Synthesis of 1,2,3-triazoles by cycloadditions of azides with enol ethers

Article abstract of DOI:10.1055/s-2005-872116

1,2,3-Triazoles were prepared in good to modest yields by cycloaddition of alkyl azides onto enol ethers under solventless conditions. The reaction can access ring-fused triazoles that are unavailable by azide-alkyne cycloadditions and is easily scalable.

Full text of DOI:10.1055/s-2005-872116

PAPER
2497
Synthesis of 1,2,3-Triazoles by Cycloadditions of Azides with Enol Ethers
S
ynthesis of 1,2,3-
a
T
riazoles rio R. Roque, Justin L. Neill, James W. Antoon, Erland P. Stevens*
Department of Chemistry, Davidson College, PO Box 7120, Davidson, NC 28035-7120, USA
Fax +1(704)8942709; E-mail: erstevens@davidson.edu
Received 24 December 2004; revised 11 March 2005
R2
R3
N
H
Y
Abstract: 1,2,3-Triazoles were prepared in good to modest yields
by cycloaddition of alkyl azides onto enol ethers under solventless
conditions. The reaction can access ring-fused triazoles that are un-
available by azide-alkyne cycloadditions and is easily scalable. The
1,2,3-triazole products bear functionality that may be readily de-
rivatized.
N
N
+
heat
R1
5
8
Y = OR, NR2,
OAc, NRAc,
Key words: azides, cycloadditions, heterocycles, nitrogen, regiose-
lectivity
H
R2
R3
R2
N
N
N
N
N
R3
N
– HY
R1
Y
R1
1,2,3-Triazoles and their benzofused analogs have been
investigated for numerous uses including halide synthons
1,1 antiviral nucleoside analogues 2,2,3 antifungals 3,4 and
transition metal ligands 45 (Figure 1).
9
7
Scheme 2
Alkenes of type 8 have the same oxidation state as alkynes
and can serve as alkyne synthons. Cycloadditions of 8
with azides afford 1,2,3-triazoline intermediates 9 which
lose HY to aromatize the ring. Alkene dipolarophiles
studied in this reaction include enol ethers,9–13 enam-
ines,10,14–18 vinylogous amides,19,20 vinyl amides,21 and vi-
nyl sulfoxides.22,23 While azide cycloadditions onto
alkenes typically require higher temperatures than
alkynes,24 alkene dipolarophiles do possess advantages.
First, alkenes of type 8 are often made from carbonyl
compounds and may be prepared with a broader range of
functionality than alkynes. Second, the electronegative Y-
group that is lost in the reaction may serve as a traceless
means of controlling the regiochemistry of the cycloaddi-
tion.10
Ph
N
N
N
N
HO
N
Ph
N
N
H
S
1
2
Bn
N
N
N
N
N
N
Ph
N
N
Bn
N
N
N
H
N
3
4
N
N
Bn
Figure 1 1,2,3-Triazoles and their benzofused analogs
The predominant method for preparing 1,2,3-triazoles 7 is
the 1,3-dipolar cycloaddition of an azide 5 onto an alkyne
6 (Scheme 1).6
Of the alkenes investigated as alkyne synthons, enamines
8 (Y = NR2) have received the most attention.10,14–18 One
drawback to the synthesis of triazoles by enamines is the
stability of the 5-amino-1,2,3-triazoline intermediates 9
(Y = NR2).10,14 Loss of the amino group from the 5-posi-
tion can be slow, and decomposition of the triazoline ring
frequently competes with triazole formation. Side reac-
tions include aziridine formation25,26 and diazonium ion
rearrangements.10 The use of enamides 8 (Y = NRAc) in
place of enamines facilitates loss of the nitrogen in the 5-
position,21 but enamides are typically less convenient to
prepare than enamines.
R2
R2
R3
N
N
N
N
N
N
+
R1
R1
R3
5
6
7
Scheme 1
This well-explored route receives continual interest be-
cause of the utility of 1,2,3-triazoles.7,8 A less explored
route to 1,2,3-triazoles is the cycloaddition of azides 5
onto alkenes 8 bearing a leaving group (Scheme 2).
To address the shortcomings of azide–enamine cycloaddi-
tions, we investigated cycloadditions of azides onto enol
ethers 8 (Y = OR). Azide–enol ether cycloadditions are
relatively unexplored relative to azide–enamine cycload-
ditions. The starting azides used in this study are available
by standard SN2 replacement of alkyl halides or the ring-
opening of epoxides with sodium azide according to liter-
SYNTHESIS 2005, No. 15, pp 2497–2502
x
x.
x
x
.
