Acid promoted metal free synthesis of triazole-fused heterocycles via intramolecular [3+2] cycloaddition

Article abstract of DOI:10.3987/COM-18-13900

A practical and efficient protocol for the synthesis of triazole-fused heterocycles through intramolecular metal free [3+2] azide-alkyne cycloaddition reaction is described. Range of acids was selected to demonstrate the reaction conditions. Organic azides and propargyl cations generated by acids gave fused triazoles including multivariate rings and heterocycles. Various fused triazoles and bistriazoles were obtained in good yields under mild reaction conditions.

Full text of DOI:10.3987/COM-18-13900

Acid Promoted Metal Free Synthesis of Trizole-Fused Heterocycles
via Intramolecular [3+2] Cycloaddition
Youlai Zhang,a Mengdi Wang,a Junru Li,a Qingtong Di,a Ziye Tian,a Baoquan Chen,a
Huan Zhang,a,* Hiroki Tanimoto,b Tsumoru Morimoto,b and Kiyomi Kakiuchib
Supporting Information
General information
All chemicals and solvents were of analytical grade and were used without further
purifications. All reactions were conducted in oven-dried (135 ℃) glassware under
an inert atmosphere of dry nitrogen. The progress of reactions was monitored by silica
gel thin layer chromatography (TLC) plates (mesh size 60Å, MERCK). Products were
purified by flash column chromatography (FCC) on 40-63 m silica gel 60 (MERCK).
1H and 13C NMR were recorded on Bruker AV-400(400 MHz) or JEOL JNM-ECP500
spectrometer (400MHz or 500MHz for 1H NMR, 100MHz or 126 MHz for 13C NMR).
Chemical shifts are reported as δ values in ppm and calibrated by residual solvent
1
peak or tetramethylsilane (δ 0 for H NMR). Abbreviations are following: s (singlet),
d (doublet), t (triplet), q (quartet), br (broad peak), m (complex multiplet). Mass
spectra were measured on HP-1100 LC-MS spectrometer. X-ray crystallography was
performed on Rigaku R-AXIS RAPID/S imaging plate diffractometer. Flush column
chromatography was performed by MERCK Silica gel 60. The progress of reactions
was monitored by silica gel thin layer chromatographyplates (MERCKTLC Silicagel
60 F254). Phosphomolybdic acid ethanol solution, ninhydrin-acetic acid butanol
solution and anisaldehyde-acetic acid-sulfuric acid ethanol solution were used as TLC
stain.
Experimental Procedure of Azido-Propargyl Alcohol
To a stirred solution of corresponding propargyl alcohol and TsCl in dichloromethane
1 / 42

was triethylamine added under nitrogen atmosphere. After 2 h, the mixture was
diluted with ethyl acetate and was washed with water and brine. Drying collected
organic layer over MgSO4 followed by silica gel column chromatography gave
tosylate compound.
To a stirred solution of tosylate compound in dry THF under an atmosphere of
nitrogen was added dropwise n-BuLi at -78 °C and the mixture was stirred for 10 min.
Benzaldehyde was then added at same temperature. After 4h, the reaction was
quenched with water. The mixture was diluted with ethyl acetate and was washed with
water and brine. Drying collected organic layer over MgSO4. The crude product can
be used to the next step without further purification.
To a stirred solution of benzyl alcohols in DMF was added sodium azide at room
temperature and the reaction mixture was heated to 50 °C. After 20 min, the reaction
mixture was diluted with ether and was washed with water and brined. Drying
collected organic layer over MgSO4 followed by silica gel column chromatography
gave azide as colorless oil.
7-azido-1,1-diphenylhept-2-yn-1-ol(1a)
The reaction with tosylate compound(0.255 g, 1.07 mmol), n-BuLi (1.55 M in hexane,
0.729 mL, 1.15 mmol) and ketone (0.15 g, 0.823 mmol) in THF (8 mL) followed by
followed by collected the organic layer under vacuum affording the product 0.45 g.
[silica gel purification (ethyl acetate / hexane = 1 / 8 to 1/3)].
Colorless solid; Rf value 0.28(ethyl acetate/hexane = 1/3); 1H NMR(500 MHz, CDCl3)
δ 7.78(d, 2H, J = 8.0 Hz), 7.60–7.57(m, 4H), 7.38–7.31(m, 6H), 7.28–7.25(m, 2H),
4.06(t, 2H, J = 6.5 Hz), 2.92(s, 1H, OH), 2.44(s, 3H), 2.34(t, 2H, J = 7.0 Hz), 1.82(tt,
2H, J = 6.5, 6.5 Hz), 1.63(tt, 2H, J = 6.5, 7.0 Hz); 13C NMR(126 MHz, CDCl3) δ
145.4, 144.8, 132.9, 129.9, 128.2, 127.8, 127.5, 125.9, 86.9, 83.9, 74.4, 69.9, 28.0,
24.3, 21.6, 18.3; HRMS (ESI) calcd for C26H26O4SNa [M+Na]+457.14495, found
457.14440.
Then the crude benzyl alcohol with sodium azide (83.47 mg, 1.28 mmol) in DMF (20
ml) followed by silica gel column chromatography (ethyl acetate / hexane = 1/10 to
1/5) gave azide 1a (0.108 g, 43%) as a colorless oil.
Colorless oil; Rf value 0.47(ethyl acetate/hexane = 1/5); 1H NMR(500 MHz, CDCl3) δ
7.60(m, 4H), 7.33(dd, 4H, J = 6.5, 6.5 Hz), 7.27(m, 2H), 3.31(t, 2H, J = 6.5 Hz),
2.76(s, 1H, OH), 2.40(t, 2H, J = 7.0 Hz), 1.66–1.76(m, 4H); 13C NMR(126 MHz,
CDCl3) δ 145.3, 128.2, 127.6, 125.9, 87.2, 83.7, 74.4, 50.9, 28.0, 25.6, 18.5; HRMS
(ESI) calcd for C19H19N3ONa [M+Na]+ 328.1426, found 328.1424.
2 / 42

