Noble Synthesis of Xanthene-based Dyes by Copper-catalyzed Azide-Alkyne Cycloaddition Reaction

Full text of DOI:10.1002/bkcs.10134

Note
DOI: 10.1002/bkcs.10134
BULLETIN OF THE
D. G. Shin et al.
KOREAN CHEMICAL SOCIETY
Noble Synthesis of Xanthene-based Dyes by Copper-catalyzed
Azide–Alkyne Cycloaddition Reaction#
*
*
Dong Geun Shin, Min Young Kim, Whikun Yi, and Jin Wook Han
Department of Chemistry, College of Natural Sciences, Institute of Nanoscience and Technology, Hanyang
University, Seoul 133-791, Korea. *E-mail: wkyi@hanyang.ac.kr; jwhan@hanyang.ac.kr
Received November 17, 2014, Accepted November 27, 2014, Published online February 10, 2015
Keywords: Xanthene dyes, Copper, Azide–alkyne cycloaddition reaction
Ever since the concept of “click” chemistry was introduced by
Sharpless in 2001, copper-catalyzed azide–alkyne cycloaddi-
tion reaction has been drawing much attention in organic syn-
thesis.1 This 1,3-dipolar cycloaddition reaction, which gives
1,2,3-triazoles (3) from azides (1) and alkynes (2) with high
selectivity and wide scope under mild reaction conditions,
has been widely utilized in combinatorial, pharmaceutical,
and materials chemistry and chemical biology (Scheme 1).2
Of those various applications, we are interested in the synthe-
sisofnewfluorescentdyesbasedonxanthenebyuseof“click”
chemistry for a new class of fluorophores as a part of our con-
tinuousefforts inthepreparation ofsmallorganic dyesfordye-
sensitized solar cell and sensor applications.3
(TBAF), azide–alkyne cycloaddition reaction was performed
with both aromatic and aliphatic azides in the presence of
10 mol% of copper(I) iodide in one pot. The “click” reaction
proceeded smoothlyatambienttemperature togivethedesired
1,2,3-triazoles 6 in good yield within 12 h. As expected, acid-
catalyzed deprotection of MOM groups on 6 with trifluoroa-
cetic acid provided a new type of xanthene-based dyes 7 hav-
ingatriazole group. Theformationofthefluorescent product 7
was easily detected by irradiation at 365 nm with a hand-held
UV lamp to exhibit yellow fluorescence.
From a preliminary evaluation of the absorbance and the
fluorescence properties of 7, it was revealed that wavelengths
of maximum absorption (λmaxAb) and maximum emission
(λmaxEm; excited at 520 nm) were similar to each other regard-
less of the R substituents in 7: λmaxAb/λmaxEm (nm/nm) = 520/
544 for 7a (R = Ph); 518/544 for 7b (R = CH2Ph); 516/540 for
7c (R = CH2CH2Ph); and 518/540 for 7d (R = CH2(CH)5Br).
Incidentally, compound 7a having an aromatic substituent
exhibited stronger absorption than the others having benzyl
or alkyl substituents, which was confirmed by comparison
of the extinction coefficients (see Table S1, Supporting Infor-
mation). Inaddition, itwasalsofoundthattheabsorptionprop-
erties of 7 were pH dependent, which can be attributed to the
presence of different protolytic forms depending on the pH.6
For example, stronger absorption was observed when pH was
increased from 6.0 to 10.5, as shown in Figure 2.
N
N
N
[Cu(I)]
R2
R1
R1–N3
R2
+
1
2
3
Scheme 1. Cu (I)-catalyzed azide–alkyne cycloaddition.
While the 1,3-dipolar cycloaddition has become a reliable
methodology as a linking reaction in various applications,4
there have also been attempts utilizing click chemistry to
assemble new fluorophores effectively.5 For example, the
cycloaddition of alkyne-functionalized xanthones or
xanthenes with azides5b and azidocoumarines with terminal
alkynes5d provided a variety of fluorescent molecules in a
combinatorial manner (Figure 1).
Insummary,wehavesynthesizedanewtypeofsmallorganic
dyesbasedonthexantheneskeletonsuccessfully,andevaluated
Here we report our preliminary results on the preparation
and spectroscopic analysis of new xanthene-type dyes having
a triazole ring that was introduced effectively by a copper-
catalyzed azide–alkyne cycloaddition reaction.
