Regioselective copper-diamine-catalyzed C-H arylation of 1,2,4-triazole ring with aryl bromides

Article abstract of DOI:10.1039/c6ra14670h

A convenient methodology for the regioselective C-H arylation of 1,2,4-triazole ring was developed. Using a benchtop stable Cu-diamine catalyst system, C-H functionalization of a simple 1,2,4-triazole substrate with various aryl bromides was regioselectively accomplished at the C5 position of the triazole ring.

Full text of DOI:10.1039/c6ra14670h

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: Z. Jamal and Y. C.
Teo, RSC Adv., 2016, DOI: 10.1039/C6RA14670H.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, 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. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this 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 shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
RSC Advances
Page 1 of 5
View Article Online
DOI: 10.1039/C6RA14670H
RSC Advances
COMMUNICATION
Regioselective Copper-Diamine-Catalyzed C-H Arylation of 1,2,4-
Triazole Ring with Aryl Bromides
Zaini Jamal and Yong-Chua Teo*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A convenient methodology for the regioselective C-H arylation of bromobenzene 2a was initially investigated. Under the typical
1,2,4-triazole ring was developed. Using a benchtop stable Cu- reaction conditions consisting of CuI (20 mol%) and LiOtBu (2.0
diamine catalyst system, the C-H functionalization of a simple equiv.), the anticipated arylation to afford 3aa was
1,2,4-triazole substrate with various aryl bromides was encouraging observed in 40% yield (Table 1, entry 1).
regioselectively accomplished at the C5 position of the triazole
Table 1. Screening of Cu-catalyzed conditions for C-H arylation of 1a with 2a.a
ring.
N
N
N
N
Developments in Cu catalysis have taken a striding step in
advancing the science of organic synthesis.1 Since their
renaissance, Cu-catalyzed cross-coupling reactions have been
at the realm of various applications for forging the C-
heteroatom and C-C bonds. With time, interests in developing
the inexpensive and low toxic Cu-catalyzed C-H
functionalization methodologies have also been growing.
The methodological evolution leading to the direct C-H
arylation of heterocycles is an evidence of the breakthrough in
contemporary copper catalysis.2 This recent development
20 mol% CuI/Ligand
PhBr
+
N
N
LiOtBu, Solvent, 24 h, 140 o
C
Ph
Bn
1a
Bn
2a
3aa
MeHN
NHMe
L2
N
N
MeHN
NHMe
L1
L3
(racemic)
Me2N
NMe2
H2N
NH2
marked the emergence of
a sustainable alternative to
L4
L5
traditional transition metal catalysis for construction of the
privileged heterocycles.3
Entry
1
Ligand
-
Solvent
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
Yieldb
The 1,2,4-triazole is an example of heterocycle with
established applications in the medicinal and material
chemistries.4 Daugulis previously demonstrated the Cu-
catalyzed direct C5 arylation of 1-methyl-1H-1,2,4-triazole with
40
50
2
L1
L2
L3
L4
L5
L2
L2
L2
L2
L2
L2
3
62
4
27
5
41
iodobenzene through
a
regioselective non-benzyne
mechanism.5 However, despite its potential, interest in
accomplishing the regioselective C-H arylation of the triazole
ring under Cu catalysis remained limited.6 Therefore, our
interest was subsequently extrapolated to the worthwhile
endeavors in developing the streamlined regioselective
approach towards C5-arylated 1,2,4-triazoles.
6
36
7
53c
45d
55e
Trace
46
8
9
10
11
12
tAmylOH
PhMe
48
Endeavoring on the development of a benchtop stable
procedure using easily accessible and inexpensive substrates,
the arylation of 1-benzyl-1H-1,2,4-triazole 1a with
aGeneral reaction conditions: 1a (0.5 mmol), 2a (3.0 equiv.), 20 mol% CuI/Ligand,
c
LiOtBu (2.0 equiv.), Solvent (0.5 mL), 140 oC, 24 h. bIsolated yield. L2 (30 mol%).
d10 mol% CuI/L2. eReaction temparature of 120 oC.
The reaction also proceeded when 20 mol% 1,10-
phenanthroline (L1) was added to the reaction system albeit
with only a slight improvement in yield (entry 2). Though
limited to the arylation of 1-methyl-1H-1,2,4-triazole with
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 5
View Article Online
DOI: 10.1039/C6RA14670H
COMMUNICATION
Journal Name
iodobenzene, L1 was previously speculated to be an effective conditions. Pyrazole substrate was also not suitable whereby
ligand for stabilizing the organocopper complex and facilitating only the starting material was recovered.
the halide displacement step.5 Therefore, with the prescience
Nonetheless, all arylations occurred regioselectively at the
in the role of a ligand, potential of other ligated Cu-catalyzed natural reactive sites as dictated by the electronic characters
systems for the direct arylation of 1a with 2a was next of the heterocycles.6b,12 Further consideration on the
considered.