6-azido-1,1-diphenylhex-2-yn-1-ol (1b)
The reaction with tosylate (0.543 g, 2.15 mmol), n-BuLi (1.58 M in hexane, 1.46 mL,
2.30 mmol) and ketone (0.28 g, 1.54 mmol) in THF (15 mL) followed by followed by
collected the organic layer under vacuum affording the product 2.2 g. [silica gel
purification (ethyl acetate / hexane = 1 / 8 to 1/4)].
Colorless oil; Rf value 0.25(ethyl acetate/hexane = 1/4); IR (NaCl, neat) νmax 3502,
1
3060, 3029, 2958, 1598, 1491, 1449, 1360, 1175 cm-1; H NMR(500 MHz, CDCl3) δ
7.75(d, 2H, J = 7.5 Hz), 7.53(m, 4H), 7.23–7.32(m, 8H), 4.15(t, 2H, J = 6.0 Hz),
2.76(s, 1H), 2.43(t, 2H, J = 6.5 Hz), 2.39(s, 3H), 1.90(tt, 2H, J = 6.5, 6.0 Hz); 13C
NMR(126 MHz, CDCl3) δ 145.1, 144.8, 132.8, 129.9, 128.2, 127.9, 127.6, 125.9,
85.5, 84.4, 74.3, 68.8, 27.7, 21.6, 15.2; LRMS (EI) 420(M+, 0.8%), 403(5), 343(100),
220(53), 105(71); HRMS (EI) calcd for C25H24O4S (M+) 420.1395, found 420.1397.
Then the crude benzyl alcohol with sodium azide (0.124 g, 1.9 mmol) in DMF (5 ml)
followed by silica gel column chromatography (ethyl acetate / hexane = 1/10 to 1/5)
gave azide 1b (0.32 g, 70%) as a colorless oil.
Colorless oil; Rf value 0.50(ethyl acetate/hexane = 1/4); IR (NaCl, neat) νmax 3426,
2933, 2099, 1490, 1449 cm-1; 1H NMR(500 MHz, CDCl3) δ 7.59(m, 4H), 7.31(m, 4H),
7.27(m, 2H), 3.43(t, 2H, J = 6.5 Hz), 2.75(s, 1H), 2.48(t, 2H, J = 7.0 Hz), 1.85(tt, 2H,
J = 7.0, 6.5 Hz); 13C NMR(126 MHz, CDCl3) δ 145.2, 128.2, 127.6, 125.9, 86.2, 84.2,
74.4, 50.2, 27.7, 16.2; HRMS (CI) calcd for C18H18N3O [M+H]+ 292.1450, found
292.1455.
8-azido-1,1-diphenyloct-2-yn-1-ol（1c）
To a stirred solution of hept-6-yn-1-ol (700.0 mg, 6.05 mmol) and TsCl (1.27 mg,
6.66 mmol) in dichloromethane (6 ml) was added triethylamine (1.01 mL, 7.26 mmol)
at 0 °C, then reaction mixture was allowed to warm up to ambient temperature. After
2 h, the mixture was diluted with ethyl acetate and was washed with water and brine.
Drying collected organic layer over MgSO4 followed by silica gel column
chromatography (ethyl acetate/ Petroleum ether = 1/25) gave tosylate compound 15c
(1.15 g, 71.7%) as a colorless oil.
Colorless oil; Rf value 0.63(ethyl acetate/Petroleum ether = 1/5); 1H NMR (400 MHz,
CDCl3) δ 7.79 (d, 2H , J = 8.4 Hz), 7.34 (d, 2H, J = 8.0 Hz), 4.02 (t, 2H, J = 6.4 Hz),
2.45 (s, 3H), 2.14 (td, 2H, J = 6.8, 2.4 Hz), 1.92 (t, 1H, J = 2.4 Hz), 1.66 (tt, 2H, J =
6.8，6.8 Hz), 1.51-1.38 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 144.7, 133.1, 129.8,
3 / 42

127.9, 84.0, 70.3, 68.5, 28.3, 27.7, 24.5, 21.7, 18.2; HRMS (ESI) calcd for C14H19O3S
[M+H]+ 267.1055, found 267.1048.
The reaction with tosylate 15c (0.25 g, 1.37 mmol), n-BuLi (1.58 M in hexane, 1.20
mL, 1.92 mmol) and ketone (0.475 g, 1.78 mmol) in THF (15 mL) followed by
collected the organic layer under vacuum affording the product 0.581 g.
Then the crude benzyl alcohol with sodium azide (0.101 g, 1.56 mmol) in DMF (5 ml)
followed by silica gel column chromatography (ethyl acetate/ petroleum ether= 20/1
to 10/1) gave azide 1c (0.331 g, 80%) as a colorless oil.
Rf value 0.475(ethyl acetate/petroleum ether = 1/5); 1H NMR (400 MHz, CDCl3) δ
7.60 (d, 4H, J = 7.2 Hz ), 7.34 (dd, 4H, J = 7.2, 7.6 Hz), 7.27–7.24 (m, 2H), 3.26 (t,
2H, J = 6.4 Hz), 2.76 (s, 1H), 2.37 (t, 2H, J = 7.0 Hz), 1.64–1.59 (m, 4H), 1.55–1.48
(m, 2H)；13C NMR (100 MHz, CDCl3) δ 145.4, 128.1, 127.5, 125.9, 87.6, 83.5, 74.4,
51.2, 28.3, 28.0, 25.9, 18.7；HRMS (ESI) calcd for C20H22N3O [M+H]+ 320.1763,
found 320.1763.
9-azido-1,1-diphenylnon-2-yn-1-ol（1d）
To a stirred solution of oct-7-yn-1-ol (0.4g，3.46mmol) and TsCl (0.725g，3.80mmol)
in dichloromethane (30 ml) was added triethylamine (0.577mL，420mmol) at 0 °C,
then reaction mixture was allowed to warm up to ambient temperature. After 2 h, the
mixture was diluted with ethyl acetate and was washed with water and brine. Drying
collected organic layer over MgSO4 followed by silica gel column chromatography
(ethyl acetate/ Petroleum ether= 1/40 to 1/30) gave tosylate compound 15d (0.721 g,
78%) as a colorless oil.
Colorless oil; Rf value 0.55(ethyl acetate/ Petroleum ether= 1/5); 1H NMR (400 MHz,
CDCl3) δ 7.79 (d, 2H , J = 8.4 Hz), 7.34 (d, 2H, J = 8.0 Hz), 4.02 (t, 2H, J = 6.4 Hz),
2.45 (s, 3H), 2.14 (td, 2H, J = 6.8, 2.4 Hz), 1.92 (t, 1H, J = 2.4 Hz), 1.68-1.63 (m, 2H),
13
1.50-1.44 (m, 2H), 1.38-1.32 (m, 4H); C NMR (100 MHz, CDCl3) δ145.4, 144.6,
128.0, 125.8, 87.3, 74.3, 70.2, 28.12, 27.6, 24.5, 21.5, 18.5; HRMS (ESI) calcd for
C15H21O3S [M+H]+ 281.1211, found 281.1216.
The reaction with tosylate 15d (1.00 g, 2.74 mmol), n-BuLi (1.60 M in hexane, 2.40
mL, 3.84 mmol) and ketone (0.50 g, 1.78 mmol) in THF (27 mL) followed by
collected the organic layer under vacuum affording the product 1.20 g.
Then the crude benzyl alcohol with sodium azide (0.200 g, 3.11 mmol) in DMF (5 ml)
4 / 42

