Regioselective Synthesis of C2-Symmetric triazolophanes via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction

Article abstract of DOI:10.1080/00397911.2011.555590

An efficient approach for the synthesis of a new class of triazolophanes by 1,3-dipolar cycloaddition reaction of highly reactive organic azides with dialkynes using Cu(I)-catalyzed azide-alkyne cycloaddition methodology (click chemistry) has been developed. All the compounds were characterized by spectral and elemental analyses.

Full text of DOI:10.1080/00397911.2011.555590

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Regioselective Synthesis of C 2-
Symmetric Triazolophanes via Copper(I)-
Catalyzed Azide-Alkyne Cycloaddition
(CuAAC) Reaction
R. Rajesh a & R. Raghunathan a
a Department of Organic Chemistry, University of Madras, Guindy
Campus, Chennai, India
Accepted author version posted online: 15 Dec 2011. Version of
record first published: 09 Apr 2012
To cite this article: R. Rajesh & R. Raghunathan (2012): Regioselective Synthesis of C 2-Symmetric
Triazolophanes via Copper(I)-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:15, 2256-2266
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Synthetic Communications1, 42: 2256–2266, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.555590
REGIOSELECTIVE SYNTHESIS OF C2-SYMMETRIC
TRIAZOLOPHANES VIA COPPER(I)-CATALYZED
AZIDE-ALKYNE CYCLOADDITION (CuAAC) REACTION
R. Rajesh and R. Raghunathan
Department of Organic Chemistry, University of Madras,
Guindy Campus, Chennai, India
GRAPHICAL ABSTRACT
Abstract An efficient approach for the synthesis of a new class of triazolophanes by
1,3-dipolar cycloaddition reaction of highly reactive organic azides with dialkynes using
Cu(I)-catalyzed azide–alkyne cycloaddition methodology (‘‘click chemistry’’) has been
developed. All the compounds were characterized by spectral and elemental analyses.
Keywords Click reaction; CuAAC; 1,3-dipolar cycloaddition; triazole; triazolophanes
INTRODUCTION
In recent years, the chemistry of heterocycles has gained new significance
because of heterocycles’ varied applications in chemical, biological, medicinal, and
materials science. Triazoles, being aromatic heterocycles present in various com-
pounds, exhibit interesting biological activities such as anti-HIV,[1] antibacterial,[2]
and antiallergic[3] activities. These compounds are variously used as chemotherapeu-
tic agents, agrochemicals, corrosion inhibitors, optical brighteners, photostabilizers,
and metal chelators.[4]
The Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction,[5] in the
paradigm of ‘‘click chemistry,’’ affords a superior regioselective 1,2,3-triazole
moiety.[6,7] This reaction has been used extensively because of its high efficiency,
versatility, and selectivity,[6b] and it is known to give highly quantitative yield under
mild reaction conditions. Click reactions are so versatile that they have opened new
Received November 20, 2010.
Address correspondence to R. Raghunathan, Department of Organic Chemistry, University of
Madras, Guindy Campus, Chennai 600 025, India. E-mail: ragharaghunathan@yahoo.com
2256

