Regioselective synthesis of either 1H- or 2H-1,2,3-triazoles via Michael addition to α,β-unsaturated ketones

Article abstract of DOI:10.3987/COM-08-S(N)73

The Michael reaction of NH-1,2,3-triazole (1) with α,β-unsaturated ketones was studied. 1H-1,2,3-triazolyl-ketones were selectively generated when 1 was combined neat with a variety of enones. The use of aprotic solvents with catalytic base gave the corresponding 2H-regioisomers. Together, these two protocols provide direct access to either the N1- or N2-substituted 1,3-triazolyl ketone regioisomers.

Full text of DOI:10.3987/COM-08-S(N)73

HETEROCYCLES, Vol. 76, No. 2, 2008
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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1141 - 1154. © The Japan Institute of Heterocyclic Chemistry
Received, 30th March, 2008, Accepted, 26th May, 2008, Published online, 29th May, 2008. COM-08-S(N)73
REGIOSELECTIVE SYNTHESIS OF EITHER 1H- OR
2H-1,2,3-TRIAZOLES VIA MICHAEL ADDITION TO
α,ß-UNSATURATED KETONES
Sen Wai Kwok, Jason E. Hein, Valery V. Fokin, and K. Barry Sharpless*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey
Pines Road, BCC 315, La Jolla, CA 92037, USA. E-Mail: sharples@scripps.edu
Dedicated to Professor Ryoji Noyori on the occasion of his 70th Birthday
Abstract – The Michael reaction of NH-1,2,3-triazole (1) with α,β-unsaturated
ketones was studied. 1H-1,2,3-triazolyl-ketones were selectively generated when 1
was combined neat with a variety of enones. The use of aprotic solvents with
catalytic base gave the corresponding 2H-regioisomers. Together, these two
protocols provide direct access to either the N1- or N2-substituted 1,3-triazolyl
ketone regioisomers.
INTRODUCTION
The regioselective synthesis of substituted-1,2,3-triazoles has become synonymous with the rapid assembly
of modular molecular architectures.1 Our focus on this robust and under-appreciated azole class led us back
to the simple parent core 1 (C2H3N3),2 which exists as a rapidly equilibrating mixture of two tautomers in
solution, shown in Figure 1.3,4 The physical properties of 1 struck us as highly unusual and in fact very like
those of water. These include its weak acid/base character (pKa = 9.3, pKb = 1.2),5 very high proton
conductivity,6 and a liquid range spanning nearly 200 degrees (14−205 °C).3,7
Figure 1. 1H- and 2H-tautomers of NH-1,2,3-triazole (1)
A small molecule with three contiguous nitrogens contributing to approximately 60% of its total weight
naturally evokes safety concerns. Indeed, there has been some debate regarding its stability.8 However,
exhaustive and precise tests by Malow et. al. have now established that NH-1,2,3-triazole is insensitive to
impact, friction, rapid heating, and even detonation.9

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Our recent studies have found that 1 engages in and supports a number of useful addition and displacement
reactions, especially when employed in the absence of any exogenous solvent. This first report is confined
to Michael additions of NH-1,2,3-triazole (1) with α,ß-unsaturated ketones in a simple and regioselective
manner. Similar transformations have been reported; however, the corresponding adducts were typically
isolated in poor yield10 or as a mixture of regioisomers.11
RESULTS AND DISCUSSION
α,β-Unsaturated ketones were simply added to neat NH-1,2,3-triazole (1) (Table 1). In all cases 1 was
employed in excess (5−15 equiv.) and served as a solvent for the enones. Upon warming the corresponding
1,4-conjugate addition adducts were obtained.
Table 1. Michael additions of 1 to α,β-unsaturated ketones under neat conditions.
Entry
1
Product
Time Yielda Entry
Product
Time
2.0 h
Yielda
67%
N
N
O
N
2.0 h 73% b
5
6
Ph
O
3e
3f
N
N
2
2.0 h
89%
2.0 h
83%
N
65%
(1.3%)c
3
4
1.5 h
6.0 h
84%c
73%
7
8
1.0 h
2.0 h
73%
(17%)c
a
b
Isolated yield after crystallization or column chromatography. Products isolated as a 2:1 mixture of
diastereomers. c Isolated yield of N2-regioisomer.

