The Journal of Organic Chemistry
Page 8 of 11
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Methyl
1-(1-phenylheptan-3-yl)-5-(4-nitrophenyl)-1,2,3-
purified by silica gel column chromatography (0% to 40% ethyl
acetate in hexanes) to give 42.8 mg (85.2%) of T13 as a colorless
liquid.
triazole-4-carboxylate and methyl 1-(1-phenylheptan-3-yl)-4-
(4-nitrophenyl)-1,2,3-triazole-5-carboxylate, T11a and T11b
Methyl 4-nitrophenylpropiolate (26.8 mg, 0.131 mmol) and 3-
azido-1-phenylheptane (41.2 mg, 0.190 mmol) were dissolved in
2 mL of CH3CN and heated to 75 oC for 10 days. The mixture was
purified by silica gel column chromatography (0% to 40% ethyl
acetate in hexanes) to give 35.1 mg (63.4%) of total product, 12.9
mg of T11a, 22.2 mg of T11b as colorless liquids.
T13
Colorless liquid. Rf = 0.33 (4:1 hexanes:ethyl acetate, UV); 1H
NMR (500 MHz, CDCl3): δ = 7.26 (t, J = 7.4 Hz, 2H), 7.19 (t, J =
7.4 Hz, 1H), 7.08 (d, J = 7.4 Hz, 2H), 4.75 (tt, J = 9.6, 4.9 Hz, 1H),
3.98 (s, 3H), 3.94 (s, 3H), 2.53 (m, 1H), 2.47 (m, 2H), 2.22 (m,
1H), 2.11 (m, 1H), 1.91 (m, 1H), 1.26 (m, 2H), 1.21 (m, 1H), 1.04
(m, 1H), 0.84 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} and DEPT NMR
(126 MHz, CDCl3): δ = 160.6(C), 159.4(C), 140.2(C), 138.9(C),
131.6(C), 128.5(CH), 128.3(CH), 126.2(CH), 61.8(CH),
53.4(CH3), 52.6(CH3), 36.5(CH2), 35.2(CH2), 32.0(CH2),
27.8(CH2), 22.1(CH2), 13.8(CH3) ppm; IR (NaCl, CDCl3): ν = 1737
cm-1; HRMS (ESI): m/z calcd for C19H26N3O4 [M+H]+ 360.1913,
found 360.1925.
T11a (regioisomer not identified)
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Colorless liquid. Rf = 0.48 (4:1 hexanes:ethyl acetate, UV); 1H
NMR (500 MHz, CDCl3): δ = 8.33 (d, J = 8.8 Hz, 2H), 7.94 (d, J =
8.8 Hz, 2H), 7.27 (t, J = 7.3 Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H), 7.11
(d, J = 7.3 Hz, 2H), 5.20 (tt, J = 9.5, 4.9 Hz, 1H), 3.83 (s, 3H), 2.61
(m, 1H), 2.56 (m, 2H), 2.31 (m, 1H), 2.20 (m, 1H), 1.99 (m, 1H),
1.31 (m, 3H), 1.12 (m, 1H), 0.88 (t, J = 7.1 Hz, 3H) ppm; 13C{1H}
and DEPT NMR (126 MHz, CDCl3): δ = 159.5(C), 147.9(C),
147.2(C), 140.4(C), 136.9(C), 130.1(CH), 128.5(CH), 128.3(CH),
126.2(CH), 126.0(C), 123.3(CH), 61.6(CH), 52.6(CH3), 36.5(CH2),
35.6(CH2), 32.2(CH2), 28.0(CH2), 22.3(CH2), 13.9(CH3) ppm; IR
(NaCl, CDCl3): ν = 1728, 1524, 1349 cm-1; HRMS (ESI): m/z calcd
for C23H27N4O4 [M+H]+ 423.2027, found 423.2016.