C2-SYMMETRIC TRIAZOLOPHANES
2257
vistas in the synthesis of natural products,[8] polymers,[9] dendrimers,[10] and
macrocycles[11] with biological potential. Consequently, this reaction would be an
effective synthetic technique to design macrocyclic compounds[12] containing a
triazole moiety under mild conditions.
Typically cyclophanes often display remarkable biological activities such as
enzyme inhibition,[13] immunosuppression,[14] and protein biosynthesis inhibition.[15]
In addition, cyclophanes containing triazole units have greater efficiency for binding
guest molecules.[16] Because of our continued interest in the synthesis of macrocycles
grafted with triazole,[17] herein we report an expeditious and facile protocol for the
synthesis of novel triazolophanes via Cu(I)-catalyzed click reaction.
RESULTS AND DISCUSSION
Our studies commenced with the synthesis of 1,3- and 1,2 bis-O-propargylated
benzene 2a,b which act as dipolorophiles. They were prepared from dihydroxy ben-
zene 1a,b by treatment with propargyl bromide in the presence of K2CO3 in dimethyl-
formamide (DMF) at room temperature Scheme 1.
The dialkyne 2a smoothly reacted with aliphatic diazide 3a in the presence of
CuSO4 and sodium ascorbate in a mixture of tetrahydrofuran (THF)–water (1:1)
as a solvent at 60 ꢀC for 4.5 h to give the triazolophane 4a in good yield Table 1,
Scheme 2.
The same protocol was extended for the synthesis of 16 to 18-membered tria-
zolophanes successfully by reacting 2a with other azides. Dialkyne 2a was reacted
with azides 3b–d to yield 16 to 18-membered triazolophanes 4b–d (Scheme 2).
The formations of the triazolophanes were confirmed by spectroscopic techni-
ques such as 1H NMR, 13C NMR, distortionless enhancement by polarization transfer
(DEPT) 135, correlation spectroscopy (COSY) NMR, mass spectrometry, and
1
elemental analysis. In the H NMR spectrum of compound 4a showed two peaks at
d 4.36 and d 5.32 corresponding to –NCH2 and –OCH2 protons respectively. The tria-
zole proton appeared as a singlet at d 7.03. The signals in 13C NMR spectrum of com-
pound 4a exhibited two peaks at d 49.21 and d 64.97, corresponding to two methylene
carbons, and a signal at d 121.48 for the triazole CH-carbon. These assignments
were based on their C,H-COSY correlation data. Moreover, the mass spectrum of
compound 4a exhibited a molecular ion peak at m=z: 326.29 (Mþ), which further con-
1
firmed the formation of triazolophane. Further, the H and 13C NMR spectra sug-
gested that 4a–d exhibited C2symmetry. After successful syntheses of triazolophanes
Scheme 1. Synthesis of dialkyne 2a,b.

2258
R. RAJESH AND R. RAGHUNATHAN
Table 1. Click reaction of dipolar azides 3a–d with dialkynes
Dialkyne
Diazide
Time (h)
Products
Yields (%)
4.5
60
7.0
70
5.5
62
9.5
58
4.0
48
(Continued )

C2-SYMMETRIC TRIAZOLOPHANES
2259
Table 1. Continued
Dialkyne
Diazide
Time (h)
Products
Yields (%)
6.5
61
5.0
52
8.5
50
4.5
71
6.0
78
(Continued )

2260
R. RAJESH AND R. RAGHUNATHAN
Table 1. Continued
Dialkyne
Diazide
Time (h)
Products
Yields (%)
6.0
69
7.5
72
from dialkyne 2a, we further reacted the dialkyne 2b with diazides 3a–d, which gave
the triazolophanes 5a–d in good yields Scheme 3. These products also showed C2
symmetry as evidenced by 1H and 13C NMR spectroscopy.
Having successfully synthesized of triazolophanes 4a–d and 5a–d, we extended
the scope of the reaction for the synthesis of triazolophanes 7a–d by reacting
dialkyne 6 with various diazides 3a–d. 3,5-O-Propargyl acetophenone 6, which was
synthesized from 3,5-dihydroxy aectophenpone using the same procedure as for
dialkyne 2a,b, underwent smooth reactions with aliphatic and aromatic diazides
3a–d to give the expected cyclophanes 7a–d in good yield Scheme 4, Table 1.
Scheme 2. Synthesis of triazolophanees 4a–d.

C2-SYMMETRIC TRIAZOLOPHANES
2261
Scheme 3. Synthesis of triazolophanes 5a–d.
The formations of the product were confirmed by spectral analyses. The
1H NMR of 7d showed two sharp singlets at d 5.36 and d 5.43 corresponding to
N-methylene and O-methylene protons respectively. The triazole proton showed a
singlet at d 6.81 and methyl proton appeared as a singlet at d 2.47. The off-resonance
proton decoupled 13C NMR spectra of 7d showed the peaks at d 54.04 and d 61.48
corresponding to two methylene carbons and methyl carbon resonated at d 29.78.
Scheme 4. Synthesis of triazolophanes 7a–d.
Figure 1. Selected 1H and 13C NMR chemical shifts of 7d.

