This
outcome suggests the possibility of the proposed metalloradical
activation mechanism. Fourth, to provide further proof of this
radical activation mechanism, we attempted to trap the
intermediate employing benzaldehyde, which is well-known[3f] to
react with azide via acyl radical intermediate (Scheme 4D).
Me
Me
OMOM
F
NC
N
N
F
F
(i), (ii), (iii)
Me
Me
HO
+
N
Br
2u
N
N
F
(5) TP003
N
F
1l
(Anxiolytic drug)
Me
N
N
(i)
Table 4. Scope of Reaction with Different Tetrazoles[a]
+
N
N
N
N
N
5.0 mol% Fe(TPP)Cl
10 mol% Zn dust, PhH
100 oC, 24 h
Me
N
N
N
6
1j
N
(7) GABAA Agonist
R
N
R
+
R
N
N
Scheme 3. Short Synthesis of Important Molecules. Conditions: (i) 5 mol%
Fe(TPP)Cl, 10 mol% Zn, PhH, 100 oC, 24 h. (ii) 5.0 mol% Pd(PPh3)4, 1.2 equiv.
2-cyano-4-fluoro phenylboronic ester, 2.0 equiv. Cs2CO3, 2/1 (PhMe/DMF),
100 oC, 12 h. (iii) 3.0 equiv. 4(N) HCl in dioxane, rt, 30 min.
– N2 gas
2a
1
4
R
(A) scope of pyrido-tetrazoles
N
N
N
N
N
N
N
N
To provide mechanistic insight of the metalloradical annulation,
we performed some preliminary control experiments (Scheme 4).
First, a deuterium labeling experiment was carried out, which
resulted almost complete preservation of the deuterium atom
into the product (Scheme 4A). This result excludes the possible
involvement of the ionic mechanism. Second, we conducted the
annulation adding an electrophilic halogenating agent (ICl),
hypothesizing that if the reaction follows an ionic mechanism, it
should afford the corresponding halo-adduct (Scheme 4B).
CF3
Ph
Ph
Ph
Ph
Me
Cl
Br
4a: 82%
4b: 96%[b]
4c: 87%[b]
4d: 74%
N
N
N
N
N
N
N
N
MeO2C
EtO2C
Et2NOC
Me
Me
Ph
Ph
Ph
Ph
Ph
4e: 88%
4f: 81%
4g: 93%
4h: 85%
F
O
MOMO
N
N
N
N
N
N
N
N
N
(A) deuterium labeling experiment:
5.0 mol% Fe(TPP)Cl
10 mol% Zn dust, PhH
100 oC, 24 h
Ph
4l: 89%
Br
Ph
4i: 95%
Me
Ph
4j: 92%
Ph
4k: 87%
N
N
N
N
D
+
Ph
D
N
N
F
Br
2a-d
>95% isotopically pure
– N2 gas
1a
Ph
3a-d
N
N
N
N
N
>91% D incorporation
(B) control experiment with an electrophile:
2.0 equiv. ICl
N
N
N
Ph
4m: 79%[c]
Br
Ph
5.0 mol% Fe(TPP)Cl
10 mol% Zn dust, PhH
100 oC, 24 h
Ph
Ph
Me
N
N
4n: 84%
4o: 81%
Br
N
4p: 86%
N
+
Ph
H
N
N
N
– N2 gas
Me
Br
Me
Br
Me
Ph
Ph
3a: conv. >94%
N
N
N
N
N
1a
2a
(C) control experiment with TEMPO:
N
N
2.0 equiv. TEMPO
Br
5.0 mol% Fe(TPP)Cl
10 mol% Zn dust, PhH
100 oC, 24 h
N
N
N
N
Ph
4q: 85%
Ph
4r: 90%
Ph
Ph
4s: 93%
4t: 87%
+
Ph
H
N
N
(B) scope of other tetrazoles & conjugated alkynes
1a
Ph
2a
3a: conv. 0%
Cl
(D) trapping experiment with aldehyde:
N
N
N
N
N
N
O
N
N
5.0 mol% Fe(TPP)Cl
10 mol% Zn dust, PhH
100 oC, 24 h
N
N
N
N
H
O
N
+
MeO
N
Ph
Ph
Ph
Ph
N
N
– N2 gas
H
4u: 77%
4v: 84%
4w: 88%
4x: 78%
OMe
1a
9: yield: >35%
8
N
N
N
N
Scheme 4. Mechanistic Studies: Control Experiments
N
N
N
N
Accordingly,
a
control experiment was performed using
benzaldehyde instead of alkyne. To our delight, we were able to
trap the intermediate (9), which is characterized by
spectroscopic data. Finally, EPR spectroscopic data (g = 1.97)
of the crude reaction mixture (see SI for details) demonstrated
the generation of the organic radical species. Thus, based on
Ph
Ph
4y: 97%
4z: 78%
4ab: 87%
4ac: 98%
[a] Reactions were conducted with 0.5 mmol scale; isolated yields. [b]
Reaction completed within 12 h at 80 oC. [c] Reaction conducted at 120 oC.