followed by silica gel column chromatography (ethyl acetate/ petroleum ether= 20/1
to 10/1) gave azide 1d (0.825 g, 95 %) as a colorless oil.
Rf value 0.475(ethyl acetate/ petroleum ether= 1/5); 1H NMR (400 MHz, CDCl3) δ
7.60 (d, 4H, J = 7.2 Hz ), 7.32 (dd, 4H, J = 7.2, 7.6 Hz), 7.27 – 7.23 (m, 2H), 3.25 (t,
2H, J = 6.8 Hz), 2.79 (s, 1H), 2.36 (t, 2H, J = 6.8 Hz), 1.64 – 1.56 (m, 4H), 1.50 –
1.36 (m, 4H)；13C NMR (100 MHz, CDCl3) δ 145.5, 128.1, 127.5, 125.9, 87.9, 83.3,
74.4, 51.3, 28.7, 28.32, 28.27, 26.1, 18.8；HRMS (ESI) calcd for C21H24N3O [M+H]+
334.1919, found 334.1914.
9-azido-1,1-diphenylnon-2-yn-1-ol（1e）
To a stirred solution of oct-7-yn-1-ol (0.3 g，1.71 mmol) and TsCl (0.360 g，1.88
mmol) in dichloromethane (10 ml) was added triethylamine (0.285 mL，2.05 mmol) at
0 °C, then reaction mixture was allowed to warm up to ambient temperature. After 2 h,
the mixture was diluted with ethyl acetate and was washed with water and brine.
Drying collected organic layer over MgSO4 followed by silica gel column
chromatography (ethyl acetate / Petroleum ether = 1/100 to 1/60) gave tosylate
compound 15e (0.525 g, 95.1%) as a colorless oil.
Colorless oil; Rf value 0.47(ethyl acetate/ Petroleum ether= 1/10); 1H NMR (400 MHz,
CDCl3) δ 7.79 (d, 2H , J = 8.4 Hz), 7.34 (d, 2H, J = 8.4 Hz), 4.01 (t, 2H, J = 6.8 Hz),
2.45 (s, 3H), 2.17 (td, 2H, J = 7.2, 2.4 Hz), 1.94 (t, 1H, J = 2.4 Hz), 1.66-1.59 (m, 2H),
1.54-1.46 (m, 2H), 1.37-1.32 (m, 2H), 1.30-1.23 (m, 8H); 13C NMR (100 MHz,
CDCl3) δ 144.6, 133.2, 129.8, 127.8, 84.7, 70.6, 68.1, 29.2，28,9, 28.8，28.6, 28.4,
25.3, 21.6, 18.3; HRMS (ESI) calcd for C18H27O3S [M+H]+ 323.1681, found
323.1685.
The reaction with tosylate 15e (0.433g, 1.34 mmol), n-BuLi (1.60 M in hexane, 0.900
mL, 1.44 mmol) and ketone (0.188 g, 1.03 mmol) in THF (10 mL) followed by
collected the organic layer under vacuum affording the product 0.470 g.
Then the crude benzyl alcohol with sodium azide (0.073g, 1.12 mmol) in DMF (5 ml)
followed by silica gel column chromatography (ethyl acetate/petroleum ether = 20/1
to 10/1) gave azide 1e (0.234 g, 67 %) as a colorless oil.
Rf value 0.475(ethyl acetate/petroleum ether = 1/5); 1H NMR (400 MHz, CDCl3) δ
7.60 (d, 4H, J = 7.2 Hz ), 7.32 (dd, 4H, J = 7.2, 8.0 Hz), 7.27–7.23 (m, 2H), 3.25 (t,
2H, J = 6.8 Hz), 2.74 (s, 1H), 2.34 (t, 2H, J = 6.8 Hz), 1.62–1.55 (m, 6H), 1.44–1.30
(m, 8H)；13C NMR (100 MHz, CDCl3) δ 145.5, 128.1, 127.4, 126.0, 88.2, 83.1, 74.4,
5 / 42

51.4, 29.3, 29.0, 28.9, 28.82, 28.78, 28.5, 26.7, 18.9；HRMS (ESI) calcd for C24H30N3O
[M+H]+ 376.2389, found 376.2389.
8-azido-1,1-diphenyloct-2-yn-1-ol（1f）
To a stirred solution of 2-(prop-2-yn-1-yl)propane-1,3-diol (120.0 mg, 1.05 mmol)
and TsCl (561.2 mg, 2.94 mmol) in dichloromethane (10 ml) was added triethylamine
(0.511 mL, 3.68 mmol) at 0 °C, then reaction mixture was allowed to warm up to
ambient temperature. After 2 h, the mixture was diluted with ethyl acetate and was
washed with water and brine. Drying collected organic layer over MgSO4 followed by
silica gel column chromatography (ethyl acetate/ Petroleum ether= 1/40 to 1/15) gave
tosylate compound (0.373g, 84%) as a colorless oil.
Colorless oil; Rf value 0.45(ethyl acetate/petroleum ether = 1/10); 1H NMR (400 MHz,
CDCl3) δ 7.75 (d, 2H , J = 8.0 Hz), 7.36 (d, 2H, J = 8.0 Hz), 4.02 (d, 4H, J = 2.8Hz),
13
2.46 (s, 6H), 2.24 (s, 3H), 1.86 (s, 1H); C NMR (100 MHz, CDCl3) δ 145.2, 132.2,
130.0, 127.9, 79.1, 71.1, 67.9, 37.3, 21.7, 17.2; HRMS (ESI) calcd for C20H23O6S
[M+H]+ 423.0936, found 423.0936.
The reaction with tosylate 15f (0.334 g, 0.790 mmol), n-BuLi (1.60 M in hexane,
0.576 mL, 0.922 mmol) and ketone (0.120 g, 0.659 mmol) in THF (8 mL) followed
by collected the organic layer under vacuum affording the product 0.370 g.
Then the crude benzyl alcohol with sodium azide (0.103 g, 1.59 mmol) in DMF (5 ml)
followed by silica gel column chromatography (ethyl acetate/petroleum ether = 20/1
to 10/1) gave azide 1f (0.148 g, 81%) as a colorless oil.
Rf value 0.45(ethyl acetate/petroleum ether = 1/5); 1H NMR (400 MHz, CDCl3) δ
7.57 (d, 4H, J = 6.4 Hz ), 7.34 (dd, 4H, J = 7.2, 7.6 Hz), 7.28 (d, 2H, J = 6.4 Hz), 3.44
(d, 4H, J = 6.0 Hz), 2.74 (br, 1H), 2.49 (d, 2H, J = 6.8 Hz), 2.09–2.03 (m, 1H)；13C
NMR (100 MHz, CDCl3) δ 145.0, 128.3, 127.7, 125.9, 85.9, 83.8, 74.5, 52.0, 38.2,
19.6；HRMS (ESI) calcd for C19H19N6O [M+H]+ 347.1620, found 347.1623.
4-(2-azidoethoxy)-1,1-diphenylbut-2-yn-1-ol (3a)
To a stirred solution of 2-(prop-2-yn-1-yloxy)ethanol (0.7 g，6.99 mmol) and TsCl
(1.60 g，8.39 mmol) in dichloromethane (10 ml) was added triethylamine (3.49 mL，
6 / 42

