Bimetallic Cu/Pd-catalyzed three-component azide-alkyne cycloaddition/isocyanide insertion: Synthesis of fully decorated tricyclic triazoles

Article abstract of DOI:10.1039/c9ob01175g

The construction of fully decorated 1,2,3-triazole-fused 5-, 6- and 7-membered rings has been disclosed via a bimetallic relay-catalyzed cascade process combining azide-alkyne cycloaddition, C(sp²)-H functionalization of intermediary 1,2,3-triazoles and isocyanide insertion. The salient features of this methodology include simple starting materials, reduced synthetic steps, good substrate scope and high efficiency.

Full text of DOI:10.1039/c9ob01175g

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. K. Kota, P. K.
Naikawadi, R. Dandela and R. Jatoth, Org. Biomol. Chem., 2019, DOI: 10.1039/C9OB01175G.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 6
View Article Online
DOI: 10.1039/C9OB01175G
COMMUNICATION
Bimetallic Cu/Pd‐catalyzed three‐component azide‐alkyne
cycloaddition/isocyanide insertion: synthesis of fully decorated
tricyclic triazoles
Received 00th January 20xx,
Accepted 00th January 20xx
K. Shiva Kumar,*a Praveen Kumar Naikawadi,a Ramanna Jatotha and Rambabu Dandelab
DOI: 10.1039/x0xx00000x
because it provides a step‐ and atom‐economical way to
construct structurally diverse organic molecules.6,7 The Meldal8
and Sharpless9 groups were independently reported the Cu‐
catalyzed azide−alkyne cycloaddiꢀon (CuAAC) for the
construction of 1,4‐disubstituted 1,2,3‐triazoles from terminal
alkynes under extremely mild conditions. However, these
classical reactions using internal alkynes results the fully
decorated 1,2,3‐triazoles with high difficulty due to their
diminished reaction rates and problems in regiocontrol.10
Thus, the development of a simple and efficient strategy to
access fully decorated 1,2,3‐triazoles is highly desirable.11
Generally, such fully decorated 1,2,3‐triazoles could be
accessed through a cycloaddition between an azide and alkyne
followed by metal catalyzed arylation of the resulting 1,2,3‐
triazole (Scheme 1a).12 With this strategy Ackermann,13a
Lautens,13b and Cai14 groups were reported a series of
annulated 1,2,3‐triazoles. Very recently, Borggraeve et al.
described a Pd‐catalyzed synthesis of triazolo[1,5‐a]indolones
via intramolecular carbonylative C–H functionalization
(Scheme 1b).15 Lautens and co‐workers developed the Cu/Pd‐
catalyzed synthesis of fully decorated polycyclic triazoles.16
This reaction involves a Cu−catalyzed chemo‐selective azide‐
alkyne cycloaddition (CuAAC) to form 1,2,3‐triazoles followed
by Pd‐catalyzed C−H functionalization with terminal alkynes.
While many of these methods are found effective to access
fully decorated 1,2,3‐triazoles, most of them are not
Construction of fully decorated 1,2,3‐triazole‐fused 5‐, 6‐ and 7‐
membered rings has been disclosed via a bimetallic relay‐
catalyzed cascade process combining azide−alkyne cycloaddiꢀon,
C(sp2)−H funcꢀonalizaꢀon of intermediatory 1,2,3‐triazoles and
isocyanide insertion. The salient features of this methodology
include simple starting materials, reduced synthetic steps, good
substrate scope and high efficiency.
Fused 1,2,3‐triazoles have gained significant attention due to
their broad applications in medicinal chemistry1 and materials
science.2 A large number of small molecules containing fused
1,2,3‐triazole skeletons have shown prominent biological and
pharmaceutical applications as depicted in Figure 1. For
example, compound
agent,3 the 1,2,3‐triazole derivative
activity towards the α‐glucosidase enzyme,4 and the
morpholine‐based triazole derivative was found to be
A
acts as a potent chemotherapeutic
B
shows a good biological
C
potential in the treatment of Alzheimer's disease.5
Consequently, the development of an efficient strategy to
access diversely fused triazoles is of great importance.
Fig.
heterocycles
1
Pharmacologically active 1,2,3‐triazole‐based
.