electronic characters could also rationalize the observed
The diamines are an important class of ligands for the differences in reactivities. Generally, with an extra nitrogen
successful reemergence of copper catalysis in organic atom, the triazole ring could be reasoned to be more electron
synthesis.7 Furthermore, the role of a diamine ligand had also deficient than either the imidazole or pyrazole ring. This
been reported in the related Cu-catalyzed C-H alkenylation of nature of the ring makes it more reactive to undergo the
oxazoles with bromoalkenes.8 Hence, we performed a set of deprotonation step at the predicted reactive C5 position.
screening experiments to assess the potential of several Hence, better yields were observed in the attempts with 1,2,4-
commercially available diamines ligands for our Cu-catalyzed triazole substrates than substrates based on the imidazole and
reaction (entry 3 – 6). The best outcome led to a 62% yield of pyrazole rings.
3aa when DMEDA (L2) was added to the reaction system
Besides the natural electronic characters, Cu coordination
(entry 3). Notably, in this attempt, no oxidative homocoupling to the heterocyclic substrates could also greatly assist the
of 1a was observed unlike in all other attempts whereby traces deprotonation step.13 This could rationalize the obvious
of the byproduct were observable.9 Therefore, L2 was difference in the reactivity between 1,2,4- and 1,2,3-triazoles.
identified as an effective diamine ligand for the Cu-catalyzed In both triazoles, the reactive or acidic C-H bonds occur at the
coupling of 1a with 2a presumably by stabilizing the C5 ring position. Therefore, in 1,2,4-triazoles, Cu coordination
organocopper complex of 1a and facilitating bromide to the N4 position of the ring could affect a more pronounce
displacement from 2a
.
acidity enhancement to the adjacent C-H bond at the C5
With the optimal 20 mol% CuI/L2 catalyst system at 140 oC position and hence facilitate its deprotonation.
(entries 7 – 9), the effect of solvent was next probed.
With 1a as the optimal substrate, studies on the arylation
However, no improvement in yield was realized; with DMF with various aryl bromides were next performed (Scheme 2).
t
notably afforded only trace yield of 3aa (entry 10). AmylOH
which was recently reported to accelerate the activation of
imidazole C-H under Ni catalysis was also ineffective (entry
11).10 Further attempts to circumvent the observed incomplete
reaction were also conducted. However, no considerable
improvement was achieved with either an extended reaction
time or increased catalyst loading. Additionally, other Cu(I)
sources (CuBr and CuCl) and bases (K3PO4 and K2CO3) were
significantly ineffective with only a trace of 3aa was formed in
each of these attempts.
N
N
N
N
N
N
Me
N
N
N
Bn
Bn
Bn
3ab, 65%
3ac, 74%
4-Me, 3ad, 60%
3-Me, 3ae, 66%
2-Me, 3af, 60%
N
N
N
N
N
N
N
N
CF3
N
Bn
Bn
With the optimal conditions of Table 1 (entry 3), our
studies were next continued by investigating the arylation of
other five-membered N-containing heterocycles.11 Generally,
all 1,2,4-triazole substrates tested were arylated at the C5 ring
Bn
F
Cl
3ag, 60%
3ah, 63%
4-CF3, 3ai, 46%
3-CF3, 3aj, 55%
2-CF3, 3ak, 31%
position to give the intended products (3ba
–
3ea) in moderate
N
N
N
N
N
40% to 50% yields (Scheme 1).
OMe
N
N
N
N
Bn
N
Bn
N
N
N
N
N
N
N
Bn
4-OMe, 3al, 56%
3-OMe, 3am, 61%
2-OMe, 3an, 43%
N
3ao, 34%
N
Ph
Ph
Ph
Bn
3ap, 71%a
R
Bn
R = nBu, 3ba, 40%
R = (E)-styryl, 3ca, 50%
R = Ph, 3da, 43%
3fa, 22%
3ga, 24%
N
N
N
N
S
N
N
S
Bn
Bn
R = p-tolyl, 3ea, 42%
Scheme 1. General reaction conditions: 1b – 1g (0.5 mmol), 2a (3.0 equiv.), 20 mol%
CuI/L2, LiOtBu (2.0 equiv.), Dioxane (0.5 mL), 140 oC, 24 h.
3ar, 56%
3aq, 45%
Scheme 2. General reaction conditions: 1a (0.5 mmol), 2b – 2r (3.0 equiv.), 20 mol%
CuI/L2, LiOtBu (2.0 equiv.), Dioxane (0.5 mL), 140 oC, 24 h. aReaction was conducted
under ligand-free conditions.
