Triazoles Synthesized from Amines and Alkynes
solution of TfN3 in toluene (2.92 mL, 1.17 mmol). The reaction
mixture was shaken at room temperature for 5 h. Reaction progress
was monitored by LC-MS or Kaiser Test.31 The resin was filtered
and washed sequentially with dichloromethane, NMP, 0.02 M
sodium diethyldithiocarbamate trihydrate solution in NMP, NMP,
methanol, NMP, and dichloromethane. The resin was resuspended
in NMP (1 mL), and then Boc-Ala-alkyne (74 mg, 0.44 mmol)
was added followed by a suspension of TBTA (15 mg, 0.029
mmol), CuSO4‚5H2O (4 mg, 0.015 mmol), and sodium L-ascorbate
(87 mg, 0.44 mmol) in NMP/H2O (1 mL:0.1 mL). The reaction
mixture was shaken at room temperature for 18 h, and the reaction
was monitored by LC-MS. The resin was filtered and washed
sequentially with dichloromethane, NMP, 0.02 M sodium dieth-
yldithiocarbamate trihydrate solution in NMP, NMP, methanol,
NMP, and dichloromethane. The resin was treated with 30%
trifluoroacetic acid in dichloromethane for 1 h to remove the Boc
group. The diazotransfer step, the Huisgen 1,3-dipolar cycloaddition
step using the appropriate alkyne, deprotection step, and intermittent
washing steps were repeated as needed to complete the synthesis.
Cleavage of the final product from the resin was effected by
suspending the resin with 40% methylamine in H2O/THF, 1:1
solution for 2 h. The resin was filtered, and the filtrate was
concentrated under vacuum. A saturated aqueous solution of sodium
bicarbonate was added, and the mixture was extracted with
dichloromethane (five times). The combined organic layers were
dried over MgSO4, filtered, and concentrated under vacuum. The
residue was purified by column chromatography (5:95 methanol/
dichloromethane) to afford compound 9 as a white solid (62 mg,
78%). 1H NMR (400 MHz, d6-DMSO) δ 8.66 (s, 1H), 8.53 (q, J )
4.6 Hz, 1H), 8.29 (s, 0.5H), 8.28 (s, 0.5H), 8.26 (s, 2H), 7.85 (d,
J ) 7.2 Hz, 2H), 7.44 (t, J ) 7.6 Hz, 2H), 7.33 (t, J ) 7.4 Hz,
1H), 6.15-6.07 (m, 3H), 4.88 (d, J ) 10.3 Hz, 1H), 2.66 (d, J )
4.9 Hz, 1H), 2.62 (d, J ) 4.5 Hz, 2H), 2.42-2.32 (m, 1H), 1.93
(d, J ) 7.1 Hz, 3H), 1.86 (d, J ) 7.0 Hz, 6H), 0.92 (d, J ) 6.7 Hz,
3H), 0.61 (d, J ) 6.6 Hz, 3H); 13C NMR (100 MHz, d6-DMSO) δ
167.6, 146.4, 146.2, 130.7, 128.8, 127.8, 125.1, 121.8, 121.7, 121.6,
120.0, 69.1, 52.3, 31.0, 25.5, 20.4, 20.4, 18.8, 18.5; HRMS m/z for
C26H33N13O [M + H]+, calcd: 544.3010, found: 544.3013.
Synthesis of Triazolamer 8 (Table 3, entry 3). A procedure
analogous to that used for the synthesis of 9 was used for the
synthesis of 8. 1H NMR (400 MHz, d4-methanol) δ 8.08 (m, 1H),
7.97 (m, 1H), 7.62 (s, 1H), 7.07-7.04 (m, 6H), 6.96-6.88 (m,
4H), 6.09-6.05 (m, 1H), 5.98 (t, J ) 7.8 Hz, 1H), 5.27 (q, J ) 6.7
Hz, 1H), 4.72-4.68 (m, 1H), 3.54 (d, J ) 8.1 Hz, 2H), 3.49 (t, J
) 7.2 Hz, 2H), 2.65 (d, J ) 1.4 Hz, 3H), 1.65 (app dd, J ) 7.2,
2.2 Hz, 3H), 1.33-1.30 (m, 12H); 13C NMR (100 MHz, d4-
methanol) δ 210.4, 171.3, 146.5, 146.4, 137.5, 137.4, 130.2, 130.12,
130.09, 129.6, 129.57, 128.1, 128.0, 124.4, 124.0, 122.1, 80.3, 60.7,
60.5, 60.1, 42.0, 41.9, 29.9, 28.8, 26.6, 21.3, 18.4; HRMS m/z for
C33H41N11O3 [M + H]+, calcd: 640.3472, found: 640.3476.
Synthesis of Triazolamers 5, 6, and 7. Compounds 5, 6, and 7
were synthesized as indicated in Scheme 2. Synthetic characteriza-
tion of these compounds has been previously reported.6
1,3-dipolar cycloaddition step may also lead to premature
cleavage especially since this step is generally performed for
18 h. Using our optimized conditions, the average yields per
step in the synthesis were high (Table 3, entries 3 and 4). We
are using these optimized conditions to develop libraries of these
oligomers to fully examine their biological potential.