24.47 mmol) at 0 °C, then reaction mixture was allowed to warm up to ambient
temperature. After 2 h, the mixture was diluted with ethyl acetate and was washed
with water and brine. Drying collected organic layer over MgSO4 followed by silica
gel column chromatography (ethyl acetate/ Petroleum ether= 1/20 to 1/10 to 1/2) gave
tosylate compound 16a (1.62 g, 91%) as a colorless oil.
1
Colorless oil; Rf value 0.3(ethyl acetate/ Petroleum ether= 1/5); H NMR (400 MHz,
CDCl3) δ 7.80(d, 2H , J = 8.0 Hz), 7.34 (d, 2H, J = 8.0 Hz), 4.19 (t, 2H, J = 4.8 Hz),
4.11 (s, 2H), 3.72 (t, 2H, J = 4.4 Hz), 2.44 (s, 3H), 2.42 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 144.8, 132.9, 129.8, 127.9, 78.9, 75.0, 68.8, 67.1, 58.3, 21.6; HRMS (ESI)
calcd for C12H14O4S [M]+ 254.0613, found 254.0610.
The reaction with tosylate 16a (1.09g，4.28mmol), n-BuLi (1.60 M in hexane, 2.88ml，
4.61mmol) and ketone (0.6g，3.29mmol) in THF (33 mL) followed by collected the
organic layer under vacuum affording the product 1.2 g.
Then the crude benzyl alcohol with sodium azide (0.214g, 3.3 mmol) in DMF (5 ml)
followed by silica gel column chromatography (ethyl acetate/ petroleum ether= 20/1
to 10/1) gave azide 3a (0.625 g, 74 %) as a colorless oil.
Rf value 0.35(ethyl acetate/ petroleum ether= 1/5); 1H NMR (400 MHz, CDCl3) δ
7.59 (d, 4H, J = 7.6 Hz ), 7.34 (dd, 4H, J = 7.2, 7.6 Hz), 7.27 (d, 2H, J = 7.2 Hz), 4.38
(s, 2H), 3.73 (t, 2H, J = 4.8 Hz), 3.42 (t, 2H, J = 4.8 Hz), 2.82 (br, 1H)；13C NMR
(100 MHz, CDCl3) δ 144.6, 128.3, 127.8, 125.9, 89.5, 82.8, 74.4, 68.5, 58.8, 50.6；
HRMS (ESI) calcd for C18H17N3O2Na [M+Na]+ 330.1218, found 330.1217.
4-(3-azidopropoxy)-1,1-diphenylbut-2-yn-1-ol（3b）
To a stirred solution of 3-(prop-2-yn-1-yloxy)propan-1-ol (0.8 g，7.01 mmol) and TsCl
(1.60 g，8.41 mmol) in dichloromethane (10 ml) was added triethylamine (3.50 mL，
24.53 mmol) at 0 °C, then reaction mixture was allowed to warm up to ambient
temperature. After 2 h, the mixture was diluted with ethyl acetate and was washed
with water and brine. Drying collected organic layer over MgSO4 followed by silica
gel column chromatography (ethyl acetate/ Petroleum ether= 1/20 to 1/10 to 1/2) gave
tosylate compound 16b (1.57 g, 83%) as a colorless oil.
1
Colorless oil; Rf value 0.3(ethyl acetate/ Petroleum ether= 1/5); H NMR (400 MHz,
CDCl3) δ 7.79(d, 2H , J = 8.4 Hz), 7.35 (d, 2H, J = 8.0 Hz), 4.13 (t, 2H, J = 6.4 Hz),
4.03 (s, 2H), 3.53 (t, 2H, J = 6.0 Hz), 2.43 (s, 3H), 2.40 (s, 1H), 1.93 (tt, 2H, J = 6.0,
13
6.0 Hz); C NMR (100 MHz, CDCl3) δ144.7, 133.0, 129.8, 127.9, 79.4, 74.5, 67.5,
65.4, 58.2, 29.1, 21.6; HRMS (ESI) calcd for C13H17O4S [M+H]+ 269.0848, found
7 / 42

269.0844.
The reaction with tosylate 16b (1.04g，3.89mmol), n-BuLi (1.60 M in hexane, 2.62ml，
4.19mmol) and ketone (0.545g，2.99mmol) in THF (33 mL) followed by collected the
organic layer under vacuum affording the product 1.15g.
Then the crude benzyl alcohol with sodium azide (0.200g, 3.06mmol) in DMF (5 ml)
followed by silica gel column chromatography (ethyl acetate/ petroleum ether= 10/1
to 5/1) gave azide 3b (0.730 g, 89 %) as a colorless oil.
Rf value 0.38(ethyl acetate/ petroleum ether= 1/5); 1H NMR (400 MHz, CDCl3) δ
7.59 (d, 4H, J = 7.6 Hz ), 7.34 (dd, 4H, J = 7.2, 7.6 Hz), 7.28 (d, 2H, J = 7.2 Hz), 4.31
(s, 2H), 3.63 (t, 2H, J = 6.0 Hz), 3.42 (t, 2H, J = 6.4 Hz), 2.93 (br, 1H)，1.86 (tt, 2H, J
= 6.0, 6.4 Hz)；13C NMR (100 MHz, CDCl3) δ 144.7, 128.2, 127.7, 125.9, 89.1, 83.1,
74.2, 66.5, 58.5, 48.2, 28.9；HRMS (ESI) calcd for C19H19N3O2Na [M+Na]+ 344.1375,
found 344.1373.
4-(4-azidobutoxy)-1,1-diphenylbut-2-yn-1-ol（3c）
To a stirred solution of 4-(prop-2-yn-1-yloxy)butan-1-ol (1.57 g，12.25 mmol) and
TsCl (2.80 g，14.70 mmol) in dichloromethane (10 ml) was added triethylamine 6.11
mL，42.87 mmol) at 0 °C, then reaction mixture was allowed to warm up to ambient
temperature. After 2 h, the mixture was diluted with ethyl acetate and was washed
with water and brine. Drying collected organic layer over MgSO4 followed by silica
gel column chromatography (ethyl acetate/ Petroleum ether= 1/15 to 1/10) gave
tosylate compound 16c (2.75 g, 80%) as a colorless oil.
Colorless oil; Rf value 0.40(ethyl acetate/ Petroleum ether= 1/5); 1H NMR (400 MHz,
CDCl3) δ 7.78(d, 2H , J = 8.4 Hz), 7.34 (d, 2H, J = 8.0 Hz), 4.08-4.03 (m, 4H), 3.47 (t,
2H, J = 6.0 Hz), 2.45 (s, 3H), 2.40 (s, 1H), 1.78-1.71 (m, 2H), 1.65-1.58 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 144.7, 133.1, 129.8, 127.8, 79.7, 74.3, 70.3, 68.9, 58.0,
25.7, 25.4, 21.6; HRMS (ESI) calcd for C14H19O4S [M+H]+ 283.1004, found
283.1008.
The reaction with tosylate 16c (1.01g，3.57mmol), n-BuLi (1.60 M in hexane, 2.40ml，
3.84mmol) and ketone (0.500g，2.74mmol) in THF (27 mL) followed by collected the
organic layer under vacuum affording the product 0.945g.
Then the crude benzyl alcohol with sodium azide (0.159g, 2.44mmol) in DMF (5 ml)
followed by silica gel column chromatography (ethyl acetate/ petroleum ether= 20/1
8 / 42