The arylation of other simple heterocycles were also
attempted. However, with only 22% 3fa and 24% 3ga
,
arylations of the 1,2,3-triazole and imidazole rings were
deemed to be markedly inefficient under our general reaction
Our arylation attempts were started with 1- and 2-
bromonaphthalene which unambiguously gave the respective
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
RSC Advances
Page 3 of 5
View Article Online
DOI: 10.1039/C6RA14670H
Journal Name
COMMUNICATION
3ab and 3ac in 65% and 74% yield. With the series of
bromotoluenes, 1a was also accordingly arylated to 3ad 3ae
L
LiOtBu
,
Cu
X
N
and 3af in good generality with nearly consistent yields (60%,
66% and 60%). Additionally, a good compatibility of F and Cl
substituents on the arylating reagents was also observed
whereby 1a was exclusively arylated to give 60% 3ag and 63%
Deprotonation/Lithiation
N
Cu Coordination
N
Bn
L
N
N
N
Cu
X
3ah
.
N
However, with electron poor aryl bromides, lower arylation
N
Bn
N
efficiencies were observed. Generally, the regioselective
arylations with 4-, 3- and 2-CF3-substituted bromobenzenes
Li
Bn
LCuX
only afforded 3ai
respectively. Analogous arylations with the electron rich
bromoanisoles were also conducted from which yields of 3al
, 3aj and 3ak in 46%, 55% and 31% yields
Transmetallation
N
L = DMEDA
X = I or Br
N
,
LiX
N
Ar
3am and 3an were obtained in the range between 43% and
61%. Noticeably, unlike the formation of 3af from 2-
bromotoluene, formations of 3ak and 3an could also be
influenced by steric factor on the 2-substituted aryl bromides.
Next, the heteroarylation of 1a was also initiated which
afforded 3ao in only 34% yield from the reaction with 3-
bromopyridine. Contrastingly, in the ligand-free reaction with
2-bromopyridine, an exceptionally reactive heteroarylation of
1a was nonetheless observed whereby up to 71% yield of 3ap
could be obtained. Further attempts to heteroarylate 1a with
bromothiophenes were also carried out. Without any
modification to the general Cu-catalyzed conditions, both 3aq
and 3ar were obtained in 45% and 56% yields respectively.
Bn
N
N
N
Reductive Elimination
CuL
Bn
N
N
Ar
N
Cu Br
ArBr
Bn
L
Oxidative Addition
Scheme 3. Plausible reaction mechanism.
In conclusion, an operationally simple Cu-catalyzed
protocol for the regioselective C-H arylation of 1,2,4-triazole
ring was successfully demonstrated. With a benchtop Cu-
diamine catalysis, the regioselective C-H arylation at the C5
Apparently,
a reaction mechanism involving benzyne
intermediate generated from the arylating reagents could be
ruled out since only single regioisomers were observed in all
cases. Therefore, a plausible reaction mechanism based on the
generally accepted mechanistic rationale of Daugulis could be
operational to sufficiently account for our observations
(Scheme 3).2b,5
ring position of
a simple 1,2,4-triazole substrate was
conveniently accomplished with various aryl bromides
including several heteroaryl bromides. Further efforts to
develop similarly simple but more reactive protocol with a
wider substrate scope are currently ongoing in our laboratory.
We would like to thank the National Institute of Education,
Nanyang Technological University for their generous financial
support (RP 5/13 TYC).
Generally, the regioselective C-H arylation was firstly
initiated by the tert-butoxide deprotonation at the C5 position
of the 1,2,4-triazole ring. This process necessarily involved the
assistance from Cu coordination to N4 position of the ring to
ultimately affect
a C5 lithiation step. Upon a Li-Cu
transmetallation step, a copper complex of 1,2,4-triazole was
next generated. Under the assisting influence of the diamine
ligand, this reactive organocopper complex would then
participate in the coupling with an aryl bromide. For this
Notes and references
1
For representative reviews on Cu catalysis, see: (a) X.-X. Guo,
D.-W. Gu, Z. Wu and W. Zhang, Chem. Rev., 2015, 115, 1622;
(b) C. Sambiagio, S. P. Marsden, A. J. Blacker and P. C.
McGowan, Chem. Soc. Rev., 2014, 43, 3525; (c) G. Evano, C.
Theunissen and A. Pradal, Nat. Prod. Rep., 2013, 30, 1467;
(d) S. E. Allen, R. R. Walvoord, R. Padilla-Salinas and M. C.
Kozlowski, Chem. Rev., 2013, 113, 6234; (e) A. E. Wendlandt,
coupling step,
a catalytic cycle involving Cu(I)/Cu(III)
intermediates might be proposed to sufficiently describe a
sequence of oxidative addition and reductive elimination steps
to afford the arylated 1,2,4-triazole product and regenerate
the Cu(I) catalyst.
A. M. Suess and S. S. Stahl, Angew. Chem. Int. Ed., 2011, 50
11062; (f) I. P. Beletskaya and A. V. Cheprakov, Coord. Chem.