2
0
0
5
Advanced online publication: 04.08.2005
DOI: 10.1055/s-2005-872116; Art ID: M10204SS
© Georg Thieme Verlag Stuttgart · New York

2498
D. R. Roque et al.
PAPER
ature procedures.27–30 Similarly, enol ethers used are Despite concerns over the stability and safety of azides,
available either commercially or by published proce- azides, especially alkyl azides, may be readily prepared,
dures.31–33
purified, and reacted without difficulty or incident.34 The
use of sealed tubes for the cycloadditions is unrelated to
azide stability. The sealed tubes minimize loss of volatile
starting materials during the high reaction temperatures.
Pressure build-up during the reactions is primarily due to
the loss of methanol from the initial triazoline cycload-
ducts. No evidence of azide decomposition was observed.
Since alkenes of enol ethers are less electron-rich than
enamine alkenes, they react less quickly than enamines in
azide cycloadditions.10 To increase the cycloaddition rate,
the azide–enol ether cycloadditions were performed at
200 °C in a sealed tube without solvent. Under these con-
ditions almost all the cycloadditions were complete within
six hours. The reactions were monitored by GC analysis The cycloaddition yields are modest to good. The reaction
and most showed very clean conversion to the desired tri- tolerates a range of functionality including esters, alco-
azole product. The results are summarized in Table 1.
hols, ketones, imides, and nitriles. Despite the high reac-
Table 1 Cycloadditions of Azides 5 and Enol Ethers 8 (Y = OR) to form 1,2,3-Triazoles 7 (Scheme 1)
Entry
1
Azide 5
Enol ether 8
1,2,3-Triazole 7
Yield (%)a
72
O
O
O
N
8a
8b
8b
O
N
N
5a
7a
N3
CH3O
CH3O
O
O
2
3
62
49
N
N
N3
CN
CN
N
7b
CN
5b
N
N
N3
N
7c
CN
CH3O
CH3O
CH3O
5c
OH
OH
4
5
67b
62
CN
O
N
5d
8b
8a
N
N
Ph
N3
7d
CN
Ph
N
N3
N
7e
5b
N
O
6
68
O
O
8a
8a
8c
O
N
N
O
O
5e
7f
CH3O
CH3O
O
O
N3
5d
N
7
8
78
68
O
N
Ph
N3
N
N
7g
Ph
OCH3
N3
N
N
5b
N
7h
9
51
OCH3
N
O
N
N
O
8c
8d
5e
7i
O
O
N3
10
11
60
66
O
N
N
N3
7j
N
5b
O
N
CH3O
CH3O
O
O
O
8a
N
N3
N
O
N
N
7k
5f
O
O
a Isolated yields following column chromatography or recrystallization.
b Crude reaction mixture contained a 10:1 mixture of regioisomers.
Synthesis 2005, No. 15, 2497–2502 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,2,3-Triazoles
2499
tion temperature, the ethyl ester of triazole 7a showed used to append a pyrazole ring 11 through a two-step pro-
almost no transesterification by methanol liberated from tocol using the dimethyl acetal of DMF followed by phe-
the enol ether (Table 1, Entry 1). The reaction accommo- nylhydrazine.37 The 4-cyano substituent of triazole 7b
dates modest steric congestion in the form of branching on reacts with sodium azide to form a tetrazole ring 12 in ex-
the azide-bearing carbon and substitution of the enol ether cellent yield following the procedure of Sharpless.38
alkene. Electronically, both simple enol ethers and capto-
O
dative alkenes undergo cycloaddition.
N
N
N
The reaction presumably follows a concerted 1,3-dipolar
cycloaddition mechanism to generate a 1,2,3-triazoline
intermediate 9 (Y = OR),10 although the putative interme-
diate was not directly observed. Under the high tempera-
ture conditions the triazoline loses an alcohol to form the
aromatic triazole product 7 (Scheme 2).
4-ClC6H4CHO
7e
CH3OH
NaOH
10
Cl
N
81%
Ph
N
N
N
N
The reactions were highly regioselective with only the cy-
cloaddition of benzyl azide (5d) and 3-methoxyprop-2-
enenitrile (8b) showing significant amounts of a second
regioisomer (Table 1, Entry 4). In this instance the regio-
selectivity of the crude mixture was approximately 10:1
with the minor regioisomer being removed by recrystalli-
zation. Where applicable, regiochemical assignments are
based on upon X-ray crystallographic evidence from re-
lated cycloadditions performed by Zhu13 and are consis-
tent with FMO analysis.35
1. HC(OMe)2NMe2
7e
2. PhNHNH2
46% (two steps)
11
H
N
N
N
N
NaN3
7b
N
N
N
ZnBr2
H2O
12
92%
Two noteworthy products are triazoles 7h and 7i (Table 1,
Entries 8 and 9). Ring-fused triazoles of this type are not
available by standard azide–alkyne cycloadditions. At-
tempts to use enamines derived from cyclic ketones to
form ring-fused triazoles have given mixed results. In
some cases cyclic enamines successfully react with azides
to afford ring-fused triazoles,16,17 while triazoline decom-
position products predominate in other instances.10,25,26
Scheme 4
In conclusion, the cycloaddition of azides onto enol ethers
provides a direct, efficient, and scalable route to 1,2,3-tri-
azoles. This reaction is able to generate triazoles that are
inaccessible by traditional azide-alkyne cycloadditions
and avoids complications of 5-amino-1,2,3-triazoline de-
composition that can accompany azide-enamine cycload-
ditions. The products of azide-enol ether cycloadditions
incorporate functional groups that are amenable to further
derivatization of the triazole products.