to 8/1) gave azide 3c (0.532 g, 78 %) as a colorless oil.
Rf value 0.39(ethyl acetate/ petroleum ether= 1/5); 1H NMR (400 MHz, CDCl3) δ
7.59 (d, 4H, J = 7.6 Hz ), 7.34 (dd, 4H, J = 7.2, 7.6 Hz), 7.28 (d, 2H, J = 7.2 Hz), 4.30
(s, 2H), 3.57 (t, 2H, J = 6.0 Hz), 3.27 (t, 2H, J = 6.4 Hz), 2.87 (br, 1H)，1.67 (tt, 4H, J
= 6.4, 6.0 Hz)；13C NMR (100 MHz, CDCl3) δ 144.7, 128.2, 127.6, 125.9, 88.9, 83.3,
74.2, 69.2, 58.3, 51.0, 26.5, 25.6；HRMS (ESI) calcd for C20H21N3O2Na [M+Na]+
358.1531, found 358.1527.
4-(3-azidopropoxy)-1,1-diphenylbut-2-yn-1-ol（5）
To a stirred solution of 3-(prop-2-yn-1-ylthio)propan-1-ol (0.680g，5.22mmol) and
TsCl (1.19 g，6.27 mmol) in dichloromethane (10 ml) was added triethylamine (1.44
mL，18.28 mmol) at 0 °C, then reaction mixture was allowed to warm up to ambient
temperature. After 2 h, the mixture was diluted with ethyl acetate and was washed
with water and brine. Drying collected organic layer over MgSO4 followed by silica
gel column chromatography (ethyl acetate/ Petroleum ether= 1/25 to 1/10) gave
tosylate compound 17 (1.17 g, 79%) as a colorless oil.
Colorless oil; Rf value 0.42(ethyl acetate/ Petroleum ether= 1/5); 1H NMR (400 MHz,
CDCl3) δ 7.79(d, 2H , J = 8.4 Hz), 7.35 (d, 2H, J = 8.4 Hz), 4.15 (t, 2H, J = 6.4 Hz),
3.18 (s, 2H), 2.73 (t, 2H, J = 6.0 Hz), 2.45 (s, 3H), 2.22 (s, 1H), 1.96 (tt, 2H, J = 6.0,
13
6.0 Hz); C NMR (100 MHz, CDCl3) δ 144.8, 132.8, 129.8, 127.8, 79.5, 71.2, 68.6,
28.1, 27.3, 21.6, 19.0; HRMS (ESI) calcd for C13H17O3S2 [M+H]+ 285.0619, found
285.0619.
The reaction with tosylate 17 (0.594g，2.09mmol), n-BuLi (1.60 M in hexane, 1.41mL，
2.25mmol) and ketone (0.293g，1.61mmol) in THF (16 mL) followed by collected the
organic layer under vacuum affording the product 0.69g.
Then the crude benzyl alcohol with sodium azide (0.155g, 3.06mmol) in DMF (5 ml)
followed by silica gel column chromatography (ethyl acetate/ petroleum ether= 10/1
to 5/1) gave azide 5 (0.320 g, 64%) as a colorless oil.
Rf value 0.40(ethyl acetate/petroleum ether = 1/5); 1H NMR (400 MHz, CDCl3) δ
7.59 (d, 4H, J = 7.6 Hz ), 7.33 (dd, 4H, J = 7.2, 7.6 Hz), 7.28 (d, 2H, J = 7.2 Hz), 3.42
(s, 2H), 3.35 (t, 2H, J = 6.4 Hz), 2.74 (t, 2H, J = 6.8 Hz), 1.86 (tt, 2H, J = 6.8, 6.4 Hz)；
13C NMR (100 MHz, CDCl3) δ 144.9, 128.2, 127.7, 125.9, 86.0, 83.3, 74.4, 49.9, 28.7,
28.2, 19.7；HRMS (ESI) calcd for C19H20N3OS [M+H]+338.1327, found 338.1325.
9 / 42

pent-4-yn-1-yl 4-methylbenzenesulfonate
To a stirred solution of 4-pentyn-1-ol 1 (100.0 mg, 1.19 mmol) and TsCl (249.3 mg,
1.31 mmol) in dichloromethane (12 ml) was added dropwise triethylamine (0.2 mL,
1.43 mmol) at 0 °C, then reaction mixture was allowed to warm up to ambient
temperature. After 2 h, the mixture was diluted with ethyl acetate and was washed
with water and brine. Drying collected organic layer over MgSO4 followed by silica
gel column chromatography (ethyl acetate / hexane = 1/10) gave tosylate (220 mg,
77.7%) as a colorless oil.
Colorless oil; Rf value 0.53(ethyl acetate / hexane = 1/3);IR (NaCl, neat) νmax = 3291,
2962, 1598, 1360, 1176 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.79 (d, 2H, J = 8.5 Hz),
7.35 (d, 2H, J = 8.5 Hz), 4.14 (t, 2H, J = 6.0 Hz), 2.45 (s, 3H), 2.25 (td, 2H, J = 6.5,
2.5 Hz), 1.88 (t, 1H, J = 2.5 Hz), 1.86 (tt, 2H, J = 6.5, 6.0 Hz); 13C NMR (126 MHz,
CDCl3) δ 144.8, 132.9, 129.8, 127.9, 82.1, 69.4, 68.7, 27.7, 21.6, 14.7; HRMS (ESI)
calcd for C12H14O3SNa [M+Na]+ 261.0561, found 261.0561.
1,11-diazido-6-phenylundeca-4,7-diyn-6-ol(7a)
The reaction with pent-4-yn-1-yl 4-methylbenzenesulfonate (1.19 g, 4.98 mmol),
n-BuLi (1.55 M in hexane, 3.49 mL, 5.23 mmol) and chloride (0.35 g, 2.49 mmol) in
THF (25 mL) followed by followed by collected the organic layer under vacuum
affording the crude product 2.89 g. The crude product can be used to the next step
without further purification.
Then the crude benzyl alcohol with sodium azide (388.5 mg, 5.98 mmol) in DMF (25
ml) followed by silica gel column chromatography (ethyl acetate / hexane = 1/20 to
1/10 to 1/2) gave azide 7a (0.724 g, 90%) as a colorless oil.
Colorless oil; Rf value 0.51(ethyl acetate/hexane = 1/2); IR (NaCl, neat) νmax 3398,
2935, 2099, 1449, 1255 cm-1; 1H NMR(500 MHz, CDCl3) δ 7.76(m, 2H),
7.35–7.41(m, 3H), 3.41(t, 4H, J = 7.0 Hz), 2.86(m, 1H, OH), 2.42(t, 4H, J = 7.0 Hz),
1.82(tt, 4H, J = 7.0, 7.0 Hz); 13C NMR(126 MHz, CDCl3) δ 142.4, 128.5, 128.4, 125.6,
83.9, 82.0, 65.0, 50.1, 27.5, 16.1; HRMS (ESI) calcd for C17H18N6ONa [M+Na]+
345.1440, found 345.1436.
1,11-diazido-6-pentylundeca-4,7-diyn-6-ol(7b)
The reaction with pent-4-yn-1-yl 4-methylbenzenesulfonate (0.915 g, 3.84 mmol),
n-BuLi (1.55 M in hexane, 2.8 mL, 4.22 mmol) and ester (0.25 g, 1.92 mmol) in THF
10 / 42