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While these additions can potentially give both N1- and N2-substituted regioisomers, TLC and LC/MS
analyses revealed that one predominant isomer was generated in each case with good to excellent
1
selectivity. Following purification, H- and 13C-NMR analysis identified theses adducts as the
corresponding 1H-triazolyl ketones (3a-h).12 In addition to giving very high regioselectivity, performing
the reaction in the absence of exogenous solvent or catalyst facilitated rapid isolation and purification of the
1H-triazolyl ketones. Once the reaction had gone to completion, as determined by TLC or LC/MS analysis,
excess NH-1,2,3 triazole was removed via Kugelrhor distillation (0.5 mmHg, T = 100 °C). This yielded the
crude adducts and simultaneously permitted excess NH-1,2,3-triazole (1) to be recovered and reused in
further transformations.13
Our protocol employing neat NH-1,2,3-triazole (1) was compatible with a variety of substrates and easily
gave access to the corresponding N1-substituted adducts. However, we observed post-reaction emergence
of the N2-substituted triazolyl isomer in two cases (Table 1, entries 7 and 8). In these examples, the reaction
mixture prior to workup by distillative concentration did not indicate significant erosion of regioselectivity.
Monitoring the product distribution prior to and during distillation revealed that the appearance of the
2H-isomer in significant quantities occurred only upon heating the sample above 100 °C. In addition, we
noted that prolonged reaction time at higher temperatures led to a drastic change in the product distribution
in the case of cyclopenten-2-one (2g).14
Figure 2. Thermal N1−N2 isomerization of 1,4-conjugate addition adduct 3c
100
3c 4c
90
80
70
60
Product
distribution 50
40
(%)
30
20
10
0
25
60
80
120
140
180
200
Te1m00perature (°C)
These observations prompted us to test the thermal stability of our products over a range of temperatures
(Figure 2). 1H-Triazolyl ketone 3c was re-dissolved in NH-1,2,3-triazole and heated using microwave
irradiation for a period of one hour. After each experiment, the product distribution was determined by
LC/MS.15 While no change occurred at lower temperatures, conversion to the N2-isomer was observed

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when the sample was heated above 80 °C. Heating samples above 120 °C gave the 2H-isomer (4c) as the
major product, with the maximal conversion occurring between 150 °C and 160 °C. This conclusively
demonstrated that the N1-regioisomer can give rise to the 2H-triazolyl ketone 4c upon extended heating.
N1- to N2-isomerism of N-substituted-1,2,3-triazoles is not unprecedented.16 One particularly outstanding
example of this phenomenon was reported in a detailed study by Birkofer and Wegner, where
N1-acylated-1,2,3-triazoles were found to undergo isomerization to the corresponding 2H-isomer upon
heating above 120 °C.17 In our system the conversion from 3c to 4c is best rationalized by assuming that the
1,4-conjugate addition is reversible under these conditions, giving rise to the 2H-isomer via an
intermolecular pathway involving retro-Michael/Michael addition. This observation reveals that 3c is the
kinetically favored isomer, while 2H-triazolyl ketone 4c is the thermodynamically more stable product.
These assumptions are supported by computational studies, which find that N2-substituted-1,2,3-triazoles
are typically 4−5 kcal/mol more stable than the corresponding 1H-regioisomer.4,18
Given these observations, we sought conditions to facilitate equilibration and hence favor the
thermodynamically more stable N2-adducts. As expected, basic conditions were effective, with K2CO3
giving the best results. Numerous solvents were compatible with this transformation; however, faster
conversions and higher yields were obtained when acetonitrile was employed.
Table 2. Michael additions of 1 to α,β-unsaturated ketones using base catalysis.
Entry
1
Enone
N1 (%)a
N2 (%)a
Entry
5
Enone
N1 (%)a
N2 (%)a
O
3c (15%) 4c (61%)
3d (16%) 4d (63%)
3g (11%) 4g (83%)
2g
2
3
6
7
3h (8%)
3i (13%)
4h (80%)
4i (65%)
3e (10%) 4e (61%)
4
3f (13%) 4f (68%)
8
3j (18%)b 4j (54%)b
a Isolated yield after column chromatography. b Product isolated as a 1:1 mixture of diastereomers.

