Efficient synthesis of N-2-aryl-1,2,3-triazole fluorophores via post-triazole arylation

Article abstract of DOI:10.1021/ol802246q

(Chemical Equation Presented) Efficient post-triazole regioselective N-2 arylation was developed from C-4, C-5 disubstituted-1,2,3-NH-triazoles. Three different approaches had been investigated, including S_NAr, Cu(I) catalyzed aryl amidation an

Full text of DOI:10.1021/ol802246q

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5389-5392
Efficient Synthesis of
N-2-Aryl-1,2,3-Triazole Fluorophores via
Post-Triazole Arylation
Yuxiu Liu,† Wuming Yan,‡ Yunfeng Chen,‡ Jeffrey L. Petersen,‡ and
Xiaodong Shi*,‡
C. Eugene Bennett Department of Chemistry, West Virginia UniVersity, Morgantown,
West Virginia 26506, and Institute of Elemento-Organic Chemistry, Nankai UniVersity,
Tianjin 200071, China
Xiaodong.Shi@mail.wVu.edu
Received September 26, 2008
ABSTRACT
Efficient post-triazole regioselective N-2 arylation was developed from C-4, C-5 disubstituted-1,2,3-NH-triazoles. Three different approaches
had been investigated, including SNAr, Cu(I) catalyzed aryl amidation and Cu(II) mediated boronic acid coupling. The N-2-aryl triazoles were
successfully synthesized with excellent yields. The structures were characterized by X-ray crystallography and some N-2-triazole products
gave strong fluorescence with various emission controlled by the C-5 groups.
Initiated by the remarkable discovery of Cu-catalyzed-azide-
alkyne-cycloaddition (CuAAC, also referred as “click chem-
istry”), the 1,2,3-triazole has become one of the most
important heterocycles in current chemistry research.1 Within
the last five years, the applications of this building block
have been extended into various research fields, as diverse
as biological science,2 material chemistry3 and medicinal
chemistry.4 One important group of triazole derivatives is
the N-2-aryl triazoles, where the two aromatic rings adopt
coplanar conformation. With the characteristic electron
density distribution, these bis-aromatic compounds give
unique photonic properties. One example is the commercially
available o-hydroxyphenyl benzotriazoles (such as Tinuvin
P), which has been applied as an efficient light absorber to
prevent polymer degradation from light radiation.5
It has been well documented that the N-2 substitution is
one major challenge for triazole derivatization. The applica-
tion of substituted azide in click-chemistry gives only N-1
products. The higher electron density on the two terminal
nitrogens allows them to have a better nucleophilic position
‡ West Virginia University.
† Nankai University.
(1) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (c) Wu, P.; Fokin,
V. V. Aldrichim. Acta 2007, 40, 7.
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1128. (b) Moorhouse, A. D.; Moses, J. E. Chemmedchem 2008, 3, 715. (c)
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J.; Lin, Y. C.; Silverman, S. M.; Lindstrom, W.; Olson, A. J.; Kolb, H. C.;
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Int. Ed. 2006, 45, 1435.
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Wang, Q. Org. Lett. 2004, 6, 4603. (b) Bock, V. D.; Speijer, D.; Hiemstra,
H.; van Maarseveen, J. H. Org. Bio. Chem. 2007, 5, 971. (c) Costa, M. S.;
Boechat, N.; Rangel, E. A.; Da Silva, F. D.; de Souza, A. M. T.; Rodrigues,
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lnik, J. C.; DeBellis, A. D.; Wood, M. G.; Lau, J. J. Phys. Chem. A. 2002,
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141.
10.1021/ol802246q CCC: $40.75
Published on Web 11/01/2008
2008 American Chemical Society

