Click chemistry approach for the regioselective synthesis of iso-indoline-1,3-dione-linked 1,4 and 1,5 coumarinyl 1,2,3-triazoles and their photophysical properties

Article abstract of DOI:10.1080/00397911.2017.1283524

Copper-catalyzed reaction of N-propargyl isoindoline-1,3-dione and 4-azidomethyl coumarins / 4-azidomethyl-1-aza coumarins under click chemistry conditions afforded 1,4-disubstituted 1,2,3-triazoles, whereas ruthenium catalysis yielded isomeric 1,5-disubstituted 1,2,3-triazoles. The two regioisomers have been distinguished by NOE studies. UV absorption for a given pair of isomers exhibited similar trend, whereas fluorescence measurements showed considerable differences. Photo physical studies on the interaction of azides with copper and ruthenium have also been performed.

Full text of DOI:10.1080/00397911.2017.1283524

Click chemistry approach for the regioselective synthesis of iso-indoline-1,3-dione
linked 1,4 and 1,5 coumarinyl 1,2,3-triazoles and their photophysical properties
Ashish Anand1, Manohar V. Kulkarni1
1Department of Studies in Chemistry, Karnatak University, Dharwad, Karnataka, India
Address correspondence to M.V. Kulkarni, E-mail: manohar274@gmail.com
Abstract
Copper catalyzed reaction of N-propargyl isoindoline-1,3-dione and 4-azidomethyl
coumarins and 4-azidomethyl-1-aza coumarins under click chemistry conditions afforded
1,4-disubstituted 1,2,3-triazoles, whereas Ruthenium catalysis yielded isomeric 1,5-
disubstituted 1,2,3-triazoles. The two isomers have been distinguished by nOe studies.
UV Absorption for a given pair of isomers exhibited similar trend, whereas fluorescence
showed considerable differences. Photo physical studies on the interaction of azides with
Copper and Ruthenium have also been carried out.
GRAPHICAL ABSTRACT
KEYWORDS: Click reaction, 1,2,3 triazoles, 2H-chromene-2-one, isoindoline-1,3-
dione, photophysical property
1

INTRODUCTION
Classical 1, 3-dipolar cycloadditions were discovered by Huisgen and co-workers [1].
Absence of selectivity in the reaction of azides and unsymmetrical alkynes was reflected
in the formation of regioisomeric mixture of 1,4 and 1,5-substituted 1,2,3-triazoles which
required elevated temperatures and also suffered low reaction rates [2,3]. An excellent
modification, effectively and independently developed by Sharpless [4] and Meldal [5]
led to renaissance of Huisgen cycloaddition, manifested in the form of Click chemistry.
Copper catalyzed reaction of azides and alkynes (CuAAc) has resulted in selective
formation of 1,4-disubstituted 1,2,3 triazoles at room temperature with enhanced rates
even under aqueous conditions [6]. Till date, CuAAc reaction is considered as the most
robust and versatile example of click chemistry which has found application in the fields
of polymers and biochemistry [7-18], designing of fluorescent biochemical markers [19],
synthesis of macrocycles [20], and in chemotherapy of tuberculosis [21]. Catalysis in
these reactions was extended to analogous metal salts of Ag(I), Pd(0/II), Pt(II), Au(I/III)
and Hg(II), which were found to be less effective [22]. Subsequently, Fokin et.al found
that Ruthenium complexes effectively catalyze the selective formation of 1,5
disubstituted 1,2,3-triazoles [23]. Among the various Ruthenium complexes employed in
this reaction, Pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride
proved to be most effective [24]. This reaction has been applied for the synthesis of 1,5-
disubstituted-1,2,3-triazole benzenesulfonamides as glycoconjugate carbonic anhydrase
inhibitors with good selectivity over cancer cell lines [25] and in designing polymer
anchored catalyst in azide alkyne cycloaddition [26]. Podophyllotoxin triazole conjugates
2

