SCHEME 2. Click Reaction of Alkynoic Acids with Benzyl
Azide in Water
membered ring enol lactones under mild aqueous reaction
conditions employing inexpensive, off-the-shelf Cu(I) salts as
catalysts.
Experimental Section
General Procedure for the Cu(I)-Catalyzed Cyclization of
Alkynoic Acids in Aqueous Media. Alkynoic acid substrates (0.2
t
mmol) were dissolved in BuOH/H
1
1
2
O (1:1, 4 mL), and CuBr (5-
0 mol %) was added. The resulting mixture was stirred at rt for
2 h, diluted with water, and extracted with ethyl acetate. The
SO
protective groups of more pronounced electron-withdrawing
character yielded enol lactones which were too labile for
isolation from aqueous media. On the other hand, the presence
of unprotected or alkylated amines suppressed the cyclization
reaction of alkynoic acid substrates. This effect may be due to
unproductive complexation of the copper via the amino group
instead of the alkyne or carboxylate, a proposed mechanism
for the metal-catalyzed cyclizations of alkynoic acids to enol
organic layers were washed twice with brine, dried over Na
2
4
,
and evaporated under reduced pressure. The crude products were
purified by filtration through a short path of silica gel with
dichloromethane or ethyl acetate/acetic acid (0-1%)13 to yield enol
lactones or their hydrolysis products, respectively. The same
procedure was applied for the cyclizations of alkynoic acids in CH
3
-
CN but in the presence of 10 mol % of K CO
2
3
.
General Procedure for the Click Reaction of Alkynoic Acids
with Azides. Alkynoic acid derivatives (0.2 mmol) were dissolved
1
a
lactones. Indeed, addition of amines (5-20 mol % of ethyl-
enediamine or morpholine) to the reaction mixture completely
inhibited the intramolecular cyclization of alkynoic acids (e.g.,
BocPraOH 1a and 4-pentynoic acid 1c).26 These findings
provided an explanation to the observation that HPraOH 1f is
a good substrate for click chemistry despite the presence of an
t
in BuOH/H
2
O (1:1, 4.0 mL), and benzyl azide (2, 0.2 mmol), Cu-
(
OAc)
2
(10 mol %), and sodium ascorbate (20 mol %) were added.
The resulting mixture was stirred at rt over night, saturated with
NaCl, and extracted with ethyl acetate. The organic layers were
washed once with brine, dried over Na SO , and evaporated under
2
4
reduced pressure. The crude products were purified by flash
2
7
unprotected carboxylic acid functionality (Scheme 1).
chromatography on silica gel with CH
corresponding 1,2,3-triazole products.
2 2
Cl /MeOH to yield the
To demonstrate the general utility of alkynoic acids for click
chemistry applications, we investigated the reaction of benzyl
azide (2) with alkynoic acids of different chain length (Scheme
Triazole 3b: Colorless oil (yield 32%); IR (neat) ν 3148, 2944,
-
1 1
1
7
743, 1228, 1074, 723 cm ; H NMR (MeOH-d
4
) δ 7.83 (s, 1H),
.39-7.27 (m, 5H), 5.58 (s, 2H), 5.25 (dd, 1H, J ) 7.5 and 4.6
2
). Unlike 4-pentynoic acid and its derivatives (n ) 2, 1a-c;
Hz), 3.27 (dd, 1H, J ) 15.4 and 4.8 Hz), 3.23 (dd, 1H, J ) 15.4
Scheme 1), alkyne substrates 7-8, 1o, and 1q yielded the
corresponding 1,2,3-triazole products 9a-d in high yields by
Cu(I) catalysis in water.28
13
and 8.0 Hz), 2.03 (s, 3H) ppm; C NMR (MeOH-d
4
) δ 172.5,
1
72.0, 144.2, 137.0, 130.1, 129.7, 129.1, 124.9, 72.7, 55.0, 28.7,
+
20.6 ppm; HR-MS [M - H + 2Na] ) 334.0769 (calcd for
Na , 334.0780).
Triazole 3c: White solid (35%); mp 129-131 °C; IR (neat) ν
C
14
H
14
N O
3 4
2
In conclusion, the presented work reveals structural limitations
of acetylenic substrates for click chemistry applications. Some
alkynoic acids, in particular, 4-pentynoic acids, are unsuitable
click substrates because of competing intramolecular cyclizations
to enol lactones that occur under reaction conditions typically
applied for the Cu(I)-catalyzed Huisgen reaction. In general,
these limitations can be circumvented by using the correspond-
ing esters of alkynoic acid substrates; however, this requires
additional protection/deprotection steps. Of the 4-pentynoic acids
examined, only HPraOH 1f was an efficient click substrate
presumably because the amine present prevents the intramo-
lecular cyclization leading to enol lactones. In addition, our
investigations of the Cu(I)-promoted cyclization of alkynoic
acids have provided a simple protocol for the synthesis of five-
-1 1
3
d
2
371, 2927, 1715, 1339, 1207, 1067, 726 cm ; H NMR (DMSO-
6
) δ 12.16 (br s, 1H), 7.93 (s, 1H), 7.40-7.27 (m, 5H), 5.55 (s,
1
3
H), 2.88-2.79 (m, 2H), 2.65-2.56 (m, 2H) ppm; C NMR
) δ 173.7, 136.2, 128.7, 128.0, 127.8, 122.5, 52.6, 33.1,
(
2
DMSO-d
6
+
13 3 2
0.8 ppm; HR-MS [M + Na] ) 254.0899 (calcd for C12H N O -
Na, 254.0905).