Our synthetic route for the new class of xanthene-based
dyes, shown in Scheme 2, is simple and straightforward, start-
ing from the methoxymethyl (MOM)-protected xanthone 4.
An ethynyl group was introduced to the xanthone by addition
reaction with lithium (trimethylsilyl)acetylide in high yield.
After the trimethylsilyl (TMS) group on the xanthenol 5
was removed by mixing with tetrabutylammonium fluoride
N
O
O
N
N
Ar
O
X
O
R
N
N
N
Xanthones
Coumarines
N
N
N
R
Y
O
Xanthenes
Figure 1. “Click” fluorophores.
# This paper is dedicated to Professor Kwan Kim on the occasion of
his honorable retirement.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1037–1039
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KOREAN CHEMICAL SOCIETY
TMS
O
HO
Li
TMS
1) TBAF
THF
2) R-N3/CuI
O
5
MOMO
OMOM
MOMO
O
4
OMOM
(92%)
R
N
R
N
N
N
N
N
HO
CF3CO2H/H2O
OMOM
O
O
O
HO
MOMO
7a: R=Ph (65%)
7b: R=CH2Ph (57%)
7c: R=CH2CH2Ph (62%)
7d: R=CH2(CH2)5Br (55%)
6a: R=Ph (67%)
6b: R=CH2Ph (76%)
6c: R=CH2CH2Ph (74%)
6d: R=CH2(CH2)5Br (70%)
Scheme 2. Synthetic route to xanthene-based dyes (7) by use of “click” chemistry.
their absorbance and fluorescence properties. By the use of
“click” chemistry, or Cu-catalyzed azide–alkyne cycloaddition
reaction, a series of xanthene dyes having 1,2,3-triazole moiety
have been prepared effectively and conveniently.
pH 10.5
pH 7.4
Emission
Experimental
pH 6.0
General Remarks. 1H and 13C NMR spectra were obtained
on a Varian (400 MHz for 1H and 100 MHz for 13C, respec-
tively, USA) spectrometer with Me4Si as internal reference.
Absorption spectra were recorded using an Optizen
2120UV spectrometer (Mecasys, Korea), and fluorescence
and excitation spectra were obtained using a FluoroMax spec-
trometer (Horiba, Japan). The absorbance values of com-
pounds 7 as a function of pH were obtained using the
sodium phosphate buffer (0.1 M, Na2HPO4 and NaH2PO4).
The azide compounds were prepared by known procedures.7
3,6-Bis(methoxymethoxy)-9H-xanthen-9-one (4). To a
solution of 3,6-dihydroxy-9H-xanthen-9-one8 (7.0 g, 30.7
mmol) in dry THF (tetrahydrofuran, 45 mL) was added
DIPEA (N,N0-diisopropylethylamine, 7 mL, 92.1 mmol) at
4 ꢀC. After the mixture was stirred for 30 min, chloromethyl
methyl ether (MOM-Cl, 16.0 mL, 92.1 mmol) was added to
the solution at that temperature. The solution was allowed
to warm to 22 ꢀC and stirred for 8 h. Aqueous HCl (5%, 35
mL) was added to the resulting mixture, and the crude product
was extracted from ethyl acetate. The organic layer was
washed with saturated NaCl and dried over anhydrous
MgSO4. After the solvent wasremoved invacuo, flash column
chromatography (hexane/dichloromethane/ethyl acetate =
350 400 450 500 550 600 650 700
Wavelength (nm)
Figure 2. Absorption spectra of 7a at various pH values and the fluo-
rescence emission spectrum at pH 7.4 (excited at 520 nm).
5 mL of dry THF was added ((trimethylsilyl)ethynyl)lithium
in 5 mL of dry THF at −78 ꢀC for 15 min, and then the mixture
was stirred at room temperature for 2 h. The reaction mixture
was extracted from dichloromethane and sodium bicarbonate.
The organic layer was dried over anhydrous MgSO4 to give 5
1
(0.29 g, 0.69 mmol, 92%) as a white solid. H NMR (400
MHz, CDCl3) δ 7.82 (d, J = 8.8 Hz, 2H), 6.90 (dd, J = 2.2,
8.4 Hz, 2H), 6.84 (d, J = 2.2 Hz, 2H), 5.19 (s, 4H), 3.48 (s,
6H), 0.21 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.3,
150.7, 129.6, 117.6, 112.6, 106.4, 103.5, 94.4, 91.4, 62.9,
56.0, 25.5; HRMS m/z calcd for C22H26NaO6Si [M + Na]+
437.1396, found 437.1942.