have been reported to exhibit antitubulin activity [27]. Ruthenium catalysis has also been
employed in the synthesis of 4-trifluoromethyl-1,4,5-trisubstituted-1,2,3-triazoles [28]
and in the synthesis of trifunctional thiourea catalysts [29].
Mechanistic studies supported by DFT calculations [30,31], has revealed that in Azide-
Alkyne cycloaddition with terminal alkynes, copper catalysis favors N1-C2 and N3-C1
bond formation [32] whereas Ruthenium complexes favor N1-C1 and N3-C2 bond
formation via a metallocycle intermediate [24]. (Fig.1)
N-alkyl iso indoline 1,3-dione linked1,2,3-triazoles have been useful as anti-
inflammatory agents[33], and have been synthesized under sonochemical conditions
[34]. Bis-coumarinyl 1,2,3-triazoles have shown anti-tubercular activity with low MIC
values[35] (Fig.2).
It is pertinent to mention the applications of coumarins and isoindoline-1,3-dione as
switchable fluorescent molecular probes for intracellular tracking [36], thiol detection
[37], and fluorescent liver receptor antagonists [38]. Water-soluble coumarin-triazole
conjugates have been employed as fluorescent probes for hydrogen peroxide [39].
Fluorescent chemosensors for DNA, RNA, and proteins have been derived from
coumarins [40]. Lockable, fluorescent molecular switch [41] is based on
coumarin/phenanthridine-fused heterocyclic systems.
In view of the cleavage of C-O and C-N bonds, complex formation by Ruthenium salts
3

[42,43] and very few reports on the synthesis of both the regioisomers [44], it was of a
considerable interest to make an appropriate choice of azide and alkyne which under
optimized conditions would lead to both 1,4 and 1,5 di-substituted triazoles.
In the present paper, we describe our results on the reactions of 4-azidomethyl coumarins
and their 1-aza analogues with N-propargyl isoindoline-1,3-dione (N-propargyl
phthalimide) using both Copper and Ruthenium under click chemistry conditions.
RESULTS AND DISCUSSION
Acetylenic dipolarophile 2 was synthesized (Scheme-1) by the reaction of potassium
phthalimide 1 with 3-bromoprop-1-yne employing potassium carbonate in acetone. Ethyl-
4-bromoacetoacetate was prepared by bromination of ethylacetoacetate at 0-5 °C [45],
which was further treated with substituted phenols 3(a-l), in presence of neat sulphuric
acid to obtain 4-(bromomethyl)-2H-chromen-2-ones 4(a-l), via Pechmann cyclization
[46]. Coumarinyl azides 5(a-l) were prepared by treating 4 with sodium azide in aqueous
acetone at room temperature and the compounds showed stability even above 100 °C.
Substituted 4-(bromomethyl)quinolin-2(1H)-ones were synthesized from substituted
acetoacetanilides 6(a-d). ω-bromoacetoacetanilides 7(a-d) obtained by bromination, were
converted into substituted
4-(bromomethyl)quinolin-2(1H)-ones 8(a-d) by heating
90 °C [47]. Azides 9(a-d) were obtained by
with concentrated sulphuric acid at
the reaction of 8(a-d) with sodium azide in aqueous DMF at room temperature.
4

The so obtained acetylenic dipolarophile and dipolar azides were made to undergo
Azide-Alkyne cycloaddition in presence of copper ascorbate in THF/water, (1:1) under
reflux for 8h to obtain exclusively 1,4 substituted 1,2,3-triazole hybrids 10(a-p)
(Scheme-2) in excellent yields and purity.
Cp*RuCl(PPh3)2 was employed as catalyst in the reaction of 6-methyl 4-
azidomethyl coumarin 5 (X=O, R=6-CH3) with N-propargyl isoindoline-1,3-dione 2.
Initial optimization of reaction condition in DCM at room temperature resulted in very
low yields of the product (Entry 1, Table 1). Attempted reaction in THF at 65 °C
resulted in better yields (Entry 2). In polar solvent like methanol, under reflux conditions
did not give any product even when the catalyst loading was doubled (Entry 3). Catalysis
under polar aprotic solvent like THF and dry dioxane at 65 °C showed drastic increase in
yields and lesser by-products (Entry 4). With a view to enhance the yield, DMF was
employed at higher temperatures, which resulted in reduced yields (Entry 5). Hence all
the Ruthenium catalyzed reactions were carried out by employing dry dioxane at 65 °C.
Under these conditions the 1,5 regioisomeric compounds were obtained 11(a-j) in 60-
80% yield (Scheme-3).
Formation of regioisomeric 1,2,3-triazoles 10 and 11 is supported by spectroscopic
data. In the case of 1,4 substituted triazole, compound 10a, (X=O, R=6-CH3) IR spectrum
showed a band at 1770 cm-1 due to the CO stretching of cyclic imide moiety and a band
at 1719 cm-1 due to lactone carbonyl stretching. Formation of triazole was further
confirmed by the 1H-NMR wherein the C5-H of the triazole ring appeared as a singlet at
5