and gives dominant N-1 products for most or reported post-
triazole derivatization. Recently, Sharpless and Fokin have
made good progress toward the N-2 alkyl substituted
triazoles.6 As they pointed out, the N-2-substituted triazoles
are thermodynamically more stable with less steric hindrance.
Therefore, N-2-substitution will be the major products when
dynamic equilibrium of the substituted triazole products
exists. However, for the N-2 aryl and nonexchangeable N-2
alkyl triazoles, which could be of more important triazole
derivatives with better stability, the selective N-2 substitution
is difficult since the regioselectivity is under kinetic control
and N-1 is the preferred nucleophilic site.
Table 1. Post-Triazole Arylation via SNAr Reactionsa
Our group has recently reported the synthesis of 4,5-
disubstituted-NH-traizoles through Lewis base catalyzed
process.7 With these compounds in hand, recently, we
reported a successful post-triazole N-2 alkylation through
substrate conformation control.8 Encouraged by these results,
we wondered if this strategy could be further extended into
the regioselective N-2-arylation (Scheme 1B). Currently, the
a 1:2 ) 1:1.5, c ) 0.2 M. b Based on the consumption of 1 by NMR.
c Isolated yields of all isomers. d Structure of N-1-3b was determined by
X-ray crystallography.
Scheme 1. N-2-aryl-1,2,3-triazole Synthesis
To our pleasure, application of 4,5-disubstituted triazole 1c and
1d gave excellent regioselectivity with N-2 as the dominant
products. As reported previously,8 the selectivity was driven
by the conformation control of the C-4 and C-5 substitute
groups. However, at higher temperature, the selectivity should
be only driven by the steric effect. To our pleasure, increasing
reaction temperature gave improved N-2 selectivity (entries
5-7), which suggested that the regioselectivity of post-triazole
arylation could be achieved at higher temperature. Notably, as
a good nucleophile, triazole can also react with less electron-
deficient substrates to form the corresponding N-2 arylation
products (entries 5-7). Encouraged by excellent regioselectivity
of SNAr reactions, we then explored the possible coupling
strategy for aromatic systems with higher electron density.
Although an increasing number of copper catalyzed N-aryl
halide coupling reactions have been reported recently, the
reaction mechanism remains unclear.11 The most likely
mechanism involves a Cu(I) oxidative addition to Cu(III)
intermediate followed by reductive elimination, which was
proposed by Buchwald, Hartwig and Stahl.12 Hartwig and
co-workers also suggested that oxidative addition of carbon-
halogen bond likely occur in the catalytic cycles with strong
ligand effects.12b Based on these remarkable works, we
rationalized that NH-triazoles might be another suitable
nitrogen source for copper mediated aryl halide amidation.
Reactions between NH-triazole 1a and phenyl iodide were
carried out with the focus on the ligand effect for optimal
performance (Table 2).
general approach for N-2-aryl triazole is from the hydrazine/
R-hydoxyketone condensation9 as shown in Scheme 1A. The
need of various aryl hydrazines and R-hydoxyketones as
starting materials significantly limited the application of this
method and only specific N-2 aryl triazole can be prepared
with good yields. Therefore, an effective regioselective N-2
arylation approach will be of great importance for the triazole
related research.10 Herein, we report an efficient Cu catalyzed
regioselective N-2 arylation through post-triazole aryl ami-
dation and their photonic emissions.
To evaluate the regioselectivity, the SNAr substitution was
first studied with a variety of 1,2,3-triazoles. The results are
listed in Table 1.
Because the arylation products 3 are stable (no C-N bond
exchange under the reaction condition), the SNAr reaction then
provided direct measurement of C-4 and C-5 groups influence
on the regioselectivity. As shown above, benzotriazole 1a gave
modest selectivity with N-1 as the major product. The applica-
tion of 4-phenyl group in 1b improved the selectivity, giving
N-2 arylation as the major product, though with poor selectivity.
(10) Reported examples for the post-triazole derivation toward N-2-
aryl-1,2,3-triazoles: (a) Lacerda, P. S. S.; Silva, A. M. G.; Tome, A. C.;
Neves, M.; Silva, A. M. S.; Cavaleiro, J. A. S.; Llamas-Saiz, A. L. Angew.
Chem., Int. Ed. 2006, 45, 5487. (b) Kim, D. K.; Kim, J.; Park, H. J. Bio
Med. Chem. Lett. 2004, 14, 2401.
(6) Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2008, 10, 3171.
(7) Sengupta, S.; Duan, H.; Lu, W.; Petersen, J. L.; Shi, X. Org. Lett.
2008, 10, 1493.
(11) Selected reviews: (a) Evindar, G.; Batey, R. A. J. Org. Chem. 2006,
71, 1802. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004,
248, 2337. (c) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M.
Chem.-Eur. J. 2004, 10, 5607. (d) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400.
(8) Chen, Y.; Liu, Y.; Petersen, J. L.; Shi, X. Chem. Commun. 2008,
28, 3254.
(9) Tang, W.; Hu, Y. Synth. Commun. 2006, 36, 2461.
5390
Org. Lett., Vol. 10, No. 23, 2008