Most reactions in Table 1 were performed on less than a
10 mmol scale in sealed vials or pressure tubes. The reac-
tion can be run on a large scale without resorting to heavy-
walled glassware and elevated pressures. A cycloaddition
between cyclohexyl azide (5b) and 3-methoxyprop-2-
enenitrile (8b) was performed on a 0.6 mol scale in a heat-
ed round-bottom flask open to the atmosphere. Methanol,
a side-product of the reaction, was removed by distillation
as it was formed. The crude product was directly recrys-
tallized in the reaction flask to afford the desired product
7b in 78% yield (Scheme 3).
NMR spectra were recorded on a JEOL JNM-ECP 400 MHz spec-
trometer. Chemical shifts are reported in ppm (d) relative to TMS as
an internal standard. IR spectra were recorded on a MIDAC Series
M spectrometer. MS (EI) were recorded with a Varian 3800 Gas
Chromatograph-Saturn 2000 Mass Spectrometer system operating
at 11.7 eV. Melting ranges were taken on an Electrothermal Mel-
Temp and are uncorrected. Elemental analyses were performed by
Galbraith Laboratories, Inc. of Knoxville, TN and Quantitative
Technologies, Inc. of Whitehouse, NJ. Merck precoated silica gel
60 F254 plates were used for TLC, and Merck 60 for column chro-
matography. Chromatography solvents were mixed on a v/v basis.
Cyclohexyl azide (5b),27 trans-2-azidocyclohexanol (5c),28 ethyl 2-
azidoethanoate (5a),29 benzyl azide (5d),27 N-(2-azidoethyl)phthal-
imide (5f),30 and 4-azidomethyl-2,2-dimethyl-1,3-dioxolane (5e),31
1-methoxycyclohexene (8c),32 and 4-methoxypent-3-en-2-one
(8d)33 were prepared according to literature procedures. All other
reagents were purchased from commercial sources and used with-
out purification. Cycloadditions performed on less than a 5 mmol
scale were performed in round-bottom screw-cap vials (Fisher 14-
959-35C). Larger scale cycloadditions were performed in a heavy-
walled pressure tube (Ace 8608-07) unless otherwise specified.
N
NC
N
N
N3
CN
+
OCH3
5b
76.9 g
0.62 mol
8b
65 mL
0.77 mol
7b
83.1 g
0.48 mol
78%
Scheme 3
Triazoles from azide–enol ether cycloadditions bear func-
tionality that may be further derivatized (Scheme 4). The
4-acetyl group of cycloadduct 7e readily undergoes an al-
dol condensation to form an a,b-unsaturated ketone 10 in
1,2,3-Triazoles 7; General Procedure
The azide 5 (1.0 equiv) and enol ether 8 (1.1–1.2 equiv) were com-
high yield.36 Likewise, the 4-acetyl group of 7e may be bined neat and sealed in a vial and heated to 200 °C in a sand bath
Synthesis 2005, No. 15, 2497–2502 © Thieme Stuttgart · New York

2500
D. R. Roque et al.
PAPER
(Caution! high pressure from alcohol generation). The reaction was
monitored for disappearance of azide by GC analysis. The crude re-
action mixture was directly chromatographed or recrystallized with-
out an aqueous extraction (Table 1).
IR (film): 3149, 2240, 1520, 1496, 1454, 1236 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.94 (s, 1 H), 7.45–7.40 (m, 3 H),
7.33–7.28 (m, 2 H), 5.61 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 132.8, 129.5, 129.5, 129.2, 128.3,
121.4, 111.3, 54.8.
Ethyl 2-(4-Acetyl-1H-1,2,3-triazol-1-yl)acetate (7a)
White solid by column chromatography; yield: 0.53 g (72%); mp
79–80 °C; Rf 0.37 (EtOAc–hexanes, 1:1).
MS (EI): m/z (%) = 184 (17, [M+]), 155 (39), 129 (15), 104 (13), 91
(100), 78 (10), 77 (10), 65 (35), 51 (16), 50 (13).
IR (film): 3145, 2996, 1749, 1686, 1530, 1208 cm–1.
Anal. Calcd for C10H8N4: C, 65.21; H, 4.38; N, 30.42. Found: C,
65.32; H, 4.46; N, 30.21.