8.23 ppm and C4-CH2 of coumarin resonated as a singlet at 5.86 ppm. C3-H of coumarin
appeared as a singlet at 5.74 ppm. Methylene protons linked to nitrogen of isoindoline-
1,3-dione resonated as a singlet at 4.80 ppm. Further the C5-H of coumarin was observed
as a singlet at 7.58 ppm whereas C7 and C8 of coumarin moiety resonated as doublets at
7.43 and 7.28 ppm respectively with a Jortho= 8.6 Hz. Isoindoline-1,3-dione protons
appeared as a multiplet at 7.89-7.81 ppm. C6-CH3 of coumarin resonated as a singlet at
2.31 ppm. In 13C-NMR, the C6-CH3 carbon resonated at 20.8 ppm, methylene carbon
linked to nitrogen of isoindoline-1,3-dione appeared at 33.3 ppm whereas the methylene
carbon linked to C4 of coumarin appeared at 49.5 ppm. C3 carbon of coumarin appeared
at 114.1 ppm whereas carbonyl carbon of the cyclic imide and lactone resonated at 167.9
and 160.1 ppm respectively. Other aromatic carbons appeared in the range 117-150.7
ppm. In EI-MS, molecular ion peak was observed at m/z 400 which confirmed the
formation of product.
Compound 11a (X=O, R=6-CH3) IR spectrum showed a band at 1770 cm-1 due to
the CO stretching of cyclic imide moiety and a band at 1724 cm-1 due to lactone carbonyl
stretching. Formation of triazole was further confirmed by the 1H-NMR wherein the C5-H
of the triazole ring appears as a singlet at 7.94 ppm and C4-CH2 of coumarin resonated as
a singlet at
6.02 ppm. The C3-H of coumarin appeared as a singlet at 5.01 ppm.
Methylene protons linked to nitrogen of isoindoline-1,3-dione resonated as a singlet at
4.98 ppm. Further the C5-H of coumarin appeared as a singlet at 7.62 ppm whereas C7
and C8 of coumarin moiety resonated as doublets at 7.48 and 7.20 ppm respectively with
a Jortho= 8.4 Hz. Isoindoline-1,3-dione protons appeared as a multiplet at 7.64-7.77 ppm.
6

C6-CH3 of coumarin resonated as a singlet at 2.42 ppm. In 13C-NMR, the C6-CH3 carbon
resonated at 20.4 ppm, methylene carbon linked to nitrogen of isoindoline-1,3-dione
appeared at 29.8 ppm whereas the methylene carbon linked to C4 of coumarin appeared at
47.4 ppm. C3 carbon of coumarin appeared at 111.3 ppm. Carbonyl carbon of the cyclic
imide and lactone resonated at 167 and 158.8 ppm respectively. Other aromatic carbons
appeared in the range 116.3-150.9 ppm. In EI-MS, molecular ion peak was observed at
m/z 400 which confirmed the formation of product.
nOe STUDIES
Spatial orientation of the two regioisomers and the appropriate assignment the two
methylene protons was studied using nOe. In 1,4 disubstituted isomer 10a (R=6-CH3)
(Structure-I), irradiation of assigned –NCH2- protons at 4.8 ppm showed increase in the
intensity of H5′, whereas, irradiation of assigned C4-CH2- at 5.8 ppm exhibited increase in
the intensity of H3, H5 and H5′. Similarly, in the case of 1,5 disubstituted isomer 11b (R =
6-CH3) (Structure-II), irradiation of assigned –NCH2- protons at 4.9 ppm showed
increase in the intensity of H4′ and C4-CH2- whereas, irradiation of assigned C4-CH2- at
6.0 ppm exhibited increase in the intensity of H3, H5 and –NCH2- protons. In light of the
above nOe data, the assignment and the proposed structure has been confirmed, (Fig. 3)
which is in agreement with recent literature reports [44].
PHOTOPHYSICAL STUDIES
UV absorption spectra (Table 2) of 1,4-isomers 10a-10j in N,N-dimethylformamide
(DMF) are characterized by the presence of an intense absorption maxima in the range of
7