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The scope of this base-catalyzed process was briefly explored (Table 2). Both cyclic and acyclic enones
reacted with 1 to afford a mixture of regioisomers with the N2-isomer being the major product. We
observed that 1,4-conjugate addition and subsequent isomerization to the 2H-triazolyl ketone proceeded
much more rapidly with cyclic systems than in the acyclic counterparts. Within the acyclic series, we noted
that the presence of an electron-withdrawing group at the α-carbon facilitated the conversion to the
N2-regioisomer (Table 2, entry 3 cf. entries 4 and 8). Furthermore, we observed that the N2-triazolyl
ketones (4c-j) were consistently more non-polar than their corresponding N1-adducts (Figure 3a,b). The
dissimilar polarity of these two regioisomers can be attributed to the large difference in both the orientation
and magnitude of the dipole moment for the N1- and N2-substituted triazolyl group (Figure 3c).19,20 This
difference in polarity not only allowed the reaction progress to be readily monitored by TLC analysis, but
also greatly facilitated the separation of the 1H- and 2H-triazolyl ketones by column chromatography.
Figure 3. Comparative analysis of 1H- and 2H-isomers by thin layer chromatography.
c)
a)
b)
a ref. 19. b ref. 20.
In conclusion, we have found complementary methods, which provide facile access to either 1H- or
2H-triazolyl ketones via 1,4-conjugate addition. Using NH-1,2,3-triazole (1) neat permits the selective
formation of the kinetically-favored N1-substituted 1,4-adducts from a variety of α,β-unsaturated ketones.
Whereas the thermodynamically-favored N2-regioisomers become the major products when catalytic base
is employed. Studies to extend the utility of this and related processes will be presented in due course.
EXPERIMENTAL
Melting points were recorded on either a Barnstead Electrothermal digital melting point apparatus (Model
IA9300) or on Thomas-Hoover capillary melting apparatus and are uncorrected. IR spectra were recorded
on pure undiluted samples using a ThermoNicolet Avatar 370 FT-IR with a Smart MIRacleTM single
reflection HATR attachment. High-resolution mass spectra (HRMS) were recorded at the mass