In the past decade, the transition‐metal‐catalyzed
functionalization of C–H bonds has found considerable interest
a.Department of Chemistry, Osmania University, Hyderabad‐500 007, India
E‐mail: shivakumarkota@yahoo.co.in; shivakumarkota@osmania.ac.in.
b.Department of Industrial and Engineering Chemistry, Institute of Chemical
Technology, IOC‐Odisha Campus, Samantpuri, Bhubaneswar‐751013, India.
† Footnotes relaꢀng to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1 Methods for the synthesis of fused 1,2,3‐triazoles
via C‐H activation/functionalization.
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 6
View Article Online
DOI: 10.1039/C9OB01175G
COMMUNICATION
Journal Name
generalized and required multiple steps. As part of our
research program on the development of novel synthetic
methodologies involving C‐H functionalizations,17 we were
interested in developing
a
new approach for the
Yield
temp
(°C)/
C3−funcꢀonalizaꢀon of 1,2,3‐triazole for the construction of
fully decorated 1,2,3‐triazole derivatives. In recent years,
transition‐metal‐catalyzed C–H bond activation and
isocyanide insertion has been a highly intriguing research
area.18 Isocyanide has been used as C1 building block in the
construction of important molecules19 and well investigated
by Orru,20 Zhu,21 Chatani,22 Pal,23 and others.24,17b
Consequently, we disclose for the first time, the C(sp2)−H
functionalization of 1,2,3‐triazoles leading to fully decorated
1,2,3‐triazole scaffolds by an isocyanide insertion strategy in a
one–pot sequential cascade manner starting from o‐
functionalized aryl azides, alkynes, and isocyanide (Scheme
1c). Moreover, the C(sp2)−H funcꢀonalizaꢀon of 1,2,3‐
triazoles followed by isocyanide insertion to form 1,2,3‐
triazoles with different ring sizes is not yet reported.
(%)b
entry catalyst
oxidant
time (h)
Ia 4a
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Air
120/18
120/18
120/18
120/18
120/18
120/18
120/18
120/18
100/18
120/18
120/15
120/18
120/18
10 48
8
‐
‐
‐
Oxoned
PhI(OAc)2
54
58
62
72
65
60
d
d
Cu(OAc)2
O2
5
6
7
8
PdCl2(PPh3)2 O2
Pd(PPh3)4
PdCl2
‐
‐
O2
O2
O2
O2
O2
O2
N2
10 54
65
12 43
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
‐
‐
10
11
12
13
‐
55
45
62
‐
‐
Pd(OAc)2
To evaluate the practicability of our proposed synthetic
pathway, o‐azido phenol (1a) and phenylacetylene (2a) were
chosen as model substrates for the synthesis of the
intermediate azide‐alkyne cycloaddition adduct, prepared
according to our previously reported protocol.17c With the
highly efficient formation of the key intermediate azide‐
alkyne cycloaddition adduct, we moved forward to study the
one‐pot preparation of triazolo[1,5‐d][1,4]oxazine (4a). Thus,
the mixture of 1a and 2a was treated with CuI and K2CO3 in
DMF at 120 °C for 2 h. Then, tert‐butyl isocyanide (3a) and
Pd(OAc)2 were added, and the resulting mixture was stirred
at 120 °C for 18 h open to the air, and we observed 48%
product formation (entry 1, Table 1) along with azide‐alkyne
cycloaddition intermediate Ia (10%). To improve the
efficiency, optimizations were carried out by altering the
reaction parameters. Screening showed that various oxidants
(Table 1, entries 1‐5) effectively gave the product 4a, and O2
balloon was superior to all other tested oxidants (Table 1 ,
entries 5). We also examined the effect of other catalysts
including PdCl2(PPh3)2, Pd(PPh3)4 and PdCl2 on this isocyanide
insertion reaction (entries 6‐8) and Pd(OAc)2 was proved to
be the best catalyst (entries 5 vs 6‐8). An attempt to reduce
the temperature to 100 °C resulted in a slightly decreased
yield of 4a (Table 1, entry 9). When the amount of catalyst
was reduced, the yield significantly decreased (Table 1,
entries 10). An attempt to reduce the time to 15 h resulted in
a decreased yield of 4a (Table 1, entry 11). In the absence of Pd
catalyst, the desired product 4a (entry 12) was not formed.