1H NMR (400 MHz, CDCl3): d = 8.26 (s, 1 H), 5.25 (s, 2 H), 4.28
(q, 2 H, J = 7.2 Hz), 2.70 (s, 3 H), 1.31 (t, 3 H, J = 7.1 Hz).
1-(1-Cyclohexyl-1H-1,2,3-triazol-4-yl)ethanone (7e)
Cream-colored solid by recrystallization from MeOH–H2O; yield:
4.5 g (72%); mp 116 °C; Rf 0.32 (EtOAc:–hexanes, 1:1).
13C NMR (100 MHz, CDCl3): d = 192.5, 165.6, 148.2, 126.9, 62.6,
50.9, 27.1, 13.9.
MS (EI): m/z (%) = 198 (35, [M+ + 1]), 169 (48), 154 (51), 126 (98),
97 (35), 96 (37), 54 (43), 53 (31), 43 (100).
IR (film): 3099, 2932, 2857, 1687, 1451 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.09 (s, 1 H), 4.51 (tt, 1 H,
J = 11.7, 3.9 Hz), 2.70 (s, 3 H), 2.24 (d, 2 H, J = 12.8 Hz), 1.95 (dt,
2 H, J = 13.7, 3.1 Hz), 1.83–1.69 (m, 3 H), 1.49 (tq, 2 H, J = 12.9,
3.5 Hz), 1.30 (tq, 1 H, J = 12.8, 3.5 Hz).
Anal. Calcd for C8H11N3O3: C, 48.73; H, 5.62; N, 21.31. Found: C,
48.75; H, 5.67; N, 21.20.
1-Cyclohexyl-1H-1,2,3-triazole-4-carbonitrile (7b)
General Procedure: White solid by recrystallization from MeOH–
H2O; yield: 1.10 g (62%); mp 110 °C; Rf 0.32 (EtOAc–hexanes,
1:1).
13C NMR (100 MHz, CDCl3): d = 193.1, 147.7, 123.1, 60.4, 33.4,
27.1, 25.0, 24.9.
MS (EI): m/z (%) = 194 (100, [M+ + 1]), 165 (20), 150 (28), 122
(22), 83 (39), 55 (46), 43 (20).
Large-Scale Procedure: Cyclohexyl azide (5b; 76.9 g, 0.62 mmol,
1.00 equiv) and 3-methoxyprop-2-enenitrile (8b; 65 mL, 0.77
mmol, 1.2 equiv) were mixed neat in a 250 mL flask equipped with
a distillation head and heated with a 200 °C sand bath. After 5 h, no
azide remained based on GC analysis. The reaction mixture solidi-
fied upon cooling to r.t. Recrystallization from MeOH–H2O (5:1,
350 mL) afforded the product; light brown solid; yield: 83.1 g
(78%).
Anal. Calcd for C10H15N3O: C, 62.15; H, 7.82; N, 21.74. Found: C,
62.26; H, 7.97; N, 21.76.
1-{1-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]-1H-1,2,3-triazol-
4-yl}ethanone (7f)
White solid by column chromatography; yield: 0.40 g (68%); mp
111–112 °C; Rf 0.27 (EtOAc–hexanes, 3:1).
IR (film): 3124, 2945, 2858, 2247, 1454, 1266, 1239, 1210 cm–1.
IR (film): 3100, 2989, 1683, 1374, 1253, 1198, 1062, 1049, 1042
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.05 (s, 1 H), 4.54 (tt, 1 H,
J = 11.7, 3.8 Hz), 2.26 (d, 2 H, J = 11.9 Hz), 1.97 (dt, 2 H, J = 13.9,
7.0 Hz), 1.72–1.83 (m, 3 H), 1.50 (tq, 2 H, J = 12.9, 3.5 Hz), 1.33
(tt, 1 H, J = 12.8, 3.7 Hz).
1H NMR (400 MHz, CDCl3): d = 8.23 (s, 1 H), 4.69–4.59 (m, 1 H),
4.53–4.42 (m, 2 H), 4.20–4.13 (m, 1 H), 3.80–3.74 (m, 1 H), 2.70
(s, 3 H), 1.39 (s, 3 H), 1.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 127.3, 120.6, 111.6, 61.1, 33.3,
24.9, 24.8.
13C NMR (100 MHz, CDCl3): d = 192.8, 148.1, 126.7, 110.4, 73.6,
66.2, 52.7, 27.2, 26.7, 25.0.
MS (EI): m/z (%) = 177 (100, [M+ + 1]), 176 (16), 83 (15), 82 (30),
67 (36), 55 (40).
MS (EI): m/z (%) = 226 (89, [M+ + 1]), 210 (100), 167 (43), 150
(23), 101 (32), 73 (15), 43 (79), 41 (17).
Anal. Calcd for C9H12N4: C, 61.34; H, 6.86; N, 31.79. Found: C,
61.45; H, 6.97; N, 31.43.