Table 2. Screening of the Reactions for Coupling with PhIa
Cu cat
co-cat.c
solvent
temp (°C)
time (h)
convn (%)d
yield (%)d
1
2
3
4
5
6
7
8
CuI
CuI
CuCl
-
DMSO
DMSO
DMSO
110
110
110
110
110
µw 160
µw 160
µw 160
µw 160
µw 160
µw 160
µw 160
µw 160
1
24
24
24
24
24
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
low
100
100
<92
<85
98
trace
60
98
53
70
trace
53
0
71
88
<79
<74
92
trace
30
86
29
47
trace
44
proline
proline
proline
proline
proline
glycine
Me-Gly
DMG
otherb Cu cat.
CuCl
DMSO
other solventsb
DMSO
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
10
11
12
13
EDA
DMEDA
TMEDA
DACH
a 1c:4a ) 1:1.5, c ) 0.2 M. b See Supporting Information. c See ref 13. Based on the H NMR with 1,3,5-trimethoxybenzene as internal standard.
d
Among all the tested reactions, the coupling product 5a
were not formed, if no ligands were applied as co-catalysts.
Although different nitrogen containing ligands have been
reported as ligands for Cu mediated amidation, proline was
identified as the best ligand for this transformation. To our
satisfaction, excellent regioselectivity was received with N-2
arylation as the dominant product. Both Cu(I) and Cu(II)
could effectively promote the reaction (entries 2-4) and
CuCl in DMSO were identified as the optimal condition.
Application of microwave initiation significantly shortened
the reaction time, giving N-2 phenyl 5a in excellent yield.
The substrate scope is listed in Table 3.
As shown in Table 3, benzotriazole 1a gave the N-1
arylation as the dominant product with only 8% N-2 product
isolated. The N-2 selectivity was increased while 4-phenyl
substituted 1b was applied, giving 60% N-2 isomer with
another 15% N-1 isomer and only trace amount of N-3
isomer. Dramatic difference was observed when 4,5-disub-
stituted triazoles were used, where, as expected, in all cases
only N-2 isomers were isolated with excellent yields. The
substrate scope of this transformation covered different
substituted groups on C-5 position and various aryl iodides.
Application of aryl bromides resulted in significant decrease
of reaction conversion and yield. Notably, the substrate 1j
gave 45% of desired N-2 arylation product 5j and 40% of
N-3-arylation product (structures were determined by X-ray
diffraction), which suggested the Cu-chelation between
phenol oxygen and triazole-N-3 position. The fact that the
steric disfavored N-3 arylation product was obtained strongly
supported the Cu(III) reductive elimination mechanism,
proposed previously by other groups based on their mecha-
nistic studies.
Table 3. Substrate Scope for Cu Catalyzed Triazole Amidationa
The strong dependence on ligands of this transformation
initiated our interest in evaluating trans-metalation as an
alternative path to further extend the substrate scope. Thus,
Scheme 2. Copper Catalyzed Transmetalation
a 1:4 ) 1:1.5, c ) 0.2 M. b Isolated yield. c N-1-5b 60% yield. d N-1-5c
11% yield. e Structure determined by X-ray crystallography. f N-3-5j 40%
yield. g Diamidation product 5v was formed in 10%.
Org. Lett., Vol. 10, No. 23, 2008
5391