Reaction under N2 atmosphere, the desired product 4a was also not
formed which suggests that oxidant is necessary for the isocyanide
insertion reaction (entry 13).
aReaction conditions: 1a (0.37 mmol), 2a (0.37 mmol), CuI
(0.04 mol), K2CO3 (0.44 mmol), DMF (2 mL), 120 °C, 2 h, and
then 3a (0.28 mmol), Pd catalyst (10 mol%), oxidant; bIsolated
yields; 5% Pd catalyst was used. d1.0 equiv. oxidant was
c
used.
corresponding products in good yields. Aromatic (4a–c, 4f−4l
and aliphatic 4d−e substituents on the triple bond
)
(
)
participated well in the reaction and in reasonably good
yields. Moreover, tert‐butyl isocyanide (4a−h and 4j−l) and
cyclohexyl isocyanide (4i) were found to be effective for
thesynthesis of 1,2,3‐triazole fused oxazine derivatives. The
structure of 4b was further confirmed by single‐crystal X‐ray
analysis.25
Scheme 3. Reaction scope for 1,2,3‐triazolefused oxazine (4a‐
a,b
m
)
R2
N
1. CuI, K2CO3
OH
N3
O
N
DMF, 120 oC, 2 h
R
R
R1
2. R2-NC
R1
(3)
Pd(OAc)2
O2, 120 oC, 18 h
N
N
1a-c
2
4a-l
4b, 70%c
4d, 68%
4a, 72%
4b
4e, 65%
4h, 67%
4k, 72%
4c, 71%
4f, 70%
4g,
65%
The scope and generality of the reaction was examined by
employing a variety of o‐azido phenols 1a−c, alkynes 2a‐e and
isocyanides 3a‐b for the synthesis of a diverse library of 1,2,3‐
triazole fused oxazines 4a−l (Table 2). The effect of electron‐
donating (t‐butyl) (4f−4i) and electron‐withdrawing groups
(chloro) (4j−4l) on o‐azido phenol was studied and produced
4j, 72%
4i, 68%
4l, 70%
aConditions: 1a‐c (0.37 mmol),
2
(0.37 mmol), CuI (0.04 mol),
(0.28
K2CO3 (0.44 mmol), DMF (2 mL), 120 °C, 2 h, and then
3
mmol), Pd(OAc)2 (10 mol%), O2 balloon; bIsolated yields;
cReaction performed on 1 mmol scale.
Table 1. Optimization of reaction conditions for the synthesis
of 4aa
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 6
View Article Online
DOI: 10.1039/C9OB01175G
Journal Name
COMMUNICATION
Compounds containing the oxazepine nucleus has a wide
range of biological and pharmaceutical properties.26 To gain
further insight into successful transformation of a variety of
1,2,3‐triazole fused derivatives, we continued our
investigation by examining various (2‐azidophenyl)methanols
8
9
10
11
12
13
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
120/18
100/18
100/18
140/15
120/15
120/20
10
13
10
‐
‐
‐
58
52
58
45
68
66
d
(
1d‐e), phenylacetylene (2a) and cyclohexyl isocyanide (3b).
aReaction conditions: 1f (0.37 mmol), 2a (0.37 mmol), CuI
(0.04 mol), K2CO3 (0.44 mmol), DMF (2 mL), 120 °C, 2 h,
andthen 3a (0.28 mmol), Pd catalyst (10 mol%), oxidant;
bIsolated yields; Reaction performed under open air; 5% Pd
catalyst was used.
The reaction afforded the formation of 1,2,3‐triazole fused
oxazepines 4m
−
o
in good yields (Scheme 2).
1. CuI, K2CO3
O
Cy
N
DMF, 120 oC, 2 h
OH
R
c
d
R2
R
+
2.
Cy NC
N
N
3b
N3
1d-e
R2
Pd(OAc)2
O2, 120 oC, 18 h
N
4m-o
2
O
Cl
Cy
N
O
N
O
Cy
N
Cy
N
After the best conditions were established, we explored the
substrate scope of this one‐pot cascade process for the
N
N
N
N
N
N
Ph
C6H5OMe-p
Ph
N
N
4o (65%)
4n (68%)
4m (65%)
construction of triazole fused indol‐ylidene derivatives (
Diverse substituents including H, Me, F, Cl and CF3 on the
phenyl group of the 1‐azido‐2‐bromobenzene ( ) were well
tolerated, to produce the desired triazole fused indol‐ylidene
products ( ) in good to excellent yields (Table 4). The various
terminal acetylene bearing electron‐donating group such as
methoxy (5c 5f, 5i and 5j), Me (5b 5e 5h 5k and 5m) and
electron‐withdrawing group such as chloro (5o) on para
position of phenyl ring proved to be viable substrates and
provided the desired product in good yield. Both tert‐butyl
5).