(20 mL) followed by followed by collected the organic layer under vacuum affording
the crude product 1.10 g. The crude product can be used to the next step without
further purification.
Then the crude benzyl alcohol with sodium azide (299.6 mg, 4.61 mmol) in DMF (38
ml) followed by silica gel column chromatography (ethyl acetate / hexane = 1/15 to
1/5 to 1/1) gave azide 7b (0.521 g, 86%) as a colorless oil.
Colorless oil; Rf value 0.45(ethyl acetate/hexane = 1/2); IR (NaCl, neat) νmax 3420,
2930, 2098, 1254 cm-1; 1H NMR(500 MHz, CDCl3) δ 3.40(t, 4H, J = 7.0 Hz), 2.45(s,
1H, OH), 2.35(t, 4H, J = 7.0 Hz), 1.84–1.76(m, 6H), 1.57–1.51(m, 2H), 1.36–1.31(m,
4H), 0.90(t, 3H, J = 7.0 Hz); 13C NMR(126 MHz, CDCl3) δ 82.2, 81.9, 63.7, 50.1,
44.1, 31.4, 27.5, 24.3, 22.5, 16.0, 14.0; HRMS (ESI) calcd for C16H24N6ONa
[M+Na]+ 339.1909, found 339.1901.
5,5-bis(azidomethyl)-1,1,9,9-tetraphenylnona-2,7-diyne-1,9-diol (13)
To a stirred solution of azide compound 121 (0.044 g, 0.218 mmol) in dry THF (5.5
mL)under an atmosphere of nitrogen was added dropwise n-BuLi (1.60 M in hexane,
0.326 mL, 0.522 mmol) at -78 °C and the mixture was stirred for 30 min. Ketone
(0.099 g, 0.544 mmol) was then added at same temperature. After 4h, the reaction was
quenched with water. The mixture was diluted with ethyl acetate and was washed with
water and brine. Drying collected organic layer over MgSO4followed by silica gel
column chromatography gave 13 (112.9 mg, 92%) as colorless oil. [silica gel
purification (ethyl acetate / hexane = 1 / 40 to 1/20 to 1/10)].
Colorless oil; Rf value 0.45(ethyl acetate/hexane = 1/5); 1H NMR(400 MHz, CDCl3) δ
7.57(d, 8H, J = 7.2 Hz), 7.32(dd, 8H, J = 6.8, 7.2 Hz), 7.28–7.25(m, 4H), 3.37 (s, 4H),
2.82(s, 2H), 2.47(s, 4H); 13C NMR(100 MHz, CDCl3) δ 144.9, 128.3, 127.8, 125.8,
86.9, 82.5, 74.5, 54.4, 42.5, 23.7; HRMS (EI) calcd for C35H30N6O2 [M+] 566.2430,
found 566.2434.
General Experimental Procedure of triazolations
To the mixture of propargyl alcohol (1.0 equiv) in dichloromethane (0.1 M to alcohols)
under nitrogen atmosphere, acid (1.2 equiv) was added at ambient temperature. After
30 minutes, the reaction was quenched with saturated sodium bicarbonate aqueous
solution, and was washed with brine. Drying the organic layer over magnesium
sulfate followed by concentration in vacuo and silica gel column chromatography
afforded triazole.
11 / 42

Diphenyl(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol (2a).
To the mixture of azido-propargyl alcohol 1a (47.0 mg, 0.154 mmol) in
dichloromethane (2 mL) under nitrogen atmosphere, TFA (38.5 µL, 0.173 mmol, 1.2
equiv) was added at ambient temperature. After 30 minutes, the reaction was
quenched with saturated sodium bicarbonate aqueous solution, and was washed with
brine. Drying the organic layer over magnesium sulfate followed by concentration in
vacuo and silica gel column chromatography afforded triazole (ethyl acetate/
petroleum ether = 1/4 to 1/1) afforded 2a (44.1mg, 94%).
Colorless oil; Rf value 0.22 (ethyl acetate/petroleum ether = 1/2); 1H NMR(500 MHz,
CDCl3) δ 7.32–7.28(m, 10H), 4.34(t, 2H, J = 6.0 Hz), 4.28(br, 1H, OH), 2.00(t, 2H, J
= 7.0 Hz), 1.93(m, 2H), 1.67(m, 2H); 13C NMR(126 MHz, CDCl3) δ 147.7, 145.2,
131.0, 127.9, 127.7, 127.5, 77.4, 46.6, 22.2, 20.6, 19.9; HRMS (ESI) calcd for
C19H19N3ONa [M+Na]+ 328.1426, found 328.1426.
(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)diphenylmethanol (2b).
The reaction with propargyl alcohol (57.2mg, 0.196mmol) and TFA (0.015mL, 0.236
mmol) in dichloromethane (2 ml) followed by silica gel column purification (ethyl
acetate/ petroleum ether = 1/5) afforded triazole 3c (56.1mg, 98%).
1
White crystal; Rf value 0.10 (EtOAc/petroleum ether = 1/2); H NMR (500 MHz,
CDCl3) δ 7.34–7.25 (m, 10H), 4.24 (t, 2H, J = 7.5 Hz), 4.19 (br-s, 1H, OH), 2.56 (tt,
13
2H, J = 7.5, 7.5 Hz), 2.07 (t, 2H, J = 7.5 Hz); C NMR (126 MHz, CDCl3) δ 145.5,
145.1, 140.2, 127.8, 127.34, 127.29, 76.6, 46.2, 27.9, 20.8; HRMS (ESI) calcd for
C18H17N3ONa [M+Na]+ 314.1269, found 314.1267.
diphenyl(5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[1,5-a]azepin-3-yl)methanol (2c)
The reaction with propargyl alcohol (67.7mg, 0.212mmol) and TFA (0.016mL, 0.254
mmol) in dichloromethane (2 ml) followed by silica gel column purification (ethyl
acetate/ petroleum ether = 1/20 ) afforded triazole 2c (58.4mg, 86%).
White solid; Rf value 0.37 (ethyl acetate/ petroleum ether= 1/10);1H NMR (400 MHz,
CDCl3) δ 7.41-7.29 (m, 8H), 7.21-7.19 (m, 2H), 6.58 (s, 1H), 3.20 (t, 2H, J = 6.8 Hz),
2.24 (t, 2H, J = 6.8 Hz), 1.53-1.45(m, 4H), 1.23-1.18(m, 2H); 13C NMR (100 MHz,
CDCl3) δ 141.0, 139.0, 129.5, 128.4, 128.3, 126.6, 77.2, 51.2, 42.8, 28.6, 26.2, 23.7;
12 / 42