Anal. Calcd for C10H15N3O3: C, 53.32; H, 6.71; N, 18.66. Found:
C, 53.36; H, 6.67; N, 18.61.
1-[(1R*,2R*)-2-Hydroxycyclohexyl]-1H-1,2,3-triazole-4-carbo-
nitrile (7c)
Pale yellow solid by chromatography; yield: 0.38 g (49%); mp 124–
125 °C; Rf 0.24 (EtOAc–hexanes, 2:3).
1-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethanone (7g)
Orange-yellow solid by recrystallization from MeOH–H2O; yield:
0.64 g (78%); mp 88–89 °C (Lit.39 mp 90 °C); Rf 0.32 (EtOAc–hex-
anes, 2:3).
IR (film): 3433, 3131, 2940, 2868, 2255, 1444, 1236, 1042 cm–1.
IR (film): 3111, 1683, 1530, 1208 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.14 (s, 1 H), 4.22 (ddd, 1 H,
J = 12.5, 9.6, 4.4 Hz), 3.96 (dt, 1 H, J = 9.7, 4.8 Hz), 2.38 (br s, 1
H), 2.29–2.17 (m, 2 H), 2.04 (dq, 1 H, J = 12.7, 3.7 Hz), 1.98–1.84
(m, 2 H), 1.55–1.37 (m, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.95 (s, 1 H), 7.42–7.38 (m, 3 H),
7.32–7.28 (m, 2 H), 5.57 (s, 2 H), 2.68 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 192.9, 148.4, 133.6, 129.3, 129.2,
128.3, 125.2, 54.5, 27.1.
13C NMR (100 MHz, CDCl3): d = 129.9, 120.4, 111.5, 72.5, 67.7,
34.3, 31.3, 24.5, 23.8.
MS (EI): m/z (%) = 202 (13, [M+ + 1]), 173 (13), 172 (64), 158 (20),
130 (22), 91 (100), 65 (32).
MS (EI): m/z (%) = 193 (100, [M+ + 1]), 164 (32), 163 (59), 122
(17), 121 (33), 107 (18), 80 (16), 67 (17), 43 (15), 41 (16).
Anal. Calcd for C11H11N3O: C, 65.66; H, 5.51; N, 20.88. Found: C,
65.74; H, 5.50; N, 20.63.
Anal. Calcd for C9H12N4O: C, 56.24; H, 6.29; N, 29.15. Found: C,
56.25; H, 6.19; N, 28.94.
1-Cyclohexyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole
(7h)
1-Benzyl-1H-1,2,3-triazole-4-carbonitrile (7d)
White solid by column chromatography; yield: 0.57 g (67%); mp
77–78 °C; Rf 0.60 (EtOAc–hexanes, 1:1).
Cream-colored solid by column chromatography; yield: 0.52 g
(68%); mp 106–108 °C; Rf 0.17 (EtOAc–hexanes, 1:1).
IR (film): 2934, 2861, 1582, 1447, 1287, 1211 cm–1.
Synthesis 2005, No. 15, 2497–2502 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,2,3-Triazoles
2501
1H NMR (400 MHz, CDCl3): d = 4.12 (tt, 1 H, J = 10.6, 4.8 Hz),
2.74 (t, 2 H, J = 5.9 Hz), 2.63 (t, 2 H, J = 5.9 Hz), 2.06–1.71 (m, 11
H), 1.48–1.23 (m, 3 H).
(E)-3-(4-Chlorophenyl)-1-(1-cyclohexyl-1H-1,2,3-triazol-4-
yl)prop-2-en-1-one (10)
Following the procedure of Kulp,36 7e (390 mg, 2.0 mmol, 1.0
equiv) and 4-chlorobenzaldehyde (290 mg, 2.1 mmol, 1.0 equiv)
were dissolved in MeOH (10 mL). Aq 40% NaOH (200 mL) was
added, and the mixture was stirred for 10 min at 40 °C. Precipitation
of the product was completed by adding H2O (5 mL) and cooling the
mixture to r.t. The product was filtered and recrystallized from 1:1
MeOH–MeCN; white solid; yield: 0.52 g (81%); mp 178–180 °C;
Rf 0.26 (EtOAc–hexanes, 1:3).
13C NMR (100 MHz, CDCl3): d = 142.9, 130.7, 58.2, 32.5, 25.4,
25.0, 22.6, 22.4, 21.8, 20.3.
MS (EI): m/z (%) 206 (45, [M+ + 1]), 205 (72), 124 (16), 95 (100),
94 (49), 68 (58), 67 (66), 55 (66), 41 (26).
Anal. Calcd for C12H19N3: C, 70.20; H, 9.33; N, 20.47. Found: C,
70.35; H, 9.34; N, 20.41.
IR (film): 3131, 2929, 2853, 1662, 1602, 1567, 1525, 1490, 1184
cm–1.