Scheme 2 Reaction scope for 1,2,3‐triazole fused oxazepines
4m‐o).
1
(
After having these encouraging results for the synthesis of
1,2,3 triazols fused oxazin/oxazepines, we continued our
investigation for the construction of triazole fused
membered heterocyclic rings. We employed 1‐azido‐2‐
5
−
,
,
,
,
5
−
bromobenzene (1f), phenylacetylene (2a) and tert‐butyl
isocyanide (3a) as model substrates. When we performed the
reaction using a similar procedure used in Table 2 The
desired, product i.e. 1,2,3‐triazole‐fusedindol‐ylidene
derivative 5a was not formed and the intermediate IIa was
detected and isolated in 85% yield. When the reaction was
performed by adding Dppf as a ligand under N2 atmosphere,
the expected product 5a was obtained in 15% yield (Table 3,
entry 2). Replacing Dppf with other ligands such as PPh3 and
xantphos did not improve the product yield (Table 3, entries
3‐4). Surprisingly, when the reaction was performed with
PCy3 as a ligand, 5a was isolated in 75% yield (Table 3, entry
5). We also examined the effect of other catalysts including
PdCl2(PPh3)2, Pd(PPh3)4 and PdCl2 on this isocyanide insertion
isocyanide (5a−i and 5k−o) and cyclohexyl isocyanide (5j
)
derivatives showed similar reactivity affording the desired
products in acceptable yields. The structure of 5b was further
confirmed by the single‐crystal X‐ray data analysis.25
Table 4 Reaction scope for 1,2,3‐triazole fused indol‐ylidene
(5).a,b
R2
N
1. CuI, K2CO3
Br
DMF, 120 oC, 2 h
R1
R
R1
R
+
N3
R2-NC
N
(3),
Pd(OAc)2
2.
N
N
PCy3, N2, 120 oC, 18 h
5
1f-k
2
reaction (Table 3, entries 6
best catalyst (Table 3, entries 5 vs 6
−
8) and Pd(OAc)2 proved to be the
8). When the amount of
5b, 74%c
5a, 75%
−
5b
catalyst was reduced, the yield significantly decreased (Table
3, entry 9). The lowering or increasing of the reaction
temperature or time was also found to be less effective
5c, 72%
5f, 70%
5e, 73%
5h, 70%
5k, 68%
5d, 75%
5g, 68%
(Table 3, entries 10−13).
Table 3 Optimization of reaction conditions for the synthesis
of 5a a
.
5i, 72%
5l, 70%
5o, 70%
5j, 70%
temp
(°C)/
time
yield (%)b
entry
catalyst
ligand
5m, 72%
II
5a
(h)
5n, 70%
1c
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)4
‐
120/18
120/18
120/18
85
62
60
55
‐
‐
15
‐
15
75
65
60
Dppf
PPh3
Xantphos 120/18
PCy3
PCy3
PCy3
120/18
120/18
120/18
‐
‐
aReaction conditions: 1f‐k (0.25 mmol), 2 (0.25 mmol), CuI(0.03
mmol), K2CO3 (0.30 mmol), DMF (2 mL), 120 °C, 2 h, and then 3
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 6
View Article Online
DOI: 10.1039/C9OB01175G
COMMUNICATION
Journal Name
(0.19 mmol), Pd(OAc)2 (10 mol%), PCy3 (0.015 mmol), N2, 120 °C, 18 Scheme 5 Plausible mechanism of Cu/Pd‐catalyzed fully decorated
h; bIsolated yields; cReaction was performed on 1 mmol scale.
tricyclic 1,2,3‐trizoles.
Conclusions
In order to understand the reactivity of aromatic and aliphatic
alkynes, we carried out a reaction between substrates 1a (1.0
equiv), aromatic alkyne 2a (0.5 equiv) and aliphatic alkyne 2d (0.5
equiv) with tert‐butyl isocyanide (3a) (1.0 equiv) under optimized
conditions (Scheme 3). These results show that 4a was obtained in
52% yield and 4d in 16% yield. This result indicates that the ary
alkyne is more selective over aliphatic alkyne for the synthesis of
fused 1,2,3‐triazole under present experimental conditions.