HRMS (ESI) calcd for C20H21N3ONa [M+Na]+ 342.1582, found 342.1582.
(4,5,6,7,8,9-hexahydro-[1,2,3]triazolo[1,5-a]azocin-3-yl)diphenylmethanol (2d)
The reaction with propargyl alcohol (55.1mg, 0.165mmol) and TFA (0.013mL, 0.198
mmol) in dichloromethane (2 ml) followed by silica gel column purification (ethyl
acetate/ petroleum ether = 1/20 ) afforded triazole 3d (46.8mg, 84%).
White solid; Rf value 0.4 (ethyl acetate/ petroleum ether= 1/10);1H NMR (400 MHz,
CDCl3) δ 7.41-7.29 (m, 8H), 7.21-7.19 (m, 2H), 6.58 (s, 1H), 3.22 (t, 2H, J = 6.8 Hz),
2.23 (t, 2H, J = 6.8 Hz), 1.57-1.46(m, 4H), 1.30-1.23(m, 2H), 1.21-1.13 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 141.0, 139.0, 129.5, 128.4, 128.3, 126.6, 77.2, 51.3, 42.9,
28.59, 28.57, 26.4, 24.0; HRMS (ESI) calcd for C21H23N3ONa [M+Na]+ 356.1739,
found 356.1747.
(5,6,7,8,9,10,11,12-octahydro-4H-[1,2,3]triazolo[1,5-a][1]azacycloundecin-3-yl)di
phenylmethanol (2e)
The reaction with propargyl alcohol (48.7mg, 0.130mmol) and TFA (0.010mL, 0.156
mmol) in dichloromethane (2 ml) followed by silica gel column purification (ethyl
acetate/ petroleum ether = 1/10 ) afforded triazole 2e (35.6mg, 73%).
White solid; Rf value 0.45 (ethyl acetate/ petroleum ether= 1/10);1H NMR (400 MHz,
CDCl3) δ 7.40-7.28 (m, 8H), 7.20-7.19 (m, 2H), 6.58 (s, 1H), 3.25 (t, 2H, J = 6.8 Hz),
2.23 (t, 2H, J = 6.8 Hz), 1.61-1.54(m, 2H), 1.52-1.45(m, 2H), 1.35-1.31 (m, 10H); 13C
NMR (100 MHz, CDCl3) δ 141.0, 139.0, 129.5, 128.4, 128.2, 126.6, 77.2, 51.4, 43.2,
29.22, 29.18, 29.1, 29.0, 28.8, 26.6, 24.3; HRMS (ESI) calcd for C24H30N3O [M+H]+
376.2389, found 376.2388.
(5-(azidomethyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)diphenylmetha
nol (2f)
The reaction with propargyl alcohol (56.7mg, 0.164mmol) and TFA (0.015mL, 0.196
mmol) in dichloromethane (2 ml) followed by silica gel column purification (ethyl
acetate/ petroleum ether = 1/10 to 1/5 to 1/1) afforded triazole 2f (56.7mg, 85%).
White solid; Rf value 0.38 (ethyl acetate/ petroleum ether= 1/1);1H NMR (400 MHz,
CDCl3) δ 7.32 (s, 10H), 4.44 (dd, 1H, J = 8.4, 12.0 Hz), 4.12 (dd, 1H, J = 8.4, 12.0
Hz), 3.49-3.38(m, 2H), 3.24-3.17(m, 1H), 2.20 (dd, 1H, J = 8.4, 12.0 Hz), 1.92 (dd,
13 / 42

1H, J = 8.4, 12.0 Hz); 13C NMR (100 MHz, CDCl3) δ 145.6, 145.2, 138.9, 128.0,
127.6, 127.3, 76.6, 53.5, 49.5, 42.3, 25.0; HRMS (ESI) calcd for C19H19N6O [M+H]+
347.1620, found 347.1627.
(6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl)diphenylmethanol (4a)
The reaction with propargyl alcohol (60.0mg, 0.195mmol) and BF3·OEt2 (0.029mL,
0.234mmol) in dichloromethane (2 ml) followed by silica gel column purification
(ethyl acetate/ petroleum ether = 1/15 to 1/2 to 1/1) afforded triazole 4a (59.2mg,
99%).
White solid; Rf value 0.25(ethyl acetate/ petroleum ether= 1/2);1H NMR (400 MHz,
CDCl3) δ 7.31 (s, 10H), 4.35 (t, 2H, J = 4.2 Hz), 4.12 (s, 2H), 3.99 (s, 1H), 3.93 (t, 2H,
J = 4.2 Hz); 13C NMR (100 MHz, CDCl3) δ 146.9, 145.1, 134.5, 128.1, 127.8, 127.4,
77.2, 63.0, 62.5, 45.7; HRMS (ESI) calcd for C18H18N3O2 [M+H]+ 308.1399, found
308.1402.
diphenyl(4,6,7,8-tetrahydro-[1,2,3]triazolo[5,1-c][1,4]oxazepin-3-yl)methanol
(4b)
The reaction with propargyl alcohol (100.0mg, 0.311mmol) and BF3·OEt2 (0.046mL,
0.373 mmol) in dichloromethane (4 ml) followed by silica gel column purification
(ethyl acetate/ petroleum ether = 1/5 to 1/2 to 1/1) afforded triazole 4b (92.2mg,
92%).
White solid; Rf value 0.18 (ethyl acetate/ petroleum ether= 1/2);1H NMR (400 MHz,
CDCl3) δ 7.34-7.29 (m, 10H), 4.65 (t, 2H, J = 4.2 Hz), 4.08 (s, 2H), 4.03 (s, 1H), 3.95
(t, 2H, J = 4.2 Hz), 2.03 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 150.1, 145.0, 134.2,
128.1, 127.8, 127.6, 77.6, 73.6, 62.1, 50.3, 29.0; HRMS (ESI) calcd for C19H20N3O2
[M+H]+ 322.1556, found 322.1562.
diphenyl(6,7,8,9-tetrahydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazocin-3-yl)methanol
(4c)
The reaction with propargyl alcohol (45.0mg, 0.134mmol) and BF3·OEt2 (0.020mL,
0.349 mmol) in dichloromethane (4 ml) followed by silica gel column purification
(ethyl acetate/ petroleum ether = 1/5 to 1/2 to 1/1) afforded triazole 4c (38.4 mg,
14 / 42