However, we did not see any halo-adduct, instead we found
desired product formation quantitatively. Thus, this finding also
discards the ionic mechanism. Third, as per our proposed
blueprint (Scheme 2) for the metalloradical activation
these experimental evidences,
a metalloradical activation
mechanism is proposed (Scheme 5). First, Zn reduces the
FeIII(TPP)Cl to form the active catalyst FeII(TPP) (A) via single
electron transfer which was confirmed by a red-shift in the UV
This article is protected by copyright. All rights reserved.

10.1002/anie.201904702
Angewandte Chemie International Edition
COMMUNICATION
spectra (SI for details). After coordination with azide nitrogen, α-
Fe(III)-nitrene radical intermediate (C) is formed by the loss of
dinitrogen from species (B). Upon subsequent trapping with
alkyne, the intermediate (C) produces γ-Fe(III)-vinyl radical
intermediate (D), which undergo radical addition intramolecularly
to the C=N bond to generate a new b-Fe(III)-alkyl radical
intermediate (E) where the fused five-membered ring is
constructed upon C-N bod formation. Subsequently, the beta-
Fe(III)-alkyl radical intermediate (E) proceeds b-radical scission
to break N–Fe bond and form C=N double bond, affording the
product (3) regenerating the catalytic cycle.
Keywords: Denitrogenative annulation • Fe-nitrene • catalysis •
nitrogen-heterocycles • Metalloradical
[1]
For selected few examples of cyclopropanation, see: a) Y. Wang, X.
Wen, X. Cui, L. Wojtas, X. P. Zhang, J. Am. Chem. Soc. 2017, 139,
1049; b) X. Xu, Y. Wang, X. Cui, L. Wojtasb, X. P. Zhang, Chem. Sci.
2017, 8, 4347; c) S. Zhu, X. Xu, J. A. Perman, X. P. Zhang, J. Am.
Chem. Soc. 2010, 132, 12796; d) S. Zhu, J. A. Perman, X. P. Zhang,
Angew. Chem. Int. Ed. 2008, 47, 8460; e) S. Zhu, J. V. Ruppel, H. Lu, L.
Wojtas, X. P. Zhang, J. Am. Chem. Soc. 2008, 130, 5042; f) Y. Chen, J.
V. Ruppel, X. P. Zhang, J. Am. Chem. Soc. 2007, 129, 12074; g) Y.
Chen, K. B. Fields, X. P. Zhang, J. Am. Chem. Soc. 2004, 126, 14718.
For selected few examples of heterocyclization and carbocyclization
except cyclopropanation, see: a) C. te Grotenhuis, N. van den Heuvel,
J. I. van der Vlugt, B. de Bruin, Angew. Chem. Int. Ed. 2018, 57, 140; b)
H. L. Jiang, K. Lang, H. J. Lu, L. Wojtas, X. P. Zhang, J. Am. Chem.
Soc. 2017, 139, 9164; c) C. te Grotenhuis, B. G. Das, P. F. Kuijpers, W.
Hageman, M. Trouwborst, B. de Bruin, Chem. Sci. 2017, 8, 8221; d) X.
Cui, X. Xu, L. M. Jin, L. Wojtas, X. P. Zhang, Chem. Sci. 2015, 6, 1219;
e) N. D. Paul, S. Mandal, M. Otte, X. Cui, X. P. Zhang, B. de Bruin, J.
Am. Chem. Soc. 2014, 136, 1090; f) B. G. Das, A. Chirila, M. Tromp, J.