290–336 nm except in the case of 5,6-benzo substitution 10e which showed
bathochromic shift with λmax at 350 nm. The emission spectra showed considerable
differences, when compared with the 1,5-isomers 11a-11j.
UV absorption spectra of the pair of isomers 10a(R = 6-CH3) and 11a(R = 6-CH3)
showed similar λmax at 320 nm with nearly same absorbance (Fig.4), whereas in the
emission spectra, the 1,5-isomer 11a exhibited a four-fold enhancement in the intensity
when compared with the corresponding 1,4-isomer 10a (Fig.5). Similar higher intensity
was observed with pairs of 10b-11b, 10c-11c and 10d-11d (Table 2). In the case of 7-
OCH3 and 5,6-benzo groups, reverse trend was observed which is clear from the intensity
values of 10e-11e and 10f-11f isomeric pairs. Similar lowering in intensity was also
observed in 1,5-isomers when X=NH, irrespective of the substituents, as can be seen in
pairs of 10h-11h, 10i-11i and 10j-11j.
Variation of fluorescence intensity is probably due to steric effect of the two bulky
phthalimido and coumarin/1-azacoumarin moieties which favors a non-planar
arrangement for the 1,5-isomer. Similar steric effects have been observed in bi-phenyls
[48] and other aromatic compounds [49].
Comparative study on the UV- Fluorescence measurement on Cu(I) and Ru(II) catalyzed
systems have shown significant differences in their photophysical behavior.
UV-fluorescence behavior in presence of Cu(I) and Ru(II) for the same set of azide and
8

alkyne was measured. Initially, UV spectra of the mixture of 10m (azide) and 2 (alkyne)
were separately recorded in two solvents viz. tetrahydrofuran and 1,4-dioxane which
showed absorbance at λabs = 356 nm and 359 nm respectively. Choice of solvents used for
CuAAC and RuAAC were identical to those which had been used for the actual reaction.
Cu (I) CATALYZED SYSTEM
The solutions of 10m (1 x 10-4 mol/L) and 2 (1 x 10-4 mol/L) were prepared in
tetrahydrofuran:water (1:1) mixture and the fluorescence was observed at λemm = 442 nm.
Fluorescence spectrum was recorded serially after the addition of 1 µM – 9 µM solution
of Cu(I), which was in turn was obtained by mixing copper sulphate pentahydrate and
sodium ascorbate followed by the addition to the mixture of 10m and 2 in
tetrahydrofuran:water (1:1) mixture. From the fluorescence plot we observed that initially
after the addition of 1 µM solution of Cu(I), a fluorescence quenching was observed.
Similar trend was observed from the addition of Cu(I) from 1-4 µM. Further increase in
the concentration of Cu(I) from 5 µM -9 µM, an increase in the intensity has been
observed. [Fig. 6] Fluorescence quenching by Cu(I) on Dansyl azide have been employed
for ligand acceleration studies and bio-conjugation applications [50]
Ru (II) CATALYZED SYSTEM
Solutions of 10m (1 x 10-4 mol/L) and 2 (1 x 10-4 mol/L) were prepared in 1,4 dioxane
and the fluorescence was observed at λemm = 432 nm.
9