In conclusion, we have successfully developed a novel and direct
one‐pot approach for the synthesis of fully decorated 1,2,3−triazole
via Cu/Pd bimetallic relay‐catalyzed cascade process combining
azide−alkyne cycloaddiꢀon, C(sp2)−H funcꢀonalizaꢀon of 1,2,3‐
triazoles and isocyanide insertion. A variety of fused 1,2,3‐ triazole
based 5‐, 6‐ and 7‐membered rings could be accessed in moderate
to good yields and we believe that this method should be useful for
organic and medicinal chemistry.
Acknowledgements
KSK thanks the University Grants Commission (UGC), New
Delhi, for a faculty position under FRP. We also thank CSIR
[02(0378)/19/EMR‐II], New Delhi, UGC startup grant [F.4‐
5/2006(BSR)] and OU‐DST‐PERSE‐II for funding this work.
Scheme 3 Reactivity study of aromatic vs aliphatic alkyne.
As mentioned above, the formation of 1,2,3‐triazole fused oxazine
is assumed to take place via 2‐(4‐phenyl‐1H‐1,2,3‐triazol‐1‐
yl)phenol intermediate Ia by CuAAC. To confirm this, we performed
Conflicts of interest
a
reaction
between
2‐(4‐phenyl‐1H‐1,2,3‐
triazol‐1
yl)phenolintermediate (Ia) and tert‐butyl isocyanide 3a. As
expected, this reaction resulted in the formation of 1,2,3‐triazole
fused oxazine 4a in 80% yield (Scheme 4).
The authors confirm that this article content has no conflict of
interest.
Notes and references
Scheme 4 Synthesis of 1,2,3‐triazole fused oxazine 4a from 2‐
(4‐phenyl‐1H‐1,2,3‐triazol‐1‐yl)phenolintermediate Ia.
Based on the these results and published reports22b,23,24ba plausible
mechanism has been sketched in Scheme 5. The o‐functionalized
aryl azides 1 reacts with terminal alkyne 2 in the presence of CuI
and K2CO3 to form the 1,2,3‐triazole intermediate I via a Cu‐
catalyzed azide‐alkyne cycloaddition (CuAAC).8,9 A Intermediate I
could be generated by the reaction of the 1,2,3‐triazol‐
phenol/alcohol with Pd(II) to form coordination complex A, which
follows the electrophilic palladation of the 1,2,3‐triazol ring to form
Pd(II)‐intermediate B. Further migratory insertion of an isocyanide
to B furnishes the seven‐or eight‐membered palladium cycle C.
Reductive elimination and tautomerization of C affords the product
3 and the Pd(0) species which then regenerates Pd(II) in the
presence of molecular oxygen (Scheme 5, Path‐A). Oxidative
palladium complex D, followed by isocyanide insertion to form
addition of bromo 1,2,3‐triazol (I) to Pd(0) catalyst leads to a E.
Activation of a 1,2,3‐triazol C‐H bond by palladium, then affords a
palladacycle F, Reductive elimination of F leads to form product 5
and Pd(0) is regenerated (Scheme 5, Path‐B).
1
2
3
For selected reviews, see: (a) S. G. Agalave, S. R. Maujan, V.
S. Pore, Chem. Asian J., 2011, , 2696‐2718; (b) A. H. El‐
6
Sagheer, T. Brown, Acc. Chem. Res., 2012, 45, 1258‐1267; (c)
P. Thirumurugan, D. Matosiuk, K. Jozwiak, Chem. Rev., 2013,
113, 4905‐4979; (d) E. Bonandi, M. S. Christodoulou, G.
Fumagalli, D. Perdicchia, G. Rastelli, D. Passarella, Drug
Discovery Today 2017, 22, 1572‐1581. and references cited
therein.
For selected reviews, see: (a) T. Muller, S. Bräse, Angew.
Chem., Int. Ed., 2011, 50, 11844‐118845; (b) Y. H. Lau, P. J.
Rutledge, M. Watkinson, M. H. Todd, Chem. Soc. Rev., 2011,
40, 2848‐2866; (c) C. Chu, R. Liu, Chem. Soc. Rev., 2011, 40,
2177‐2188; (d) D. Astruc, L. Liang, A. Rapakousiou, J. Ruiz,
Acc. Chem. Res., 2012, 45, 630‐640; (e) W. Xi, T. F. Scott, C. J.