2262
R. RAJESH AND R. RAGHUNATHAN
The triazole carbon appeared at d 121.87 and the carbonyl carbon was seen at d
197.6 Fig. 1. The C2-symmetric structure of triazolophane 7d was assigned on the
basis of 1H and 13C NMR analysis. As outlined in Table 1, the triazolophanes were
synthesized in excellent yields. The structures of all the compounds were confirmed
by spectral analysis.
CONCLUSION
In conclusion, we have accomplished new triazole-grafted cyclophanes synthe-
sized by Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction methodology
in good yields. Notably, this process is capable of generating 16- to 19-membered tria-
zolophanes successfully. Further work is in progress for screening of the biological
and material studies for these synthesized compounds.
EXPERIMENTAL
All melting points are uncorrected. NMR spectra (1D and 2D) were recorded
on a Bruker 300-MHz instrument in CDCl3 using tetramethylsilane (TMS) as internal
standard. Chemical shifts are given in parts per million (d scale), and coupling
constants are given in hertz.
Representative Procedure for the Synthesis of Triazolophanes
To a solution of 1 mmol of dialkyne 2a and 1.1 mmol of xylylazide 3d in 80 ml of
1:1 THF=H2O were added 0.4 mmol of CuSO4 and 0.6 mmol of sodium ascorbate,
and the solution were stirred at 60 ꢀC for 9.5 h. Completion of the reaction was
evidenced by TLC analysis. The organic solvent was then removed in vacuum, and
the residue was diluted with DCM, washed with water and brine solution, and dried
over Na2SO4. The solution was concentrated, and the residue was subjected to
column chromatography using chloroform=methanol (9:1) as eluent to give the pure
compound 4d in good yield.
Compound 4a
Colorless solid; mp: 121–123 ꢀC. 1H NMR (300 MHz, CDCl3): d 1.68 (m, 4H),
4.36 (m, 4H), 5.32 (s, 4H), 6.26 (s, 1H), 6.66 (d, 2H, J ¼ 8.1 Hz), 7.03 (s, 2H), 7.15 (t,
1H, J ¼ 8.4 Hz). 13C NMR (75 MHz, CDCl3): d 25.82, 49.21, 64.97, 121.48, 131.26,
132.50, 133.41, 145.64, 152.15. MS EI m=z: 326.29 (Mþ). Anal. calcd. for
C16H18N6O2: C, 58.88; H, 5.56; N, 25.75. Found: C, 58.97; H, 5.45; N, 25.83.
Compound 4b
1
Colorless solid; mp: 152–155 ꢀC. H NMR (300 MHz, CDCl3): d 5.26 (s, 4H),
5.65 (s, 4H), 6.15 (s, 1H), 6.46 (d, 2H, J ¼ 6.9 Hz), 6.56 (s, 2H), 7.03 (t, 1H,
J ¼ 7.8 Hz), 7.43 (m, 2H), 7.52 (d, 2H, J ¼ 3.6 Hz). 13C NMR (75 MHz, CDCl3): d
51.24, 61.85, 99.10, 110.53, 121.61, 130.47, 132.17, 132.63, 133.09, 145.19, 158.14.
MS EI m=z: 374.32 (Mþ). Anal. calcd. for C20H18N6O2: C, 64.16; H, 4.85; N,
22.45. Found: C, 64.22; H, 4.78; N, 22.53.