Fluorescence was recorded serially after the addition of 1 µM -8 µM solution of Ru(II) to
the mixture of 10m and 2 in 1,4 dioxane. From the fluorescence plot we observed that,
after the addition of 1 µM solution of Ru(II), there is a fluorescence quenching. [Fig.7]
Similar trend was observed from the addition of Ru(II) from 2 µM – 8 µM and λemm was
shifted to 433 nm.
Our studies have shown that increasing concentrations of Cp*RuCl(PPh3)2 resulted in
quenching of azide fluorescence whereas with Cu(I) there was an initial decrease,
followed by an increase in fluorescence intensity. This deviation in fluorescence
quenching may be attributed to in situ formation of bis (copper intermediates) forming a
dinuclear copper complex. [51, 52]
EXPERIMENTAL
Typical procedure for the synthesis of 2-(prop-2-ynyl)isoindoline-1,3-dione (2).
The synthesis is as per the literature report [53].
Typical procedure for the synthesis of 2-((1-((6-methyl-2-oxo-2h-chromen-4-
yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)isoindoline-1,3-dione (10a).
.
To a solution of compound 9 (1.0 mmol) in THF ⁄ H2O, 1: 1(v ⁄ v), CuSO4 5H2O (0.15
mmol), sodium carbonate (0.15 mmol), ascorbic acid (0.3 mmol) were added. The
mixture was stirred at room temperature for 15 min. then, 6-methyl-4-azidomethyl
coumarin 5a (1.0 mmol) was added, and the resulting reaction mixture was refluxed on
water bath until the starting material was consumed as judged by TLC. Then, the reaction
10

mixture was cooled, separated solid was filtered, washed with water and recrystallised
from DMF. White; Yield 82%; m.p: 198-200 °C; 1H-NMR (400 MHz, DMSO-d6, TMS)
(ppm): 8.23(s, 1H, Tri-H), 7.80-7.27(m, 7H, Ar-H), 5.86(s, 2H, -C4-CH2), 5.74(s, 1H, C3-
H), 4.80(s, 2H, -N-CH2), 2.31(s, 3H, -CH3); 13C-NMR (100 MHz, DMSO-d6) (ppm):
20.8, 33.3, 49.5, 114.1, 117.0, 117.1, 123.7, 125.2, 131.9, 133.9, 134.1, 135.1, 143.2,
149.9, 150.4, 150.7, 160.1, 167.9; EI-MS m/z 400(M·+, 13%); Anal. Calcd. for
C22H16N4O4 (%), Calcd: C, 66.00; H, 4.03; N, 13.99; found: C, 65.95; H, 4.00; N, 13.95
Typical procedure for the synthesis of 2-((3-((6-methyl-2-oxo-2H-chromen-4-
yl)methyl)-3H-1,2,3-triazol-4-yl)methyl)isoindoline-1,3-dione (11a).
To a solution of alkyne 9 (1.0 mM) in dry dioxane (5 mL), 18 mg (22 µM) of
Cp*RuCl(PPh3)2 was added and the R.B flask was purged with nitrogen gas. The
reaction mixture was warmed to 50 °C and stirred for 30 minutes. Azide 5 (1.0 mM) was
dissolved in 5 mL of dry dioxane and added to the reaction mixture which was stirred at
60 °C for 18 hrs. Progress of the reaction was checked using T.L.C. The separated silky
maroon-purple precipitate was filtered, washed with cold dioxane and dried. Dark brown
solid; Yield 75 %; m.p: 256-258 °C; 1H-NMR (400 MHz, DMSO-d6, TMS) (ppm):
7.94(s, 1H, Tri-H), 7.77-7.19(m, 7H, Ar-H), 6.02(s, 2H, -C4-CH2), 5.01(s, 1H, C3-H),
4.98(s, 2H, -N-CH2), 2.42(s, 3H, -CH3); 13C-NMR (100 MHz, DMSO-d6) (ppm): 20.4,
29.9, 47.4, 111.3, 116.3, 116.3, 122.9, 124.4, 130.9, 133.4, 133.6, 133.7, 134.5, 134.6,
150.4, 150.9, 158.8, 167.0; EI-MS m/z 400(M·+,100%); Anal. Calcd. for C22H16N4O4 (%),
Calcd: C, 66.00; H, 4.03; N, 13.99; found: C, 65.98; H, 4.00; N, 13.95
11