Triazole 3d: White solid (96%); mp 79-81 °C; IR (neat) ν 3377,
-1
1
2
948, 1731, 1438, 1219, 1201, 1173, 1051, 721 cm ; H NMR
(MeOH-d ) δ 7.76 (s, 1H), 7.39-7.28 (m, 5H), 5.56 (s, 2H), 3.76
4
(t, 1H, J ) 6.2 Hz), 3.63 (s, 3H), 3.09 (dd, 1H, J ) 14.5 and 5.7
13
Hz), 3.02 (dd, 1H, J ) 14.5 and 7.0 Hz) ppm; C NMR (MeOH-
d
4
) δ 176.0, 145.1, 137.1, 130.1, 129.7, 129.2, 124.7, 55.3, 55.0,
+
5
2.6, 50.0, 31.6 ppm; HR-MS [M + Na] ) 261.1347 (calcd for
, 261.1352).
Triazole 3e: White solid (94%); mp 89-92 °C; IR (neat) ν 2912,
13 17 4 2
C H N O
(
26) Click reaction of BocPraOH 1a with azide 2 in the presence of
amines (e.g., 20 mol% of morpholine) yielded again mixtures of triazole
a and enol lactone 4a, presumably because the triazole formed acts as a
-1 1
1706, 1413, 1355, 1294, 1227, 1058, 725 cm ; H NMR (DMSO-
d
6
) δ 7.87 (s, 1H), 7.41-7.22 (m, 5H), 5.57 (s, 2H), 4.28-4.22
3
(
m, 1H), 3.58 (s, 3H), 3.05 (dd, 1H, J ) 14.8 and 6.6 Hz), 2.95
chelator yielding a Cu(I) species capable of catalyzing the intramolecular
enolization. In fact, addition of the Cu(I)-stabilizing chelator trisbenzyl-
triazole amine TBTA (1 equiv with respect to Cu(I) catalyst; ref 27a)
accelerated the cyclization of BocPraOH 1a, and enol lactone 4a was formed
in 6 h at rt as the sole product despite the presence of azide 2. Similar
observations were made with 4-pentynoic acid (1c).
(dd, 1H, J ) 14.8 and 9.8 Hz), 2.51 (br s, 1H), 1.33 (s, 9H) ppm;
13
C NMR (CDCl
23.1, 78.3, 53.5, 52.6, 51.8, 28.1, 27.2 ppm; HR-MS [M + Na]
363.1686 (calcd for C18 Na, 383.1695).
Triazole 3g: Colorless oil (yield 91%); IR (neat) ν 2950, 1741,
3
) δ 172.2, 155.3, 143.1, 136.2, 128.7, 128.0, 127.7,
+
1
)
24 4 4
H N O
(27) Click reaction of azides and terminal alkynes proceeds efficiently
-
1 1
with Cu(I) catalysts that are complexed by nitrogen ligands. See for
example: (a) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. Org.
Lett. 2004, 6, 2853-2855. (b) Girard, C.; O¨ nen, E.; Aufort, M.; Beauvi e` re,
S.; Samson, E.; Herscovici, J. Org. Lett. 2006, 8, 1689-1692.
1219, 1044, 729 cm ; H NMR (CDCl
3
) δ 7.33-7.25 (m, 4H),
7.20-7.15 (m, 2H), 5.46 (dd, 1H, J ) 14.8 Hz), 5.42 (dd, 1H, J )
1
3
1
4.8 Hz), 5.24 (dd, 1H, J ) 7.4 and 5.0 Hz), 3.62 (s, 3H), 3.27-
13
.15 (m, 2H), 1.98 (s, 3H) ppm; C NMR (CDCl
3
) δ 170.1, 169.8,
(28) Click reactions of propiolic acid 7 (Xie; J.; Seto, C. T. Bioorg Med.
42.7, 134.9, 129.2, 128.8, 128.0, 122.3, 77.2, 71.3, 54.1, 52.5,
Chem. 2007, 15, 458-473) and 5-hexynoic acid 1o (White, M., A.; Johnson,
+
J. J.; Koberstein, J. T.; Turro, N. J. J. Am. Chem. Soc. 2006, 128, 11356-
28.0, 20.6 ppm; HR-MS [M + Na] 326.1112 (calcd for C15
Na, 326.1117).
17 3 4
H N O -
1
1357) have been reported.
J. Org. Chem, Vol. 72, No. 26, 2007 10249