Rev., 2004, 248, 2337.
,
2
3
For early examples on Cu-mediated and Cu-catalyzed C-H
arylation of heterocycles, see: (a) T. Yoshizumi, H. Tsurugi, T.
Satoh and M. Miura, Tetrahedron Lett., 2008, 49, 1598; (b)
H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2007, 129
,
12404; (c) F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi and
S. Viel, Eur. J. Org. Chem., 2006, 693; (d) S. Pivsa-Art, T.
Satoh, Y. Kawamura, M. Miura and M. Nomura, Bull. Chem.
Soc. Jpn., 1998, 71, 467.
(a) R. Rossi, F. Bellina, M. Lessi and C. Manzini, Adv. Synth.
Catal., 2014, 356, 17; (b) L. G. Mercier and M. Leclerc, Acc.
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
RSC Advances
Page 4 of 5
View Article Online
DOI: 10.1039/C6RA14670H
COMMUNICATION
Journal Name
Chem. Res., 2013, 46, 1597; (c) F. Bellina and R. Rossi,
Tetrahedron, 2009, 65, 10269; (d) L. Ackermann, R. Vicente
and A. R. Kapdi, Angew. Chem. Int. Ed., 2009, 48, 9792; (e) I.
V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007, 36
1173.
,
4
5
(a) C. H. Zhou and Y. Wang, Curr. Med. Chem., 2012, 19, 239;
(b) A. D. M. Curtis and N. Jennings, in Comprehensive
Heterocyclic Chemistry III, eds. C. A. Ramsden, E. F. V. Scriven
and R. J. K. Taylor, Elsevier, Oxford, 2008, pp. 159-209.
The use of LiOtBu under Cu/1,10 phenanthroline catalysis
was found optimal for suppressing the reaction from
proceeding by a benzyne-type mechanism, see: H.-Q. Do, R.
M. K. Khan and O. Daugulis, J. Am. Chem. Soc., 2008, 130
15185.
,
6
For related studies on the C-H arylation of triazoles, see: (a)
R. Tadikonda, M. Nakka, S. Rayavarapu, S. P. K. Kalidindi and
S. Vidavalur, Tetrahedron Lett., 2015, 56, 690; (b) J. M. Joo,
P. Guo and D. Sames, J. Org. Chem., 2013, 78, 738; (c) T.
Kawano, T. Yoshizumi, K. Hirano, T. Satoh and M. Miura, Org.
Lett., 2009, 11, 3072; (d) S. Chuprakov, N. Chernyak, A. S.
Dudnik and V. Gevorgyan, Org. Lett., 2007,
For a review on Cu-diamine catalysis, see: D. S. Surry and S.
L. Buchwald, Chem. Sci., 2010, , 13.
F. o. Besselièvre, S. Piguel, F. Mahuteau-Betzer and D. S.
Grierson, Org. Lett., 2008, 10, 4029.
9, 2333.
7
8
9
1
The oxidative homocoupling of azoles under Cu catalysis was
previously reported, see: Y. Li, J. Jin, W. Qian and W. Bao,
Org. Biomol. Chem., 2010,
10 K. Muto, T. Hatakeyama, J. Yamaguchi and K. Itami, Chem.
Sci., 2015, , 6792.
8, 326.
6
11 For an overview on the (hetero)arylation of five-membered
heterocycles, see: F. Bellina, S. Cauteruccio and R. Rossi,
Curr. Org. Chem, 2008, 12, 774.
12 (a) J. M. Joo, B. B. Touré and D. Sames, J. Org. Chem., 2010,
75, 4911; (b) R. Goikhman, T. L. Jacques and D. Sames, J. Am.
Chem. Soc., 2009, 131, 3042.
13 (a) J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom, R. D.
Larsen and M. M. Faul, J. Am. Chem. Soc., 2010, 132, 3674;
(b) F. Bellina, S. Cauteruccio and R. Rossi, Eur. J. Org. Chem.,
2006, 1379.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
RSC Advances
View Article Online
DOI: 10.1039/C6RA14670H
Regioselective Copper-Diamine-Catalyzed C-H Arylation of
1,2,4-Triazole Ring with Aryl Bromides
Zaini Jamal and Yong-Chua Teo*
Natural Sciences and Science Education, National Institute of Education, Nanyang
Technological University, Nanyang Walk, Singapore 637616, Singapore.
Graphical Abstract
A bench-top protocol using simple Cu-diamine catalysis for the regioselective C5-H arylation of
1,2,4-triazole ring with (hetero)aryl bromides.
* Natural Sciences and Science Education,
National Institute of Education, Nanyang
Technological University, 1 Nanyang Walk,
Singapore 6371616 Fax: (65) 6896 9414; Tel:
(65) 6790 3846; yongchua.teo@nie.edu.sg