C2-SYMMETRIC TRIAZOLOPHANES
2263
Compound 4c
Ash-colored solid; mp: 151–153 ꢀC. 1H NMR (300 MHz, CDCl3): d 5.32 (s, 4H),
5.45 (s, 4H), 6.32 (m, 1H), 6.52 (d, 2H, J ¼ 8.1 Hz), 6.85 (s, 1H), 6.99 (s, 2H), 7.04 (t,
1H, J ¼ 8.4 Hz), 7.39 (s, 3H). 13C NMR (75 MHz, CDCl3): d 53.75, 61.86, 102.55,
109.19, 121.37, 127.31, 129.23, 129.97, 130.10, 135.66, 145.30, 158.41. MS EI m=z:
374.45 (Mþ). Anal. calcd. for C20H18N6O2: C, 64.16; H, 4.85; N, 22.45. Found: C,
64.08; H, 4.93; N, 22.55.
Compound 4d
Ash-colored solid; mp: 151–155 ꢀC. 1H NMR (300 MHz, CDCl3): d 5.40
(s, 4H), 5.69 (s, 4H), 6.29 (s, 1H), 6.81 (d, 2H, J ¼ 8.1 Hz), 7.05 (s, 2H), 7.24 (s,
4H), 7.18 (t, 1H, J ¼ 8.2 Hz). 13C NMR (75 MHz, CDCl3): d 53.91, 62.09, 105.21,
110.17, 121.30, 126.91, 130.32, 131.54, 145.63, 154.15. MS EI m=z: 374.36 (Mþ).
Anal. calcd. for C20H18N6O2: C, 64.16; H, 4.85; N, 22.45. Found: C, 64.22; H,
4.79; N, 22.38.
Compound 5a
1
Colorless solid; mp: 123–125 ꢀC. H NMR (300 MHz, CDCl3): d 1.75 (m, 4H),
4.39 (m, 4H), 5.19 (s, 4H), 7.01 (s, 2H), 7.13 (m, 4H). 13C NMR (75 MHz, CDCl3):
d 25.6, 48.9, 64.8, 116.9, 121.6, 122.9, 145.7, 149.4. MS EI m=z: 326.29 (Mþ). Anal.
calcd. for C16H18N6O2: C, 58.88; H, 5.56; N, 25.75. Found: C, 58.97; H, 5.45; N, 25.83.
Compound 5b
1
Colorless solid; mp: 149–153 ꢀC. H NMR (300 MHz, CDCl3): d 5.29 (s, 4H),
5.81 (s, 4H), 7.06 (s, 2H), 7.16 (m, 4H), 7.39 (d, 2H, J ¼ 3.6 Hz), 7.49 (d, 2H,
J ¼ 3.8 Hz). 13C NMR (75 MHz, CDCl3): d 52.32, 62.09, 100.32, 110.91, 117.25,
121.72, 123.12, 132.81, 145.59, 150.09. MS EI m=z: 374.37 (Mþ). Anal. calcd. for
C20H18N6O2: C, 64.16; H, 4.85; N, 22.45. Found: C, 64.21; H, 4.78; N, 22.37.
Compound 5c
1
Colorless solid; mp: 150–153 ꢀC. H NMR (300 MHz, CDCl3): d 5.05 (s, 4H),
5.47 (s, 4H), 6.88 (s, 1H), 7.09 (s, 2H), 7.18 (m, 4H), 7.32 (m, 3H). 13C NMR
(75 MHz, CDCl3): d 54.35, 65.76, 103.10, 109.98, 117.24, 121.83, 123.45, 127.67,
135.82, 145.86, 150.01. MS EI m=z: 374.36 (Mþ). Anal. calcd. for C20H18N6O2: C,
64.16; H, 4.85; N, 22.45. Found: C, 64.09; H, 4.91; N, 22.50.
Compound 5d
1
Ash-colored solid; mp: 153–156 ꢀC. H NMR (300 MHz, CDCl3): d 5.31 (s,
4H), 5.72 (s, 4H), 6.96 (s, 2H), 7.09 (m, 4H), 7.16 (s, 4H). 13C NMR (75 MHz,
CDCl3): d 53.68, 62.81, 117.61, 121.80, 123.03, 130.18, 138.61, 144.75, 150.51. MS
EI m=z: 374.45 (Mþ). Anal. calcd. for C20H18N6O2: C, 64.16; H, 4.85; N, 22.45.
Found: C, 64.23; H, 4.91; N, 22.38.