4,5,6,7-Tetrahydro-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-
1H-benzo[d][1,2,3]triazole (7i)
Orange-yellow solid by column chromatography; yield: 0.18 g
(51%); mp 86–87 °C; Rf 0.27 (EtOAc–hexanes, 1:1).
1H NMR (400 MHz, CDCl3): d = 8.21 (s, 1 H), 7.92 (s, 2 H), 7.64
(d, 2 H, J = 8.8 Hz), 7.40 (d, 2 H, J = 8.4 Hz), 4.54 (tt, 1 H, J = 11.7,
3.8 Hz), 2.27 (d, 2 H, J = 11.4 Hz), 2.00–1.92 (m, 2 H), 1.84–1.70
(m, 3 H), 1.50 (tq, 2 H, J = 13.1, 3.3 Hz), 1.31 (tq, 1 H, J = 12.8, 3.5
Hz).
IR (film): 2985 (m), 2938 (s), 2859 (m), 1586 (w), 1443 (m), 1376
(m), 1212 (s), 1158 (m), 1057 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 4.48 (quint, 1 H, J = 5.7 Hz), 4.38
(dd, 1 H, J = 14.1, 4.9 Hz), 4.28 (dd, 1 H, J = 14.1, 5.7 Hz), 4.13
(dd, 1 H, J = 8.8, 6.2 Hz), 3.88 (dd, 1 H, J = 8.8, 5.8 Hz), 2.77–2.71
(m, 2 H), 2.70–2.63 (m, 2 H), 1.90–1.77 (m, 4 H), 1.34 (s, 3 H), 1.33
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 183.0, 148.1, 142.9, 136.6, 133.3,
129.9, 129.2, 124.3, 122.8, 60.5, 33.5, 25.03, 24.98.
MS (EI): m/z (%) = 317 (79, [M+ + 1]), 316 (70), 315 (61), 253 (64),
205 (44), 178 (53), 170 (47), 115 (26), 55 (66), 43 (100).
Anal. Calcd for C17H18ClN3O: C, 64.66; H, 5.75; N, 13.31. Found:
C, 64.45; H, 5.87; N, 13.42.
13C NMR (100 MHz, CDCl3): d = 143.2, 132.9, 109.9, 74.5, 66.7,
49.7, 26.5, 25.2, 22.6, 22.4, 21.8, 20.2.
MS (EI): m/z (%) = 238 (98, [M+ + 1]), 237 (65), 222 (86), 179 (81),
162 (39), 122 (65), 108 (77), 95 (43), 81 (44), 79 (44), 67 (65), 43
(100), 41 (43).
1-Cyclohexyl-4-(1-phenylpyrazol-5-yl)-1H-1,2,3-triazole (11)
Following the procedure of Penning and Talley,37 7e (500 mg, 2.6
mmol, 1.00 equiv), dimethyl acetal of DMF (370 mg, 2.8 mmol, 1.1
equiv), and p-TsOH (10 mg) were mixed neat and heated to 175 °C
with stirring. After 1 h, all 7e had been consumed based on GC anal-
ysis. Solid phenylhydrazine hydrochloride (380 mg, 2.60 mmol,
1.00 equiv) was added, and the reaction heated for 45 min at 200 °C.
The reaction was cooled to r.t., H2O (30 mL) was added, and the
mixture was stirred to precipitate the product. The crude, dark solid
was filtered and recrystallized from 7:1 MeOH–H2O to afford the
product; cream-colored solid; yield: 0.35 g (46%); mp 121–122 °C;
Rf 0.32 (EtOAc–hexanes, 1:3).
Anal. Calcd for C12H19N3O2: C, 60.74; H, 8.07; N, 17.71. Found: C,
60.82; H, 8.26; N, 17.53.
1-(1-Cyclohexyl-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (7j)
White solid by column chromatography; yield: 0.28 g (60%); mp
76–77 °C; Rf 0.21 (EtOAc–hexanes, 1:9).
IR (film): 2936, 2859, 1681, 1561, 1452, 1422, 1388, 1363, 1280,
1179 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.13 (tt, 1 H, J = 11.4, 4.2 Hz),
2.69 (s, 3 H), 2.59 (s, 3 H), 2.14–1.94 (m, 6 H), 1.82–1.74 (m, 1 H),
1.51–1.28 (m, 3 H).
IR (film): 2936, 2858, 1598, 1503, 1452, 1390 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.73 (d, 1 H, J = 1.8 Hz), 7.49–
7.37 (m, 5 H), 6.92 (s, 1 H), 6.88 (d, 1 H, J = 1.8 Hz), 4.35 (tt, 1 H,
J = 11.5, 3.8 Hz), 2.11 (m, 2 H), 1.87 (dt, 2 H, J = 13.6, 3.1 Hz),
1.76–1.69 (m, 1 H), 1.60 (dq, 2 H, J = 12.3, 3.3 Hz), 1.41 (tq, 2 H,
J = 12.9, 3.5 Hz), 1.22 (tq, 1 H, J = 12.8, 3.5 Hz).