N. H. Reek, B. de Bruin, J. Am. Chem. Soc. 2014, 38, 8968; g) X. Cui,
X. Xu, L. Wojtas, M. M. Kim, X. P. Zhang, J. Am. Chem. Soc. 2012, 134,
19981; h) X. Xu, H. Lu, J. V. Ruppel, X. Cui, S. L. de Mesa, L. Wojtas,
X. P. Zhang, J. Am. Chem. Soc. 2011, 133, 15292.
Cl
[2]
N
N
N
N
III
Fe
Zn(0)
Ar
1
2
Zn+2
N
N
N
N
N
N
N
N
N
N
N
N
II
Fe
N
N
3
1
N
(A)
N2
active catalyst for
annulation
Ar
N
N
N
II
Fe
N
N
•
N
N
III
Fe
N
N
N
N
(B)
[3]
a) H. Lu, H. Jiang, L. Wojtas, X. P. Zhang, Angew. Chem. Int. Ed. 2010,
49, 10192; b) H. Lu, V. Subbarayan, J. Tao, X. P. Zhang,
Organometallics 2010, 29, 389; c) H. Lu, J. Tao, J. E. Jones, L. Wojtas,
X. P. Zhang, Org. Lett. 2010, 12, 1248; d) H. Lu, H. Jiang, Y. Hu, L.
Wojtas, X. P. Zhang, Chem. Sci. 2011, 2, 2361; e) H. Lu, Y. Hu, H.
Jiang, L. Wojtas, X. P. Zhang, Org. Lett. 2012, 14, 5158; f) L.-M. Jin, H.
Lu, Y. Cui, C. L. Lizardi, T. N. Arzua, L. Wojtas, X. Cui, X. P. Zhang,
Chem. Sci. 2014, 5, 2422; g) H. Lu, C. Li, H. Jiang, C. L. Lizardi, X. P.
Zhang, Angew. Chem. Int. Ed. 2014, 53, 7028; h) O. Villanueva, N. M.
Weldy, S. B. Blakey, C. E. MacBeth, Chem. Sci. 2015, 6, 6672; i) H. Lu,
K. Lang, H. Jiang, L. Wojtas, X. P. Zhang, Chem. Sci. 2016, 7, 6934; j)
P. F. Kuijpers, M. J. Tiekink, W. B. Breukelaar, D. L. J. Broere, N. P.
van Leest, J. I. van der Vlugt, J. N. H. Reek, B. de Bruin, Chem. Eur. J.
2017, 23, 7945; k) Z.-Y. Gu, Y. Liu, F. Wang, X. Bao, S.-Y. Wang, S.-J.
Ji, ACS Catal. 2017, 7, 3893; l) Y.-D. Du, Z.-J, Xu, C.-Y, Zhou, C.-M,
Che, Org. Lett. 2019, doi: 10.1021/acs.orglett.8b03765.
Metalloradical Activation
Mechanism
(E)
N2
N
Ar
•
•
N
N
N
N
N
III
Fe
N
N
III
N
N
N
N
Fe
(C)
(D)
Ar
Scheme 5. Proposed Metalloradical Activation Mechanism
In conclusion, we have developed
a new metalloradical
activation concept for the intermolecular denitrogenative
annulation, which completely overturn the traditionally more
favored click reaction. It has been demonstrated that the
reaction proceeds via an unprecedented metalloradical
activation mechanism. The method requires commercially
available cheap Fe(TPP)Cl catalyst in combination of a catalytic
amount of Zn dust as reducing agent. This is the first report for
the denitrogenative intermolecular annulation via metal-nitrene
formation. The developed method shows a wide range of
substrate scope and functional group tolerance. The synthetic
utility of the developed method is showcased with the short
synthesis of valuable bioactive molecules.[16] We do believe that
the developed concept will have extensive impact in this area for
solving the long-standing challenging problem for the overriding
the traditional click chemistry towards intermolecular annulation.
[4]
[5]
a) J. V. Ruppel, J. E. Jones, C. A. Huff, R. M. Kamble, Y. Chen, X. P.
Zhang, Org. Lett. 2008, 10, 1995; b) V. Subbarayan, J. V. Ruppel, S.
Zhu, J. A. Perman, X. P. Zhang, Chem. Commun. 2009, 4266; c) L.-M.
Jin, X. Xu, H. Lu, X. Cui, L. Wojtas, X. P Zhang, Angew. Chem. Int. Ed.
2013, 52, 5309; d) H. Jiang, K. Lang, H. Lu, L. Wojtas, X. P. Zhang,
Angew. Chem. Int. Ed. 2016, 55, 11604; e) H. Jiang, K. Lang, H. Lu, L.
Wojtas, X. P. Zhang, J. Am. Chem. Soc. 2017, 139, 9164.
For the first report of denitrogenative annulation by metalloradical
activation mechanism, see: S. Roy, S. K. Das, B. Chattopadhyay,
Angew. Chem. Int. Ed. 2018, 57, 2238.
[6]
[7]
B. Chattopadhyay, C. I. Rivera Vera, S. Chuprakov, V. Gevorgyan, Org.
Lett. 2010, 12, 2166.
For selected pioneering examples, see: a) R. Harder, C. Wentrup, J.