The representative procedure for compounds 6: 3,6-Bis
(methoxymethoxy)-9-(1-phenyl-1H-1,2,3-triazol-4-yl)-
9H-xanthen-9-ol (6a). A solution of 5 (0.86 g, 2.07 mmol)
and TBAF (3.1 mL, 3.1 mmol) was stirred in 15 mL of THF
for 1 h. To the resulting solution was added azidobenzene
(0.49 g, 2.08 mmol) and CuI (0.04 g, 0.20 mmol), and then
the mixture was stirred for 12 h. After the reaction, the crude
product was extracted from dichloromethane and brine. The
product was purified by column chromatography (hexane/
ethyl acetate = 2:1) to give 6a (0.64 g, 2.07 mmol, 67%).
1
1:1:0.2) afforded 4 (8.12 g, 84% yield) as a white solid. H
NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.8 Hz, 2H), 7.08
(d, J = 2.0 Hz, 2H), 7.01 (dd, J = 2.4, 8.8 Hz, 2H), 5.29 (s,
4H), 3.52 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 175.6,
162.1, 157.7, 128.1, 116.5, 113.9, 103.0, 94.3, 56.3; HRMS
m/z calcd for C17H16NaO6 [M + Na]+ 339.0845, found
339.0839.
3,6-Bis(methoxymethoxy)-9-((trimethylsilyl)ethynyl)-
9H-xanthen-9-ol (5). Toasolutionof 4(0.24 g, 0.75 mmol) in
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1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.69 (d, J = 7.6 Hz,
2H), 7.49 (m, 5H), 6.87 (d, J = 2.4 Hz, 2H), 6.82 (dd, J = 2.0,
8.8 Hz, 2H), 5.18 (s, 4H), 3.82 (s, 1H), 3.47 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 158.0, 155.8, 150.7, 137.0, 129.7, 128.7,
120.4, 119.1, 118.8, 112.7, 103.4, 94.3, 66.3, 56.1; HRMS m/z
calcd for C25H23N3NaO6 [M + Na]+ 484.1485, found
484.1492.
3,6-Bis(methoxymethoxy)-9-(1-benzyl-1H-1,2,3-triazol-4-
yl)-9H-xanthen-9-ol (6b). 1H NMR (400 MHz, CDCl3) δ 7.35
(m, 5H), 7.24(s, 1H), 7.22(m, 2H), 6.81(d, J = 2.8 Hz, 2H), 6.77
(dd, J = 2.4, 8.4 Hz, 2H), 5.44 (s, 2H), 5.15 (s, 4H), 3.81 (s, 1H),
3.45(s, 6H);13CNMR (100 MHz, CDCl3)δ157.7, 150.5, 134.3,
129.5, 128.9, 128.6, 127.9, 120.8, 118.7, 112.4, 103.2, 94.2,
66.1, 55.9, 54.0; HRMS m/z calcd for C26H25N3NaO6 [M +
Na]+ 498.1641, found 498.1635.
6-Hydroxy-9-(1-phenylethyl-1H-1,2,3-triazol-4-yl)-3H-
xanthen-3-one(7c). 1HNMR(400 MHz,DMSO-d6)δ8.51(s,
1H), 7.46 (d, J = 8.8 Hz, 2H), 7.26 (m, 5H), 6.80 (d, J = 8.8 Hz,
2H), 6.74 (s, 2H), 4.85 (t, J = 7.2 Hz, 2H), 3.31 (t, J = 7.2 Hz,
2H); 13C NMR (100 MHz, DMSO-d6) δ 157.0, 137.5, 131.3,
128.9, 128.5, 126.7, 114.5, 103.2, 51.0, 35.7; HRMS m/z calcd
for C23H17N3NaO3 [M + Na]+ 406.1168, found 406.1162.