CONCLUSION
Regioselectivity associated with CuAAC and RuAAC under Click Chemistry conditions
has been confirmed using coumarinyl azides and 2-(prop-2-ynyl) isoindoline-1, 3-dione.
UV spectra for a pair of isomers were similar while Fluorescence spectra showed a
fourfold increase in intensity for the 1,5 isomer. Significant difference in fluorescence
quenching of azide was observed under CuAAC and RuAAC reaction conditions. This
observation may be useful for the study of HOMO-LUMO interactions of metal centers
with azides.
ACKNOWLEDGEMENTS
One of the authors, Ashish Anand is grateful to UGC-MRP, F.No. 41-333/2012(SR),
New Delhi, for the financial assistance. The authors thank NMR Research Center, Indian
Institute of Science (IISc), Bangalore and University Sophisticated Instrumentation
Center (USIC), Dharwad for spectral analysis. Authors profusely thank Prof.
J.S.Kadevarmath and Mrs. Nirupama J.M, Dept. of Physics, Karnatak University,
Dharwad for photophysical measurements. Our hearty thanks to Prof. Chung Ming Sun,
NCTU Taiwan, Dr. Chidambar Kulkarni, Eindhoven University of Technology,
Netherlands for their support.
12

REFERENCES
1.
(a) R. Huisgen, In 1,3-Dipolar Cycloaddition Chemistry (ed. A. Padwa), Wiley,
New York, 1984, 1-176. (b) A. Padwa, In Comprehensive Organic Synthesis, (eds. B. M.
Trost and I. Fleming), 1991, 4, 1069-1109.
2.
3.
4.
Huisgen R. Angew. Chem. Int. Ed. 1963, 2, 633.
Huisgen R. Angew. Chem. Int. Ed. 1963, 2, 565.
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2002, 41, 2596.
5.
6.
Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
(a) Wang,Q.; Chittaboina, S.; Barnhill, H. N. Lett. Org. Chem. 2005, 2, 293(b)
Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 12491262; (c) Wu, P.; Fokin,
V. V. Aldrichimica Acta 2007, 40, 7.(d) Hein, C. D.; Liu, X. M.; Wang, D. Pharm. Res.
2008, 25, 2216.
7.
8.
Lutz, J.F. Angew. Chem. Int. Ed. 2007, 46, 1018.
Wu, P.; Feldman, A.K.; Nugent, A.K.; Hawker, C.J.; Scheel, A.; Voit, B.; Pyun,
J.; Frechet, J.M.J.; Sharpless, K.B.; Fokin, V.V. Angew. Chem. Int. Ed. 2004, 43, 3928.
9.
Hawker, C.J.; Wooley, K.L. Science 2005, 309, 1200.
10.
Malkoch, M.; Thibault, R.J.; Drockenmuller, E.; Messerschmidt, M.; Voit, B.;
Russell, T.P.; Hawker, C.J. J. Am. Chem. Soc. 2005, 127, 14942.
11. Sumerlin, B.S.; Tsarevsky, N.V.; Louche, G.; Lee, R.Y.; Matyjaszewski, K.
Macromolecules 2005, 38, 7540.
12.
13.
Bock, V.D.; Hiemstra, H.; van Maarseveen, J.H. Eur. J. Org. Chem. 2006, 1, 51.
Vogt, A.P.; Sumerlin, B.S. Macromolecules 2006, 39, 5286.
13

14.
15.
Binder, W.H.; Sachsenhofer, R. Macromol. Rapid Commun. 2007, 28, 15.
Chen, G.; Tao, L.; Mantovani, G.; Ladmiral, V.; Burt, D.P.; Macpherson, J.V.;
Haddleton, D.M. Soft Matter 2007, 3, 732.
16.
17.
18.
381.
19.
20.
Fournier, D.; Hoogenboom, R.; Schubert, U.S. Chem.Soc. Rev. 2007, 8, 1369.
Gondi, S.R.; Vogt, A.P.; Sumerlin, B.S. Macromolecules 2007, 40, 474.
Hawker, C.J.; Fokin, V.V.; Finn, M.G.; Sharpless, K.B.; Austr. J. Chem. 2007, 60,
Horisawa, K. Front Physiol. 2014, 457, 1.
a) Pasini, D. Molecules 2013, 18, 9512. b) Zhu, Y.Y.; Wang, G.T.; Li, Z.T. Org.
Biomol. Chem. 2009, 7, 3243.
21.
a) Labadie, G. R.; de la Iglesia, A.; Morbidon, H. R. Molec. Divers. 2011, 4,
1017. b) Kumar, K. K.; Seenivasan, P. S.; Kumar, V.; Das, T. M. Carbohydr. Res. 2011,
14, 2084.
22.
23.
Hein, J.E.; Fokin, V.V. Chem. Soc. Rev. 2010, 39, 1302.
(a) Zhang, L.; Chen, X.; Xue, P.; Sun, H.; Williams, I. D.; Sharpless, K. B.;
Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998. (b) Rasmussen, L. K.; Boren,
B. C.; Fokin, V. V. Org. Lett. 2007, 9, 5337.
24.
G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923.
25. A. J. Salmon, M. L. Williams, A. Maresca, C. T. Supuran and S. A. Poulsen,
Bioorg. Med. Chem. Lett. 2011, 21, 6058.
26. Molla, R. A.; Roy, A. S.; Ghosh, K.; Salam, N.; Iqubal, Md. A.; Tuhina, K.;
Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Xhao, H.; Lin, Z.; Jia,
Islam, Sk M. J. Organomet. Chem. 2015, 776, 170.
14