Am. Chem. Soc. 1976, 98, 1259; b) C. Wentrup, H.-W. Winter, J. Am.
Chem. Soc. 1980, 102, 6159; c) R. A. Evans, M. W. Wong, C. Wentrup,
J. Am. Chem. Soc. 1996, 118, 4009; d) C. Wentrup, M. Kuzaj, H.
Lüerssen, Angew. Chem. Int. Ed. Engl. 1986, 25, 480; e) C. Wentrup,
Tetrahedron 1970, 27, 367; f) D. Kvaskoff, M. Vosswinkel, C. Wentrup,
J. Am. Chem. Soc. 2011, 133, 5413.
Acknowledgements
This
work
was
supported
by
CSIR-EMR-II
grant
(02(0259)/16/EMR-II), Ramanujan fellowship grant and DST-
SERB CRG grant (CRG/2018/000133). SR and SKD thank
CSIR for SRF and HK thanks CSIR for JRF. We thank the NMR
and mass spectrometry facility at CBMR, and the Director, for
the research facilities.
[8]
For leading reviews on denitrogenative annulations of 1,2,3-triazoles
using transition metal catalysts, see: a) B. Chattopadhyay, V.
Gevorgyan, Angew. Chem. Int. Ed. 2012, 51, 862; b) A. V. Gulevich, V.
Gevorgyan, Angew. Chem. Int. Ed. 2013, 52, 1371; c) H. M. L. Davies,
J. S. Alford, Chem. Soc. Rev. 2014, 43, 5151.
This article is protected by copyright. All rights reserved.

10.1002/anie.201904702
Angewandte Chemie International Edition
COMMUNICATION
[9]
For first report of intramolecular annulation of 1,2,3,4-tetrazole via
metal-nitrene, see: a) S. K. Das, S. Roy, H. Khatua, B. Chattopadhyay,
J. Am. Chem. Soc. 2018, 140, 8429; b) For the first denitrogenative
annulation with monocyclic 1,2,3,4-tetrazoles via metal-carbene
intermediate, see: T. Nakamuro, K. Hagiwara, T. Miura, M. Murakami,
Angew. Chem. Int. Ed. 2018, 57, 5497.
[13] C. K. Prier, R. Zhang, A. R. Buller, S. Brinkmann-Chen, F. H. Arnold,
Nat. Chem. 2017, 9, 629.
[14] Possibility of the annulation product (3a) from the click product (3a’)
was discard by the control experiment with the independently
synthesized click product (3a’) under the optimized annulation
conditions.
[10] Notably, this is the first example of metalloradical activation of organic
azides for radical annulation with alkynes.
[15] Importantly, performing a reaction at 130 oC temperature in presence of
Fe(TPP)Cl and Zn dust, we observed only annulation product and no
click reaction occurred, which is demonstrating that our reaction
conditions is highly effective even at high reaction temperature.
[16] For Fe-catalyzed nitrogen heterocycle synthesis, see: E. T. Hennessy,
T. A. Betley, Science 2013, 340, 591.
[11] B. J. Stokes, H. Dong, B. E. Leslie, A. L. Pumphrey, T. G. Driver, J. Am.
Chem. Soc. 2007, 129, 7500.
[12] For lower reactivity of 2-pyridyl diazo-compounds in Rh-catalyzed
reactions, see: H. M. L. Davies, R. J. Townsend, J. Org. Chem. 2001,
66, 6595.
This article is protected by copyright. All rights reserved.

10.1002/anie.201904702
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
A unique concept for
Satyajit Roy, Hillol
Khatua, Sandip Kumar
Das and Buddhadeb
Chattopadhyay*
Fe(II)-Metalloradical Activation Approach for Annulation Overcoming Click Chemistry
the intermolecular
denitrogenative
annulation of 1,2,3,4-
tetrazoles and
alkynes is
discovered
employing a catalytic
amount of Fe(TPP)Cl
and Zn dust. This
concept overcomes
the traditional click
reaction between
organic azide and
alkynes.
N
N
N
N
N
Ar
N
N
III
II
Fe
N
Fe
Cl
N
N
N
Page No. – Page No.
N
N
N2
reducing
agent
N
Metalloradical Pathway
Annulation
N
A Fe(II)-Based
Metalloradical
Activation Approach:
Overriding
Traditional Click
Chemistry Towards
Denitrogenative
Annulation
Ar
Ionic Pathway
N
N
N
III
III
III
Click-Chemistry
Ar
Fe
Cl
Fe
Fe
N
Cl
N
Ar
FeIII
Ar
N
N
N
N
N
N
Ar
This article is protected by copyright. All rights reserved.