85%).
White solid; Rf value 0.25 (ethyl acetate/ petroleum ether= 1/2);1H NMR (400 MHz,
CDCl3) δ 7.34-7.28 (m, 10H), 4.81 (t, 2H, J = 4.2 Hz), 4.10 (s, 2H), 3.65 (t, 2H, J =
4.2 Hz), 1.98 (tt, 2H, J = 4.2, 4.2 Hz), 1.52 (tt, 2H, J = 4.2, 4.2 Hz); 13C NMR (100
MHz, CDCl3) δ 148.0, 144.9, 134.8, 128.2, 127.9, 127.7, 71.7, 63.4, 49.7, 29.7, 27.5,
24.5; HRMS (ESI) calcd for C20H22N3O2 [M+H]+ 336.1712, found 336.1712.
diphenyl(4,6,7,8-tetrahydro-[1,2,3]triazolo[5,1-c][1,4]thiazepin-3-yl)methanol(6)
The reaction with propargyl alcohol (98.0mg, 0.290mmol) and BF3·OEt2 (0.043mL,
0.349 mmol) in dichloromethane (4 ml) followed by silica gel column purification
(ethyl acetate/ petroleum ether = 1/5 to 1/2 to 1/1) afforded triazole 6 (74.6mg, 76%).
White crystal; Rf value 0.28 (ethyl acetate/petroleum ether = 1/1);1H NMR (400 MHz,
CDCl3) δ 7.35–7.28 (m, 10H), 4.57 (t, 2H, J = 4.8 Hz), 3.12 (s, 2H), 2.92–2.89 (m,
2H), 2.17–2.12 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 148.5, 144.8, 136.0, 128.1,
127.8, 127.7, 77.5, 50.5, 34.3, 28.8, 23.9; HRMS (ESI) calcd for C19H20N3OS [M+H]+
338.1327, found 338.1320.
bis(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)(phenyl)methanol(8a)
The reaction with propargyl alcohol (117.6 mg, 0.372 mmol) and TsOH·H2O (83.3mg,
0.438 mmol) in dichloromethane (4 ml) followed by silica gel column purification
(ethyl acetate/hexane
=
1/5 to 1/2 to 1/1 to ethyl acetate then
methaol/dichloromethane = 1/30 to 1/20 to 1/10) afforded triazole 8a (100.8mg,
86%).
1
White crystal; Rf value 0.14(dichloromethane/methanol = 10/1); H NMR(500 MHz,
CDCl3) δ 7.57–7.55 (m, 2H), 7.31–7.28 (m, 2H), 7.25–7.22 (m, 1H), 5.72(s, 1H, OH),
4.30–4.19 (m, 4H), 2.64–2.43 (m, 8H); 13C NMR(126 MHz, CDCl3) δ 144.8, 143.9,
140.2, 127.9, 127.4, 126.3, 71.9, 46.3, 27.9, 21.3; HRMS (ESI) calcd for
C17H18N6ONa [M+Na]+ 345.1440, found 345.1430.
1,1-bis(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)hexan-1-ol(8b)
15 / 42

The reaction with propargyl alcohol 8b (127.1 mg, 0.402 mmol) and TMSOTf (0.087
mL, 0.482 mmol) in dichloromethane (4 ml) followed by silica gel column
purification (ethyl acetate/hexane = 1/5 to 1/2 to 1/1 to ethyl acetate then
methaol/dichloromethane = 1/30 to 1/20 to 1/10) afforded triazole 8b (92.1mg, 72%).
1
White crystal; Rf value 0.1(methaol/dichloromethane = 1/20); H NMR(500 MHz,
CDCl3) δ 4.31 (s, 1H, OH), 4.24 (t, 4H, J = 7.5 Hz), 2.98–2.87 (m, 4H), 2.71 (tt, 4H, J
13
= 7.5, 7.5 Hz), 2.21–2.17 (m, 2H), 1.30–1.23 (m, 6H), 0.81–0.79 (m, 3H); C
NMR(126 MHz, CDCl3) δ 144.7, 138.9, 71.3, 46.3, 41.4, 31.8, 28.1, 22.9, 22.5, 21.6,
14.0; HRMS (ESI) calcd for C16H24N6ONa [M+Na]+ 339.1909, found 339.1903.
(4,4',6,6'-tetrahydro-5,5'-spirobi[pyrrolo[1,2-c][1,2,3]triazole]-3,3'-diyl)bis(diphe
nylmethanol) (14)
To the mixture of propargyl alcohol 13 (26.6 mg, 0.047 mmol) in dichloromethane (1
ml), TsOH·H2O (22.6 mg, 0.117 mmol) was added at ambient temperature. After 30
minutes, the reaction was quenched with saturated sodium bicarbonate aqueous
solution, and was washed with brine, followed by silica gel column purification
(MeOH/CH2Cl2 = 1/80 to 1/60 to 1/40 to 1/30) afforded triazole 14 (26.0 mg, 98%).
1
White solid; Rf value 0.36(MeOH/CH2Cl2 = 1/20); H NMR(400 MHz, CDCl3) δ
7.32–7.27(m, 20H), 4.34(d, 2H, J = 12.0 Hz), 4.20 (d, 2H, J = 12.0 Hz), 2.29(d, 2H, J
= 16.4 Hz), 2.07(d, 2H, J = 16.4 Hz); 13C NMR(100 MHz, DMSO) δ 146.9, 146.3,
138.3, 127.6, 127.0, 126.7, 75.7, 60.1, 55.8, 34.7; HRMS (ESI) calcd for
C35H30N6O2Na [M+Na]+ 589.2328, found 589.2326.
References
1. Y. Yoshida, S. Takizawa, and H. Sasai, Tetrahedron:Asymmetry, 2012, 23, 843.
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