Methyl
1-(1-phenylheptan-3-yl)-4-phenylsulfonyl-1,2,3-
triazole-5-carboxylate and methyl 1-(1-phenylheptan-3-yl)-5-
phenylsulfonyl-1,2,3-triazole-4-carboxylate, T14a and T14b
Methyl phenylsulfonylpropiolate (32.3 mg, 0.144 mmol) and 3-
azido-1-phenylheptane (49.4 mg, 0.227 mmol) were dissolved in
2 mL of CH3CN and heated to 75 oC for 5h. Attempts to separate
the regioisomers by column chromatography were unsuccessful,
but produced 27.8 mg (43.6%) of total product as a colorless liquid
(2.2 : 1 ratio of isomers by 1HNMR). Rf = 0.43, 0.38 (4:1
hexanes:ethyl acetate, UV); 1H NMR of major regioisomer (500
MHz, CDCl3): δ = 8.13 (d, J = 7.7 Hz, 2H), 7.70 (t, J = 7.7 Hz, 1H),
7.62 (t, J = 7.7 Hz, 2H), 7.22 ( t, J = 7.3 Hz, 2H), 7.17 (t, J = 7.3
Hz, 1H), 7.02 (d, J = 7.3 Hz, 2H), 4.91 (tt, J = 9.3, 5.0 Hz, 1H),
3.98 (s, 1H), 2.46 (m, 3H), 2.26 (m, 1H), 2.06 (m, 1H), 1.93 (m,
1H), 1.23 (m, 3H), 1.01 (m, 1H), 0.84 (t, J = 7.1 Hz, 3H) ppm; 1H
NMR of minor regioisomer (500 MHz, CDCl3): δ = 8.13 (d, J = 7.8
Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 2H), 7.29 (t,
J = 7.4 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.4 Hz, 2H),
5.30 (tt, J = 8.3, 5.1 Hz, 1H), 4.01 (s, 3H), 2.46 (m, 2H), 2.26 (m,
2H), 2.06 (m, 1H), 1.93 (m, 1H), 1.23 (m, 2H), 1.09 (m, 1H), 0.90
(m, 1H), 0.80 (t, J = 7.3 Hz, 3H) ppm; 13C{1H} and DEPT NMR of
major regioisomer (126 MHz, CDCl3): δ = 157.9(C), 148.3(C),
139.9(C), 139.66(C), 134.1(CH), 129.1(CH), 128.7(CH),
128.50(CH), 128.17(CH), 126.26(CH), 62.3(CH), 53.6(CH3),
36.1(CH2), 35.3(CH2), 32.0(CH2), 27.8(CH2), 22.2(CH2),
13.74(CH3) ppm; 13C{1H} and DEPT NMR of minor regioisomer
(126 MHz, CDCl3): δ = 160.3(C), 140.3(C), 139.61(C), 137.7(C),
134.9(CH), 129.5(CH), 129.3(C), 128.52(CH), 128.4(CH),
128.23(CH), 126.24(CH), 62.7(CH), 53.2(CH3), 37.2(CH2),
35.4(CH2), 32.1(CH2), 27.9(CH2), 22.3(CH2), 13.77(CH3) ppm; IR
(NaCl, CDCl3): ν = 1741, 1334, 1163 cm-1; HRMS (ESI): m/z calcd
for C23H28N3SO4 [M+H]+ 442.1795, found 442.1780.
T11b (regioisomer not identified)
Colorless liquid. Rf = 0.30 (4:1 hexanes:ethyl acetate, UV); 1H
NMR (500 MHz, CDCl3): δ = 8.26 (d, J = 8.7 Hz, 2H), 7.32 (d, J =
8.7 Hz, 2H), 7.28 – 7.21 (m, 3H), 7.04 (d, J = 6.8 Hz, 2H), 4.08 (tt,
J = 9.4, 5.3 Hz, 1H), 3.87 (s, 3H), 2.49 (m, 3H), 2.32 (m, 1H), 2.11
(m, 1H), 1.91 (m, 1H), 1.18 (m, 2H), 1.03 (m, 2H) 0.83 (t, J = 7.3
Hz, 1H) ppm; 13C{1H} and DEPT NMR (126 MHz, CDCl3): δ =
161.2(C), 148.6(C), 139.8(C), 132.8(C), 131.1(CH), 128.7(CH),
128.2(CH), 126.5(CH), 123.7(CH), 59.4(CH), 52.2(CH3),
36.4(CH2), 35.0(CH2), 31.9(CH2), 28.1(CH2), 22.2(CH2),
13.7(CH3) ppm; IR (NaCl, CDCl3): ν = 1728, 1528, 1350 cm-1;
HRMS (ESI): m/z calcd for C23H27N4O4 [M+H]+ 423.2027, found
423.2014.
Methyl
and
1-(1-phenylheptan-3yl)-1,2,3-triazole-4-carboxylate
methyl 1-(1-phenylheptan-3-yl)-1,2,3-triazole-5-
carboxylate, T12a and T12b
Methyl propiolate (21.8 mg, 0.259 mmol) and 3-azido-1-
phenylheptane (36.3 mg, 0.167 mmol) were dissolved in 2 mL of
CH3CN and heated to 75 oC for 36 h. The mixture was purified by
silica gel column chromatography (0% to 40% ethyl acetate in
hexanes) to give 26.3 mg (52.2%) of total product: 4.2 mg of T12a,
22.1 mg of T12b as colorless liquids.