27.
Imperio, D.; Pirali, T.; Galli, U.; Pagliai, F.; Cafici, L.; Canonico, P. L.; Sorba,
G.; Genazzani, A. A.; Tron, G. C. Bioorg. Med. Chem. 2007, 15, 6748.
28.
29.
30.
31.
Zhang, C.T.; Zhang, X.; Qing, F. L. Tetrahedron Lett. 2008, 49, 3927.
Takasu, K.; Azuma, T.; Takemoto, Y. Tetrahedron Lett. 2010, 51, 2737.
Boz, E.; Nurcan, S. T. J. Organomet. Chem. 2013, 724, 167.
Wang, T. H.; Wu, F.L.; Chiang, G. R.; He, S.T.; Lo, Y.H. J. Organomet. Chem.
2014, 774, 57.
32.
33.
Palaniraja, J.; Roopan, S. M. Chem. Sci. Rev. Lett. 2014, 10, 93.
de Assis, S. P. O.; da Silva, M. T.; de Oliveira, R. N.; de M. Lima, V. L. Scientific
World J. 2012, 925925, 1.
34.
da Silva, M.T.; de Oliveira, R. N.; Valenca, W. O.; Barbosa, F. C. G.; da Silva,
M. G.; Camara C. A. J. Braz. Chem. Soc. 2012, 10, 1839.
35.
Naik, R.J.; Kulkarni, M.V.; Pai, K.S.R. Nayak, P.G. Chem. Biol. Drug Des. 2012,
80, 516.
36.
Yan, S. F.; Belov, V. N.; Bossi, M. L.; Hell, S. W. Eur. J. Org. Chem. 2008, 15,
2503.
37.
Liu, X.; Gao, L.; Yang, L.; Zou, L.; Chen, W.; Song, X. RSC Adv. 2015, 5, 18177.
Kishida, K.; Aoyama, A.; Hashimoto, Y.; Miyachi, H. Chem. Pharm. Bull. 2010,
38.
11, 1525.
39.
Du, Y. L.; Ni, Y. N.; Li, M.; Wang, B. Tetrahedron Lett. 2010, 8, 1152.
40.
Zhou, Y.; Liu, K.; Li, J.Y.; Fang, Y.; Zhao, T.C.; Yao, C. Org. Lett. 2011, 6,
1290.
15

41.
Nichols, J. M.; Bishop, L. M.; Bergman, R.G.; Ellman, J. A. J. Am. Chem. Soc.
2010, 132, 12554.
42.
43.
44.
Mohana, K. N.; Prasad, N. J. Chil. Chem. Soc. 2008, 4, 1697.
Su, S.H.; Yang, D.Y. ARKIVOC 2012, vi, 253.
Chouaib, K.; Romdhane, A.; Delemasure, S.; Dutartre, P.; Elie, N.; Touboul, D.;
Jannet, H. B. Arab. J. Chem. 2016, doi:10.1016/j.arabjc.2015.12.013.
45.
Burger, A.; Ullyot, G.E. J. Org. Chem. 1947, 12, 342.
46.
Kulkarni, M.V.; Patil, V.D. Arch. Pharm. 1981, 314, 708.
Anand, A.; Yenagi, J.; Tonannavar, J.; Kulkarni, M.V. Green Chem. 2016, 18,
47.
2201.
48.
Nijegorodov, N.; Luhanga, P.V.C.; Nkoma, J.S.; Winkoun, D.P. Spectrochim.
Acta Mol. Biomol. Spectrosc. 2006, 64, 1.
49. Nijegorodov, N.; Zvolinsky, V.; Luhanga, P.V.C. J. Photochem. and Photobio. A
2008, 196, 219.
50.
Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn, M. G. J. Am. Chem. Soc.
2004, 126, 9152.
51.
Makarem, A.; Berg, R.; Rominger, F.; Straub, B. F. Angew. Chem. Int. Ed. 2015,
54, 7431.
52.
Liqun, J.; Tolentino, D. R.; Melaimi, M.; Bertrand, G. Sci. Adv. 2015,
1:e1500304.
53.
Okunrobo, L. O.; Usifoh, C. O.; Scriba, G.K.E. Acta Poloniae Pharmaceutica.
Drug Research 2006, 63, 25.
16