Kloxin, C. N. Bowman, Adv. Funct. Mater., 2014, 24, 2572‐
2590. and references cited therein.
L. S. Kallander, Q. Lu, W.Chen, T. Tomaszek, G. Yang, D. Tew,
T. D. Meek, G. A. Hoffmann, C. K. Schulz‐ Pritchard, W. W.
Smith, C. A. Janson, M. D. Ryan, G.‐F. Zhang, K. O. Johanson,
R. B. Kirkpatrick, T. F. Ho, P. W. Fisher, M. R. Mattern, R. K.
Johnson, M. J. Hansbury, J. D. Winkler, K. W. Ward, D. F.
Veber, S. K. Thompson, J. Med. Chem., 2005, 48, 5644‐5647.
K. B. Mishra, S. Shashi, V. K. Tiwari, RSC Adv., 2015, 5, 86840‐
86848.
B. Whittaker, C. Steele, D. Hardick, M. Dale, V. Pomel, A.
Quattropani, D. Beher, Eur. Pat. Appl., 2014, EP 2687528 A1.
(a) C. C. C. Johansson Seechurn, M. Kitching, T. Colacot, V.
Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062‐5085;
Angew. Chem., Int. Ed., 2012, 124, 5150‐5174; (b) X. Chen,
K.M. Engle, D.‐H. Wang, J.‐Q. Yu, Angew. Chem., Int. Ed.,
2009, 48, 5094‐5115.
4
5
6
7
(a) C. ‐L. Sun, B. ‐J. Li, Z. ‐J. Shi, Chem. Rev., 2011, 111, 1293‐
1314; (b) H. Huang, X. Ji, W. Wu, H. Jiang, Chem. Soc. Rev.,
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 6
View Article Online
DOI: 10.1039/C9OB01175G
Journal Name
COMMUNICATION
2015, 44, 1155‐1171; (b) T. W. Lyons, M. S. Sanford, Chem.
Rev., 2010, 110, 1147‐1169.
C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem., 2002,
67, 3057‐3064.
V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem., Int. Ed., 2002, 41, 2596‐2599.
8
9
10 (a) 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; (b) S. Ding, G. Jia, J. Sun, Angew. Chem., Int. Ed.,
2014, 53, 1877‐1880.
11 (a) Z. Zhang, Q. Zhou, F. Ye, Y. Xia, G. Wu, M. L. Hossain, Y.
Zhang, J. Wang, Adv. Synth. Catal., 2015, 357, 2277‐2286; (b)
C. D. Smith, M. F. Greaney, Org. Lett., 2013, 15, 4826‐4829;
(c) S. Ding, G. Jia, J. Sun, Angew. Chem., Int. Ed., 2014, 53
,
1877‐1880.
12
(
a) S. Chuprakov, N. Chernyak, A. S. Dudnik, V. Gevorgyan,
Org. Lett., 2007,
K. Oshima, Chem. Asian J., 2007,
9
, 2333–2336; (b) M. Iwasaki, H. Yorimitsu,
, 1430–1435; (c) L.
2
Ackermann, H. K. Potukuchi, D. Landsberg, R. Vicente, Org.
Lett., 2008, 10, 3081–3084; (d) L. Ackermann, R. Vicente, R.
Born, Adv. Synth. Catal., 2008, 350, 741–748; (e) R.
Jeyachandran, H. K. Potukuchi, L. Ackermann, Beilstein J.
Org. Chem., 2012, 8, 1771–1777.
13 (a) L. Ackermann, R. Jayachandran, H. K. Potukuchi, P. Novak,
L. Buttner, Org. Lett., 2010, 12, 2056−2059; (b) J. M.
Schulman, A. A. Friedman, J. Panteleev, M. Lautens, Chem.
Commun., 2012, 48, 55−57.
14 Q. Cai, J. Yan, K. Ding, Org. Lett., 2012, 14, 3332‐3335.
15 C. Veryser, G. Steurs, L. Van Meervelt, W. M. De Borggraeve,
Adv. Synth. Catal., 2017, 359, 1271‐1276.