13C NMR (100 MHz, CDCl3): d = 194.7, 143.2, 135.5, 57.8, 32.5,
27.7, 25.3, 24.9, 8.9.
MS (EI): m/z (%) = 207 (10, [M+]), 164 (57), 137 (11), 136 (100),
126 (34), 108 (16), 97 (33), 94 (15), 83 (24), 82 (25), 81 (10), 68
(17), 67 (39), 55 (63), 54 (32), 53 (12), 43 (37), 42 (18), 41 (20).
13C NMR (100 MHz, CDCl3): d = 140.4, 139.8, 137.7, 134.3, 129.0,
128.5, 126.0, 119.1, 107.3, 66.1, 33.3, 24.94, 24.89.
Anal. Calcd for C11H17N3O: C, 63.74; H, 8.27; N, 20.27. Found: C,
63.86; H, 8.48; N, 19.93.
MS (EI): m/z (%) = 294 (59, [M+ + 1]), 293 (81), 292 (100), 265
(71), 183 (84), 169 (33), 168 (49), 156 (53), 155 (36), 55 (42).
Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87. Found: C,
69.32; H, 6.51; N, 23.86.
2-[2-(4-Acetyl-1H-1,2,3-triazol-1-yl)ethyl]isoindoline-1,3-dione
(7k)
Light brown solid by recrystallization from MeCN–MeOH; yield:
0.48 g (66%); mp 212–214 °C; Rf 0.25 (EtOAc–hexanes, 1:1).
5-(1-Cyclohexyl-1H-1,2,3-triazol-4-yl)-1H-tetrazole (12)
Following the procedure of Sharpless,38 7b (3.48 g, 20.0 mmol, 1.00
equiv), NaN3 (1.46 g, 22.5 mmol, and 1.12 equiv), and ZnBr2 (4.50
g, 20.0, 1.00 equiv) were dissolved in H2O (40 mL) and refluxed.
After 24 h, the reaction was diluted with EtOAc (100 mL), CH2Cl2
(100 mL), and 3 M HCl (30 mL) to dissolve all solids. The organic
layer was separated and concentrated in vacuo. Aq 0.25 M NaOH
(200 mL) was added, and the resulting suspension was filtered. The
filtrate was acidified with 3 M HCl (40 mL) to afford a precipitate.
The precipitate was filtered and dried in an oven at 100 °C to give
the product; white solid; yield: 4.0 g (92%); mp 227 °C (dec.); Rf
0.18 (EtOAc).
IR (film): 3092, 1773, 1707, 1680, 1532, 1360, 1221, 1045 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.85 (s, 1 H), 7.90–7.82 (m, 4 H),
4.74–4.66 (m, 2 H), 4.09–4.01 (m, 2 H), 2.51 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 191.6, 167.4, 147.0, 134.6, 131.4,
127.9, 123.2, 48.1, 37.8, 27.1.
MS (EI): m/z (%) = 285 (14, [M+ + 1]), 256 (15), 241 (32), 174 (15),
175 (100), 161 (18), 160 (75), 147 (37), 133 (39), 130 (53), 129
(23), 109 (57), 105 (24), 104 (29), 102 (14), 77 (33), 76 (33), 54
(18), 53 (14), 51 (14), 50 (27), 43 (38).
IR (Nujol): 3149, 3087, 1643, 988 cm–1.
Anal. Calcd for C14H12N4O3: C, 59.15; H, 4.25; N, 19.71. Found: C,
59.21; H, 4.24; N, 19.68.
Synthesis 2005, No. 15, 2497–2502 © Thieme Stuttgart · New York

2502
D. R. Roque et al.
PAPER
(16) Nomura, Y.; Takeuchi, Y.; Tomoda, S.; Ito, M. M. Bull.
Chem. Soc. Jpn. 1981, 46, 1800.
(17) Palacios, F.; Ochoa de Retana, A. M.; Pagalday, J.; Sanchez,
J. M. Heterocycles 1995, 40, 543.
1H NMR (400 MHz, DMSO-d6): d = 9.00 (s, 1 H), 4.64 (tt, 1 H,
J = 11.5, 3.8 Hz), 2.19–2.09 (m, 2 H), 1.93–1.79 (m, 4 H), 1.70 (br
d, 1 H, J = 12.8 Hz), 1.46 (tq, 2 H, J = 13.3, 3.1 Hz), 1.27 (tq, 1 H,
J = 12.7, 3.3 Hz).
(18) Palacios, F.; Ochoa de Retana, A. M.; Pagalday, J.; Sanchez,
J. M. Org. Prep. Proced. Int. 1995, 27, 603.
(19) Peng, W.; Zhu, S. Synlett 2003, 187.