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spectrometry facility at The Scripps Research Institute, La Jolla, CA, USA. Analytical HPLC was
performed on an Agilent HP 1100 series LC/MS with a variable wavelength diode array detector. 1H NMR
13
(400 MHz and 500 MHz) and C NMR (100 MHz, 125 MHz, and 150 MHz) spectra were recorded on
Bruker DRX-500, Bruker DRX-600 spectrometers in CDCl3 unless otherwise noted. Chemical shifts were
reported as part per million (ppm) downfield of TMS. The proton signal of residual, non-deuterated solvent
(δ 7.26 for CHCl3, δ 2.50 for DMSO-d6) was used as internal reference for 1H spectra. 13C spectra, chemical
shifts were reported relative to the δ 77.0 resonance of CDCl3. Coupling constants (J) are reported in Hertz
(Hz). Flash column chromatography was performed using Merck Kieselgel 60 (230-400 mesh) silica gel.
Analytical TLC was performed on precoated glass plates (Merck Kieselgel 60 F254). All chemicals
purchased from vendors were used as received without further purification. NH-1,2,3-triazole (1) was
purchased from AK scientific. Recovered NH-1,2,3-triazole (see Method A) was re-purified prior to reuse
by vacuum distillation (0.5 mmHg) at 65 °C over a short path apparatus and stored in Nalgene bottle at 4
°C.
Method A: General procedure for the synthesis of 1H-triazolyl-ketones using neat NH-1,2,3-triazole.
NH-1,2,3-Triazole (1, 5−15 equivalents, amount adjusted to obtain a homogeneous solution) was added to
α,β-unsaturated ketone. The reaction mixture was heated (50−80 °C) for 2−6 h and monitored by TLC or
LC/MS. Upon complete consumption of starting material, excess triazole was removed by Kugelrohr
distillation (0.5 mmHg, T = 100 °C). The residue was purified by column chromatography over silica gel.
In situations where the product solidified or precipitated from the reaction mixture, product was triturated
(MeOH or EtOAc/hexanes) and collected by vacuum filtration.
Representative example for reactions employing trituration:
1,3-Diphenyl-3-(1H-1,2,3-triazol-1-yl)propan-1-one (3c)
NH-1,2,3-Triazole (1) (24.8 mL, 480 mmol) was added to chalcone (2c) (10.00 g, 48.00 mmol). The
reaction was warmed to 80 °C in an open Erlenmeyer flask and stirred vigorously. Progress was monitored
by TLC (30% EtOAc/hexanes) and LC/MS. After 1.5 h conversion was complete and the flask was cooled
to room temperature. The product precipitated from the mixture and was triturated with small amount of
MeOH and collected by filtration to afford 3c as a white solid (11.12 g, 84%): Rf = 0.1 (30%
EtOAc/hexanes); mp 107.0−109.0 °C; IR (υ[cm-1]) = 3097, 1681, 1454, 1376, 1333, 1213, 1081, 1027,
1001, 962, 751, 716, 690; 1H NMR (CDCl3, 500 MHz): δ 7.97−7.95 (m, 2H), 7.68 (app s, 1H), 7.60 (app s,
1H), 7.59−7.55 (m, 1H), 7.47−7.44 (m, 2H), 7.37−7.31 (m, 5H), 6.32 (dd, J = 8.5, 5.0, 1H), 4.66 (dd, J =
178, 8.8, 1H), 3.74 (dd, J = 18.0, 5.0, 1H); 13C NMR (CDCl3, 125 MHz): δ 195.8, 139.1, 136.1, 133.8, 133.6,