the reactions between the triazoles and boronic acids were
investigated (Scheme 2).
To our pleasure,transmetalation indeed produced the
desired N-2 arylation product under milder conditions. With
triazole 1c, the N-2 isomer was the only product isolated
(1a and 1b gave less than 40% N-2 isomers). Screening of
reaction conditions gave THF as the best solvent (see other
conditions in the Supporting Information). The turnover of
the copper catalyst can also be effectively achieved with the
assistance of oxygen gas. We then focused on applying this
strategy for the synthesis of N-2 aryl substrates that were
difficult to be prepared from aryliodide amidation. The results
are summarized in Figure 1.
Figure 1. Products from coupling with arylboronic acid. Reaction
conditions: 1c/boronic acid ) 1:1.5, c ) 0.1 M, THF, 0.2 equiv
Cu(OAc)2, 2 equiv. pyridine, O2 1 atm, 50 °C, 24 h.
Figure 2. Photonic luminescence of selected N-aryl triazoles:
samples were measured in CH3OH, c ) 10 µM; λex ) 254 nm.
Finally, with a series of new N-2 aryl triazoles in hand,
the photonic properties were studied. To our excitement,
besides the strong UV absorptions, the new triazole deriva-
tives produce strong photonic luminescence and their emis-
sion pattern depends on the substituted groups.
with aryl iodide was observed and optimal condition allowed
the formation of N-2 aryl products in excellent yields.
Alternative approaches, including SNAr and boronic acid
transmetalations, had also been proved effective with excel-
lent regioselectivity. Moreover, the newly prepared N-2 aryl
products gave interesting photonic luminescent emission,
which re-emphasized the significance of the N-2-aryl-
triazoles and reported methodologies. Considering the ex-
tremely fast growth of the 1,2,3-triazole related research, we
believe that the reported synthesis and photonic investigation
will benefit the researchers in various fields.
The importance of fluorescence active molecules has been
well documented in various research fields.14 As shown in
the Figure 2A, the N-2-aryl group is crucial for photonic
emission (the emission of N-1 aryl analogues is significantly
weaker). More importantly, the 4,5-substituted triazoles
provided significant increase of the emission compared to
benzotriazole derivatives (Figure 2B). More detailed studies
regarding the photonic properties of these newly discovered
PL molecules are currently under investigation in our group
and will be reported in due course. This new group of
fluorophores just provided other examples for the importance
of reported regioselective post-triazole arylation for the
preparation of N-2 aryl triazoles.
Acknowledgment. We deeply appreciate Prof. Nick Wu
and Mr. Ming Li from Department of Mechanical &
Aerospace Engineering, WVU for the help with fluorescence
measurement and Prof. Quan Lin at National Key Laboratory
of Supramolecular Chemistry, Jilin University, China for
helpful discussions. We thank the C. Eugene Bennett
Department of Chemistry, the Eberly College of Arts and
Science, and the WV Nano Initiative at West Virginia
University for the financial support. X.S. thanks ACS-PRF
for financial support.
In conclusion, the first regioselective post triazole-arylation
was developed through substrate controlled N-arylation. The
importance of ligand effect in the copper mediated coupling
(12) (a) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem.
2007, 72, 6190. (b) Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.;
Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 9971. (c) Huffman, L. M.;
Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196.
(13) Me-Gly: N-methyl glycine; DMG: N,N-dimethyl glycine; EDA:
ethylenediamine;DMEDA: N,N′-dimethylethylenediamine;TMEDA: N,N,N′,N′-
tetramethylethylenediamine; DACH: trans-diaminocyclohexane.
(14) Selected examples: (a) Dunn, B.; Zink, J. I. J. Mater. Chem. 1991,
1, 903. (b) Calzaferri, G.; Pauchard, M.; Maas, H.; Huber, S.; Khatyr, A.;
Schaafsma, T. J. Mater. Chem. 2002, 12, 1. (c) de Silva, A. P.; Fox, D. B.;
Moody, T. S.; Weir, S. M. Pure Appl. Chem. 2001, 73, 503.
Supporting Information Available: Experimental details,
spectrographic data, and XRD information. This material is
available free of charge via the Internet at http://pubs.acs.org.
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