2264
R. RAJESH AND R. RAGHUNATHAN
Compound 7a
1
Colorless solid; mp: 127–130 ꢀC. H NMR (300 MHz, CDCl3): d 1.18 (m, 4H),
2.49 (s, 3H), 4.29 (m, 4H), 5.28 (s, 4H), 6.37 (t, 1H, J ¼ 2.1 Hz), 6.79 (s, 2H), 7.17 (d,
2H, J ¼ 1.8 Hz). 13C NMR (75 MHz, CDCl3): d 27.25, 29.79, 49.25, 62.50, 107.52,
110.76, 121.72, 139.47, 144.48, 158.45, 196.31. MS EI m=z: 326.29 (Mþ). Anal. calcd.
for C18H20N6O3: C, 58.69; H, 5.47; N, 22.81. Found: C, 58.76; H, 5.41; N, 22.76.
Compound 7b
1
Colorless solid; mp: 157–160 ꢀC. H NMR (300 MHz, CDCl3): d 2.40 (s, 3H),
5.25 (s, 4H), 5.32 (s, 4H), 6.44 (t, 1H, J ¼ 2.1 Hz), 6.95 (s, 2H), 7.05 (d, 2H,
J ¼ 1.2 Hz), 7.21 (m, 2H), 7.36 (m, 2H). 13C NMR (75 MHz, CDCl3): d 29.78,
53.85, 62.03, 107.21, 109.31, 121.75, 127.22, 129.28, 130.02, 135.74, 139.19, 158.50,
197.55. MS EI m=z: 416.33 (Mþ). Anal. calcd. for C22H20N6O3: C, 63.45; H, 4.84;
N, 20.18. Found: C, 63.57; H, 4.75; N, 20.28.
Compound 7c
1
Colorless solid; mp: 158–160 ꢀC; H NMR (300 MHz, CDCl3): d 2.42 (s, 3H),
5.29 (s, 4H), 5.35 (s, 4H), 6.45 (m, 1H, J ¼ 2.3), 6.77 (s, 1H), 6.97 (s, 2H), 7.03 (d,
J ¼ 1.2, 2H), 7.32 (s, 3H). 13C NMR (75 MHz, CDCl3): d 29.78, 53.85, 62.03,
107.21, 109.35, 121.75, 127.22, 129.28, 130.02, 135.74, 139.19, 158.50, 197.55. MS
EI m=z: 416.33 (Mþ). Anal. calcd. for C22H20N6O3: C, 63.45; H, 4.84; N, 20.18.
Found: C, 63.58; H, 4.77; N, 20.27.
Compound 7d
1
Colorless solid; mp: 156–159 ꢀC. H NMR (300 MHz, CDCl3): d 2.47 (s, 3H),
5.36 (s, 4H), 5.43 (s, 4H), 6.41 (t, 1H, J ¼ 2.4 Hz), 6.81 (s, 2H), 6.88 (d, 2H, J ¼
1.8 Hz,), 7.06 (s, 4H). 13C NMR (75 MHz, CDCl3): d 29.78, 54.04, 61.48,106.79,
110.32, 121.87, 129.36, 135.71, 138.45, 144.86, 157.80, 197.63. MS EI m=z: 416.34
(Mþ). Anal. calcd. for C22H20N6O3: C, 63.45; H, 4.84; N, 20.18. Found: C, 63.57;
H, 4.73; N, 20.25.
ACKNOWLEDGMENTS
The authors thanks the Department of Science and Technology–Funding for
Infrastructure in Science and Technology for NMR facilities and financial assistance,
and R. R. thanks the Council for Scientific and Industrial Research and the Univer-
sity Grants Commission, New Delhi, for financial assistance.
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