HETEROCYCLES, Vol. 76, No. 2, 2008
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129.1, 128.7, 128.6, 128.2, 126.8, 124.2, 60.4, 44.3; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C17H16N3O, 278.1288; found, 278.1285.
Representative example for reactions employing Kugelrohr distillation:
1-Phenyl-3-(1H-1,2,3-triazol-1-yl)butan-1-one (3e)
NH-1,2,3-Triazole (1) (3.7 mL, 64 mmol) was added to 1-phenylbut-2-en-1-one (2e) (1.88 g, 12.9 mmol) in
a screw-top scintillation vial. The vial was capped and then warmed to 80 °C and stirred vigorously.
Progress was monitored by TLC (30% EtOAc/hexanes) and LC/MS. After 2 h the reaction was complete
and was cooled to room temperature. The reaction mixture was transferred to a Kugelrohr apparatus and all
volatile material was removed by distillation (0.5 mmHg, T = 100 °C, 20–25 min). After cooling to room
temperature, the residue was taken up in EtOAc (5 mL) and then a large excess of hexanes (100−150 mL)
was added. A precipitate formed and was collected by filtration to give 3e as a white powder (1.54 g, 56%).
The filtrate was concentrated under vacuum and again diluted with EtOAc (5 mL). Precipitation with a
second washing of hexanes (100 mL) gave a precipitate which was isolated by filtration to give a second
crop of 3e (0.17 g, 6%), total isolated yield of the two fractions = 1.71 g, 62%: Rf = 0.16 (50%
EtOAc/hexanes); mp 76.5−78.0 °C; IR (υ[cm-1]) = 3130, 3111, 2977, 2933, 1683, 1449, 1367, 1213, 1077,
1000, 953, 795, 761, 688; 1H NMR (CDCl3, 500 MHz): δ 7.93−7.91 (m, 2H), 7.67 (br s, 1H), 7.66 (br s, 1H),
7.59−7.56 (m, 1H), 7.47−7.44 (m, 2H), 5.34 (dqd, J = 7.3, 6.5, 5.8, 1H), 3.92 (dd, J = 17.8, 7.3, 1H), 3.46
(dd, J = 18.2, 5.8, 1H), 1.74 (d, J = 6.5, 3H); 13C NMR (CDCl3, 125 MHz): δ 196.4, 136.2, 133.7, 133.2,
128.7, 128.0, 123.3, 52.8, 45.1, 21.5; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C12H14N3O, 216.1131;
found, 216.1129.
2-(2-(1H-1,2,3-Triazol-1-yl)propan-2-yl)-5-methylcyclohexanone (3a)
Prepared using method A, R-(+)-pulegone (2a) (812 μL, 5 mmol), NH-1,2,3-triazole (1) (1.45 mL, 25
mmol), 80 °C. NH-1,2,3-Triazole was removed via Kugelrohr distillation. The oily residue was purified by
column chromatography (50−80% EtOAc/hexanes) to afford 3a (mixture of diastereomers ~ 2:1) as a
yellow oil (0.80 g, 73%): IR (υ[cm-1]) = 3120, 2954, 1709, 1456, 1369, 1298, 1221, 1123, 1070, 1015, 783.
Major diastereomer: 1H NMR (CDCl3, 500 MHz): δ 7.66 (d, J = 1.0, 1H), 7.63 (d, J = 1.0, 1H), 3.43−3.30
(m, 1H), 2.28 (ddd, J = 12.8, 4.0, 2.3, 1H), 2.09−2.03 (m, 1H), 1.92−1.78 (m, 2H), 1.78 (s, 3H), 1.72 (s, 3H),
1.63−1.53 (m, 1H), 1.46 (qd, J = 13.0, 3.0, 1H), 1.39−1.30 (m, 1H), 0.99 (d, J = 6.0, 3H); 13C NMR (CDCl3,
125 MHz): δ 209.2, 132.52, 121.64, 62.57, 58.2, 51.7, 36.0, 33.9, 28.3, 26.3, 24.16, 22.1.
Minor diastereomer: 1H NMR (CDCl3, 500 MHz): δ 7.66 (d, J = 1.0, 1H), 7.63 (d, J = 1.0, 1H), 3.43−3.30
(m, 1H), 2.63 (ddd, J = 13.0, 6.0, 0.5, 1H), 2.44−2.36 (m, 1H), 2.09−2.03 (m, 1H), 1.92−1.78 (m, 1H), 1.79