(20) Peng, W.; Zhu, S. Tetrahedron 2003, 59, 4395.
(21) Kadaba, P. K. J. Org. Chem. 1992, 57, 3075.
(22) Sasaki, T.; Eguchi, S.; Yamaguchi, M.; Esaki, T. J. Org.
Chem. 1981, 46, 1800.
(23) Freeze, S.; Norris, P. Heterocycles 1999, 51, 1807.
(24) Huisgen, R.; Möbius, L.; Mueller, G.; Stangl, H.; Szeimies,
G.; Vernon, J. M. Chem. Ber. 1965, 98, 3992.
(25) Ondrus, T. T.; Knaus, E. E.; Giam, C. S. Can. J. Chem. 1979,
57, 2342.
13C NMR (100 MHz, DMSO-d6): d = 148.6, 133.0, 123.7, 59.7,
32.7, 24.60, 24.57.
Anal. Calcd for C9H13N7: C, 49.30; H, 5.98; N, 44.72. Found: C,
49.14; H, 5.83; N, 44.32.
Acknowledgment
We thank The Merck Company Foundation/American Association
for Advancement of Science Undergraduate Science Research Pro-
gram and Davidson College for financial support.
(26) Warren, B. K.; Knaus, E. E. J. Med. Chem. 1981, 24, 462.
(27) Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413.
(28) Mordini, A.; Russo, F.; Valacchi, M.; Zani, L.;
Degl’Innocenti, A.; Reginato, G. Tetrahedron 2002, 58,
7153.
References
(1) Katritzky, A. R.; Rogovoy, B. V. Chem. Eur. J. 2003, 9,
4586.
(2) Yokoyama, M.; Nakao, E.; Sujuno, K.; Watanabe, S.; Togo,
H. Heterocycles 1990, 31, 1669.
(29) Guanti, G.; Riva, R. Tetrahedron: Asymmetry 2001, 12,
1185.
(3) Caamano, O.; Figueira, M. J.; Fernandez, R.; Garcia, M. D.;
Nieto, M. I.; De Clerq, E.; Balzarini, J. Nucleosides,
Nucleotides Nucleic Acids 2001, 20, 1137.
(4) Vicentini, C. B.; Brandolini, V.; Guarneri, M. Farmaco
1992, 47, 1021.
(5) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org.
Lett. 2004, 6, 2853.
(6) Huisgen, R.; Knorr, R.; Möbius, L.; Szeimies, G. Chem. Ber.
1965, 98, 4014.
(7) Rostovstev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem. Int. Ed. 2002, 67, 3057.
(8) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der
Eycken, E. Org. Lett. 2004, 6, 4223.
(9) Scarpati, R.; Sica, D.; Lionetti, A. Gazz. Chim. Ital. 1963,
93, 90.
(10) Huisgen, R.; Möbius, L.; Szeimies, G. Chem. Ber. 1965, 98,
1138.
(11) Chabala, J. C.; Christensen, B. G.; Ratcliffe, R. W.
Tetrahedron Lett. 1985, 26, 5407.
(30) Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.;
Sharpless, K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125,
9588.
(31) Gibson, F. S.; Park, M. S.; Rapoport, H. J. Org. Chem. 1994,
59, 7503.
(32) Garcia Martinez, A.; Martinez Alvarez, R.; Arranz Aguirre,
J.; Subramanian, L. R. J. Chem. Soc., Perkin Trans. 1 1986,
1595.
(33) Kraus, G. A.; Krolski, M. E.; Sy, J. Org. Synth. 1988, 57,
202.
(34) See footnote 77 in: Kolb, H. C.; Finn, M. G.; Sharpless, K.
B. Angew. Chem. Int. Eng. 2001, 41, 2004.
(35) Fleming, I. Frontier Orbitals and Organic Reactions;
Wiley: London, 1976, 148.
(36) Kulp, S. S. J. Chem. Educ. 1988, 65, 742.
(37) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Doctor, S.; Graneto, M. J.; Lee, L. F.;
Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D.
J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.;
Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1347.
(12) Häbich, D.; Barth, W. Heterocycles 1989, 29, 2083.
(13) Peng, W.-m.; Zhu, S.-Z. J. Fluorine Chem. 2002, 116, 81.
(14) Pocar, D.; Stradi, R.; Rossi, L. M. J. Chem. Soc., Perkin
Trans. 1 1972, 619.
(15) Pocar, D.; Stradi, R.; Rossi, L. M. J. Chem. Soc., Perkin
Trans. 1 1972, 769.
(38) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66,
7945.
(39) L’abbe, G.; Van Essche, G. Bull. Soc. Chim. Belg. 1991,
100, 289.
Synthesis 2005, No. 15, 2497–2502 © Thieme Stuttgart · New York