16 Z. Qureshi, J. Y. Kim, T. Bruun, H. Lam, M. Lautens, ACS
Catal., 2016, 6, 4946‐4952.
17 (a) K. S. Kumar, S. R. Meesa, P. K. Naikawadi, Org. Lett., 2018,
20, 6079‐6083; (b) K. S. Kumar, B. Rajesham, N. P. Kumar, M.
S. Ramulu, R. Dandela, ChemistrySelect, 2018, 3, 4581‐4585;
(c) K. S. Kumar, P. K. Naikawadi, B. Rajesham, D. Rambabu,
New J. Chem., 2019, 43, 4333‐4337.
18 B. Song, B. Xu, Chem. Soc. Rev., 2017, 46, 1103‐1106.
19 Selected reviews and accounts see: (a) A. Dçmling, I. Ugi,
Angew. Chem., Int. Ed., 2000, 39, 3168‐3210; (b) A. V. Lygin,
A. de Meijere, Angew. Chem., Int. Ed., 2010, 49, 9094‐9124;
(c) G. Qiu, Q. Ding, J. Wu, Chem. Soc. Rev., 2013, 42, 5257‐
5269; (d) S. Lang, Chem. Soc. Rev., 2013, 42, 4867‐4880.
20 (a) V. Estévez, G. Van Baelen, B. H. Lentferink, T. Vlaar, E.
Janssen, B. U. W. Maes, R. V. A. Orru, E. Ruijter, ACS Catal.,
2014, 4, 40‐43; (b) T. Vlaar, L. Bensch, J. Kraakman, C. M. L.
VandeVelde, B. U. W. Maes, R. V. A. Orru, E. Ruijter, Adv.
Synth. Catal., 2014, 356, 1205‐1209.
21 (a) G. Qiu, Q. Wang, J. Zhu, Org. Lett., 2017, 19, 270‐273; (b)
Mamboury, Q. Wang, J. Zhu, Chem. ‐Eur. J., 2017, 23, 12744‐
12748.
22 (a) M. Tobisu, K. Koh, T. Furukawa, N. Chatani, Angew.
Chem., Int. Ed., 2012, 51, 11363‐11366; (b) M. Tobisu, S.
Imoto, S. Ito, N. Chatani, J. Org. Chem., 2010, 75, 4835‐4840.
23 (a) S. B. Nallapati, B. Prasad, B. Y. Sreenivas, R. Sunke, Y.
Poornachandra, C. G. Kumar, B. Sridhar, S. Shivashankar, K.
Mukkanti, M. Pal, Adv. Synth. Catal., 2016, 358, 3387‐3393.
24 (a) W. Hao, J. Tian, W. Li, R. Shi, Z. Huang, A. Lei, Chem. Asian
J., 2016, 11, 1664‐1667; (b) A. H. Shinde, S. Arepally, M. D.
Baravkar, D. S. Sharada, J. Org. Chem., 2017, 82, 331‐342.
25 The CIF files have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC 1587528 (4b) and CCDC 1864070 (5b).
26 (a) D. Yang, C. Wan, M. He, C. Che, Y. Xiao, B. Fu, Z. Qin, Med.
Chem. Comm., 2017,
Chem. Lett., 2012,
8, 1007‐1014; (b) B. Blass, ACS Med.
3
, 873‐874; (c) X. Q. Deng, C. X. Wei, F.
N.Li, Z. G. Sun, Z. S. Quan, Eur. J. Med. Chem., 2010, 45
,
3080‐ 3086.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 5
Please do not adjust margins

Organic & Biomolecular Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C9OB01175G
GRAPHICAL ABSTRACT
Construction of fully decorated 1,2,3−triazole has been disclosed via bimetallic relay-
catalyzed cascade process combining azide−alkyne cycloaddition, C(sp2)−H
functionalization of 1,2,3- triazoles and isocyanide insertion.
R2
1. CuI, K2CO3
1. CuI, K2CO3
N
R
R
R2
N
DMF, 120 oC, 2 h
R
DMF, 120 oC, 2 h
O
n
X
n
R1
R1
+
2
2.
R
NC , Pd(OAc)2
R2 NC, Pd(OAc)2
O2, 120 oC, 18 h
n = 0, 1; X = OH
N
N3
N
N
2.
N
R1
PCy3, N2, 120 oC, 18 h
N
N
n = 0; X = Br
sequential one-pot three component reaction