In conclusion, we have reported efficient solid- and solution-
phase syntheses of peptido-triazole oligomers in which each
amide bond in a peptide has been replaced with a triazole ring.
Although the methodology developed herein has been tuned
specifically for the synthesis of triazolamers, it may find general
application (e.g., for the synthesis of triazole-based dendrimers30)
as the use of these reactions becomes more widespread.
Experimental Section
General Procedure for Triazole Formation from an Amine
via in Situ Azide Generation (Synthesis of 3: Table 1, entry 7).
To a solution of H-Phe-OMe‚HCl (50 mg, 0.23 mmol) and ZnCl2
(3 mg, 0.023 mmol) in H2O, (5 mL) triethylamine (0.097 mL, 0.70
mmol), and methanol (16 mL) was added a solution of TfN3 in
dichloromethane (5 mL, 0.70 mmol) followed by 4-phenyl-1-butyne
(30 mg, 0.23 mmol), CuSO4‚5H2O (12 mg, 0.046 mmol), TBTA
(25 mg, 0.046 mmol), and sodium L-ascorbate (46 mg, 0.23 mmol).
The reaction mixture was stirred at room temperature for 18 h,
and a saturated aqueous solution of sodium bicarbonate was added.
The mixture was extracted with dichloromethane (four times), the
combined organic layers were dried over MgSO4, filtered, and
concentrated under vacuum. The residue was purified by column
chromatography (3:7 ethyl acetate/hexanes) to afford compound 3
as a light-yellow oil (23 mg, 30%). 1H NMR (400 MHz, d6-DMSO)
δ 7.91 (s, 1H), 7.27-7.22 (m, 2H), 7.21-7.16 (m, 6H), 7.12-
7.08 (m, 2H), 5.77 (dd, J ) 10.6, 5.2 Hz, 1H), 3.69 (s, 3H), 3.54
(dd, AB pattern, J ) 14.3, 5.2 Hz, 1H), 3.45 (dd, AB pattern, J )
14.2, 10.7 Hz, 1H), 2.88 (app s, 4H); 13C NMR (100 MHz, d6-
DMSO) δ 168.8, 146.0, 141.0, 135.9, 128.8, 128.31, 128.26, 128.18,
126.8, 125.9, 122.2, 62.8, 52.8, 36.6, 34.7, 26.9; HRMS m/z for
C20H22N3O2 [M + H]+, calcd: 336.1712, found: 336.1713.
General Procedure for Triazole Formation from an Amine
via One-Pot Sequential Diazotransfer and Huisgen 1,3-Dipolar
Cycloaddition (Synthesis of 3: Table 2, entry 1). To a solution
of H-Phe-OMe‚HCl (23 mg, 0.11 mmol) and ZnCl2 (1.5 mg, 0.011
mmol) in H2O (1 mL) and triethylamine (0.045 mL, 0.32 mmol)
was added a solution of TfN3 in dichloromethane (1.7 mL, 0.32
mmol) and methanol (3.5 mL). The reaction mixture was stirred at
room temperature for 1.5 h and monitored by thin layer chroma-
tography. A solution of TBTA (11 mg, 0.021 mmol) in dichlo-
romethane (0.5 mL) and a solution of sodium L-ascorbate (8.5 mg,
0.043 mmol) and CuSO4‚5H2O (5 mg, 0.021 mmol) in H2O (0.5
mL) were added to the mixture followed by 4-phenyl-1-butyne (14
mg, 0.11 mmol). The reaction mixture was subjected to microwave
irradiation at 80 °C for 5 min. A saturated aqueous solution of
sodium bicarbonate was added, and the mixture was extracted with
dichloromethane (four times). The combined organic layers were
dried over MgSO4, filtered, and concentrated under vacuum. The
residue was purified by column chromatography (2:8 ethyl acetate/
hexanes) to afford compound 3 as a white solid (33 mg, 93%).
Synthesis of Triazolamer 9 (Table 3, entry 4). PAM resin was
swelled in dichloromethane (1 mL) for 15 min, and a solution of
ZnCl2 (4 mg, 0.029 mmol), methanol (0.5 mL), and triethylamine
(0.081 mL, 0.58 mmol) was added, followed by a 0.4 mmol/mL
Acknowledgment. P.S.A. is grateful for financial support
from the Research Corporation (Cottrell Scholar Award) and
NYU (Whitehead Fellowship). We thank the NSF for equipment
Grants MRI-0116222 and CHE-0234863, and the NCRR/NIH
for Research Facilities Improvement Grant C06 RR-16572
Supporting Information Available: Copies of spectra of
compounds 3, 8, and 9. This material is available free of charge
JO701292H
(30) Wu, P.; Malkoch, M.; Hunt, J. N.; Vestberg, R.; Kaltgrad, E.; Finn,
M. G.; Fokin, V. V.; Sharpless, K. B.; Hawker, C. J. Chem. Commun. 2005,
5775-5777.
(31) Kaiser, E.; Colescot, R. L.; Bossinger, C. D.; Cook, P. I. Anal.
Biochem. 1970, 34, 595-598.
J. Org. Chem, Vol. 72, No. 21, 2007 7967