Table 1: Optimization of conditions for the synthesis of Cp*RuCl(PPh3)2 catalysed
1,5-disubstituted 1,2,3-triazoles.
Entry Catalyst (in
moles)
Solvent
Temperature
Time (hrs) Yield (%)
(°C)
25
1.
2.
3.
4.
1.1 x 10-5
1.1 x 10-5
2.2 x 10-5
2.2 x 10-5
DCM
THF
10
12
10
12
5
65
20a
Trace
75a
MeOH
Dry
60
60
Dioxane
DMF
5.
2.2 x 10-5
110
10
10a
a= isolated yields
17

Table 2: UV-visible and fluorescence spectral data of compounds 10(a-j) and 11(a-j)
Compound
λabs (nm)
ε
λem
Fluorescen Stokes
(nm)
ce intensity shift (υabs -
(a.u)
21
υem)
10a (R= 6-CH3, X=O)
10b (R= 7, 8-CH3,
X=O)
320
290
5,490
422
412
7,554
10,211
13,570
05
10c (R= 7-CH3, X=O)
312
8,090
13,430
8,930
398
410
427
11
6,926
9,792
5,152
10d (R= 5,7-CH3, X=O) 290
05
10e (R= 5,6 Benzo,
X=O)
350
1023
10f (R= 7-OCH3, X=O) 322
16,290
12,560
6,300
7,090
5,900
4,680
14,010
396
440
425
391
399
452
453
365
35
5,803
10,059
7,721
4,545
4,699
9,127
12,171
10g (R= 7-Cl, X=O)
10h (R= 6-Cl, X=NH)
10i (R= H, X=NH)
305
343
332
151
158
129
77
10j (R= 8-CH3, X=NH) 336
11a (R= 6-CH3, X=O)
11b (R= 7, 8-CH3,
X=O)
320
292
76
11c (R= 7-CH3, X=O)
315
7,370
448
449
458
170
54
9,425
11,742
6,575
11d (R= 5,7-CH3, X=O) 294
11,360
11,940
11e (R= 5,6 Benzo,
X=O)
352
600
18

11f (R= 7-OCH3, X=O) 322
15,030
9,900
5,270
5,160
4,270
399
435
402
392
400
115
60
49
57
35
5,993
9,798
4,364
4,430
4,762
11g (R= 7-Cl, X=O)
11h (R= 6-Cl, X=NH)
11i (R= H, X=NH)
305
342
334
11j (R= 8-CH3, X=NH) 336
19

Scheme 1. Synthesis of 4-azidomethyl coumarin 5 and their 1-aza analogues 9.
20

Scheme 2. Synthesis of Copper(I) catalyzed 1,2,3-triazoles.
21

Scheme 3. Synthesis of Cp*RuCl(PPh3)2 catalyzed 1,2,3-triazoles.
22

Figure1. Preferred C-N bond formations in CuAAc and RuAAC catalysed reactions.
23

Figure 2. Structurally related 1,2,3-triazoles
24

Figure 3. NOE effects for regioisomers 10a and 11a
25

Figure 4. UV overlay spectrum of the isomers 10a and 11a; (R=6-CH3, X=O)
26

Figure 5. Fluorescence overlay spectrum of the isomers 10a and 11a; (R=6-CH3, X=O)
27

Figure 6. Fluorescence quenching on addition of Cu(I) from 1µM -9µM
28

Figure 7. Fluorescence quenching on addition of Ru(II) from 1µM -8µM.
29