6-Hydroxy-9-(1-(6-bromohexyl)-1H-1,2,3-triazol-4-yl)-
1
3H-xanthen-3-one (7d). H NMR (400 MHz, DMSO-d6) δ
8.85 (s, 1H), 7.80 (d, J = 9.6 Hz, 2H), 6.89 (d, J = 9.2 Hz,
2H), 6.82 (s, 2H), 4.57 (t, J = 8.8 Hz, 2H), 3.53 (t, J = 8.8
Hz, 2H), 1.86 (m, 4H), 1.42 (m, 4H); 13C NMR (100 MHz,
DMSO-d6) δ 157.4, 137.8, 131.8, 129.0, 121.2, 114.5,
103.1, 49.9, 35.0, 32.0, 29.3, 26.9, 25.0; HRMS m/z calcd
for C21H20BrN3NaO3 [M + Na]+ 464.0586, found 464.0581.
3,6-Bis(methoxymethoxy)-9-(1-phenylethyl-1H-1,2,3-tria-
zol-4-yl)-9H-xanthen-9-ol (6c). 1H NMR (400 MHz, CDCl3) δ
7.31 (d, J = 8.8 Hz, 2H), 7.23(m, 3H), 7.00(m, 2H), 6.90(s, 1H),
6.83 (d, J = 2.4 Hz, 2H), 6.79 (dd, J = 2.4, 8.8 Hz, 2H), 5.18 (s,
4H), 4.51 (t, J = 2.8 Hz, 2H), 3.78 (s, 1H), 3.48 (s, 6H), 3.16
(t, J = 2.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 157.8,
154.5, 150.5, 136.8, 129.6, 128.8, 128.7, 128.6, 126.9, 121.5,
118.8, 112,4, 103.2, 94.3, 77.3, 56.0, 36.6; HRMS m/z calcd
for C27H27N3NaO6 [M + Na]+ 512.1798, found 512.1794.
3,6-Bis(methoxymethoxy)-9-(1-(6-bromohexyl)-1H-
1,2,3-triazol-4-yl)-9H-xanthen-9-ol (6d). 1H NMR (400 MHz,
CDCl3) δ 7.40 (d, J = 8.6 Hz, 2H), 7.23 (s, 1H), 6.85 (d, J = 2.3
Hz, 2H), 6.80 (dd, J = 2.2, 8.6 Hz, 2H), 5.19 (s, 4H), 4.27 (t, J =
7.4 Hz, 2H), 3.83(brs,1H), 3.52(t, J = 6.6 Hz, 2H), 3.48 (s, 6H),
1.26 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 157.8, 150.5,
129.6, 120.7, 118.9, 112.5, 103.2, 94.3, 60.1, 55.8, 49.9, 44.5,
33.3, 29.7, 27.1, 20.8, 13.9; HRMS m/z calcd for
C25H30BrN3NaO6 [M + Na]+ 570.1216, found 570.1215.
The representative procedure for compounds 7: 6-
Hydroxy-9-(1-phenyl-1H-1,2,3-triazol-4-yl)-3H-xanthen-
3-one (7a). A solution of 6a (0.41 g, 0.89 mmol) in 5 mL of
CF3CO2H/H2O (9.5/0.5) was stirred at 0 ꢀC for 12 h. After
the reaction, the crude reaction mixture was extracted from
(i-PrOH/dichloromethane = 1:3) and brine. The product was
purified by column chromatography (MeOH/dichloro-
methane = 1:9) to give 7a (0.21 g, 0.65 mmol, 65%) as a yel-
low solid. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.07
(d, J = 8.0 Hz, 2H), 7.72 (m, 4H), 7.75 (t, J = 8.0 Hz, 1H), 6.74
(d, J = 8.8 Hz, 2H), 6.65 (s, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 156.2, 138.7, 136.1, 130.8, 129.7, 129.0,
120.5, 114.2, 103.2; HRMS m/z calcd for C21H13N3NaO3
[M + Na]+ 378.0855, found 378.0849.
Acknowledgments. This work was supported by National
Research Foundation of Korea Grant funded by the Basic Sci-
ence Research Program (2012R1A6A1029029) and by the
Korean Government (KRF 2011-0028850).
Supporting Information. Experimental details, characteri-
zation of the new compounds, and spectroscopic data are
available in the online version of this paper.
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157.8, 138.8, 136.2, 132.2, 129.6, 129.1, 128.8 115.2,
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Bull. Korean Chem. Soc. 2015, Vol. 36, 1037–1039
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