T12a (regioisomer not identified)
Colorless liquid. Rf = 0.50 (4:1 hexanes:ethyl acetate, UV); 1H
NMR (500 MHz, CDCl3): δ = 8.15 (s, 1H), 7.26 (t, J = 7.4 Hz, 2H),
7.19 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 7.4 Hz, 2H), 5.38 (tt, J = 9.5,
4.8 Hz, 1H), 3.91 (s, 3H), 2.49 (m, 3H), 2.24 (m, 1H), 2.15 (m, 1H),
1.94 (m, 1H), 1.29 (m, 2H), 1.24 (m, 1H), 1.03 (m, 1H) 0.85 (t, J =
7.2 Hz, 3H) ppm; 13C{1H} and DEPT NMR (126 MHz, CDCl3): δ =
159.1(C), 140.7(C), 137.7(CH), 128.4(CH), 128.3(CH),
126.1(CH), 60.7(CH), 52.3(CH3), 36.8(CH2), 35.5(CH2),
32.2(CH2), 27.9(CH2), 22.3(CH2), 13.8(CH3) ppm; IR (NaCl,
CDCl3): ν = 1735 cm-1; HRMS (ESI): m/z calcd for C17H24N3O2
[M+H]+ 302.1858, found 302.1857.
Room temperature cycloaddition
Methyl 3-(phenylsulfonyl)-2-propynoate (41.7 mg, 0.186 mmol)
and t-butylbenzyl azide (31.4 mg, 0.166 mmol) were combined in
0.6 mL CD3CN at room temperature. At time zero, the azide :
alkyne ratio was 1.0 : 0.68 based on integrations of azide CH2Ar
(δ = 4.36, I = 2.00), sulfone OCH3 (δ = 3.82, I = 2.04). After 5 hours,
92% of the alkyne had been converted to triazole, based on
integrations of T10a OCH3 (δ = 3.93, I = 1.90), T10b OCH3 (δ =
3.91, I = 1.40), and 10 OCH3 (δ = 3.82, I = 0.29).
T12b (regioisomer not identified)
Colorless liquid. Rf = 0.24 (4:1 hexanes:ethyl acetate, UV); 1H
NMR (500 MHz, CDCl3): δ = 8.05 (s, 1H), 7.28 (t, J = 7.3 Hz, 2H),
7.21 (t, J = 7.3 Hz, 1H), 7.10 (d, J = 7.3 Hz, 2H), 4.53 (tt, J = 9.6,
5.0 Hz, 1H), 3.98 (s, 3H), 2.47 (m, 2H), 2.30 (m, 1H), 2.23 (m, 1H),
1.91 (m, 2H), 1.28 (m, 2H), 1.19 (m, 1H), 1.02 (m, 1H), 0.84 (t, J
= 7.2 Hz, 3H) ppm; 13C{1H} and DEPT NMR (126 MHz, CDCl3): δ
Competition Experiments with t-butylbenzyl azide:
A
representative procedure for the competition experiments is as
follows.
Amide (4) vs Nitroaryl (3)
=
161.3(C), 140.0(C), 128.6(CH), 128.3(CH), 126.3(CH),
N-butyl propiolamide (23 mg, 0.18 mmol), methyl 4-
nitrophenylpropiolate (37 mg, 0.18 mmol), and 4-t-butylbenzyl
azide (3.4 mg, 0.018 mmol) were combined in 0.60 mL of CD3CN
in an NMR tube. NMR of the initial solution revealed a ratio of
azide : amide : nitro of 1 : 8.3 : 9.9, based on integrations of azide
CH2Ar (δ = 4.35, I = 2.00), amide CH2NH (δ = 3.19, I = 17.98),
amide CCH (δ = 3.16, I = 6.84), and nitro OCH3 (δ = 3.84, I =
29.81).The reaction mixture was heated to 75 oC in an oil bath.
After 5 days, NMR confirmed all of the azide had been consumed.
126.2(CH), 62.1(CH), 52.2(CH3), 37.0(CH2), 35.4(CH2), 32.0(CH-
2), 27.9(CH2), 22.1(CH2), 13.8(CH3) ppm; IR (NaCl, CDCl3): ν =
1725 cm-1; HRMS (ESI): m/z calcd for C17H24N3O2 [M+H]+
302.1858, found 302.1859.
Dimethyl
dicarboxylate, T13
Dimethyl acetylenedicarboxylate (30.2 mg, 0.213 mmol) and 3-
azido-1-phenylheptane (30.4 mg, 0.140 mmol) were dissolved in
2 mL of CH3CN and heated to 75 oC for 24 h. The mixture was
1-(1-phenylheptan-3-yl)-1,2,3-triazole-4,5-
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