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(s, 3H), 1.73 (s, 3H), 1.63−1.53 (m, 1H), 1.50−1.44 (m, 1H), 0.90 (d, J = 7.5, 3H); 13C NMR (CDCl3, 125
MHz): δ 209.7, 132.54, 121.67, 62.60, 58.6, 49.7, 31.9, 30.7, 26.2, 24.23, 23.9, 18.4; HRMS (ESI-TOF)
(m/z): [M + H]+ calcd for C12H20N3O, 222.1601; found, 222.1605.
1,4-Diphenyl-2-(1H-1,2,3-triazol-1-yl)butane-1,4-dione (3b)
Prepared using method A, 1,4-diphenylbut-2-ene-1,4-dione (2b) (0.70 g, 2.96 mmol), NH-1,2,3-triazole (1)
(2.6 mL, 44.4 mmol) 65 °C. After 0.5 h, a white solid precipitated from the reaction mixture and was
pulverized. Reaction mixture was heated for an additional 1.5 h. After this time MeOH was added to the
flask and the suspension was stirred vigorously for 20 min. The precipitate was then collected by filtration
to afford 3b as a white solid (0.81 g, 89%): mp 180.0−182.0 °C; IR (υ[cm-1]) = 3121, 3101, 2970, 2911,
1695, 1670, 1594, 1448, 1406, 1294, 1186, 1080, 1008, 830, 798, 764, 729, 686; 1H NMR (DMSO-d6, 500
MHz): δ 8.42 (d, J = 0.7, 1H), 8.05−7.99 (m, 4H), 7.76 (br s, 1H), 7.69−7.65 (m, 2H), 7.56−7.52 (m, 4H),
6.96 (dd, J = 6.5, 6.9, 1H), 4.26 (dd, J = 18.1, 6.9, 1H), 4.01 (dd, J = 18.1, 6.2, 1H); 13C NMR (DMSO-d6,
150 MHz): δ 197.3, 194.3, 137.0, 136.5, 135.6, 135.4, 135.0, 130.3, 130.1, 129.9, 129.4, 126.6, 60.1, 41.6;
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H16N3O2, 306.1237; found, 306.1236.
4-Phenyl-4-(1H-1,2,3-triazol-1-yl)butan-2-one (3d)
Prepared using method A, 4-phenylbut-3-en-2-one (2d) (0.73 g, 5 mmol), NH-1,2,3-triazole (1) (1.45 mL,
25 mmol), 80 °C. NH-1,2,3-Triazole was removed via Kugelrohr distillation. Solid residue was
re-dissolved in small amount of EtOAc and then hexanes was added slowly to give a fine precipitate. This
solid was triturated to afford 3d as a white solid (0.78 g, 72%): mp 110.0−113.0 °C; IR (υ[cm-1]) = 3089,
1714, 1493, 1455, 1362, 1218, 1169, 1120, 1088, 1028, 816, 753, 719, 694; 1H NMR (CDCl3, 500 MHz): δ
7.65 (d, J = 0.5, 1H), 7.49 (d, J = 1.0, 1H), 7.35−7.28 (m, 3H), 7.26−7.24 (m, 2H), 6.05 (dd, J = 9.3, 4.8, 1H),
4.07 (dd, J = 17.5, 9.5, 1H), 3.15 (dd, J = 17.8, 4.8, 1H), 2.20 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 204.3,
138.8, 138.9, 129.1, 128.6, 126.6, 124.1, 60.1, 48.5, 30.3; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C12H14N3O, 216.1131; found, 216.1130.
4-Methyl-4-(1H-1,2,3-triazol-1-yl)pentan-2-one (3f)
Prepared using method A, mesityl oxide (2f) (572 μL, 5 mmol), NH-1,2,3-triazole (1) (1.45 mL, 25 mmol)
80 °C. NH-1,2,3-Triazole was removed via Kugelrohr distillation. The oily residue was purified by column
chromatography (50−85% EtOAc/hexanes) to afford 3f as a pale yellow oil (0.69 g, 83%): IR (υ[cm-1]) =
3129, 2983, 2937, 1715, 1435, 1367, 1290, 1220, 1146, 1071, 1018, 952, 784; 1H NMR (CDCl3, 500 MHz):
δ 7.66−7.65 (m, 2H), 3.20 (s, 2H), 2.00 (s, 3H), 1.77 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 205.0, 133.0,

HETEROCYCLES, Vol. 76, No. 2, 2008
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121.2, 59.7, 53.4, 31.2, 28.2; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C8H14N3O, 168.1131; found,
168.1129.
3-(1H-1,2,3-Triazol-1-yl)cyclopentanone (3g)
Prepared using method A, cyclopent-2-enone (2g) (2.07 g, 25 mmol), NH-1,2,3-triazole (1) (7.3 mL, 126
mmol), 50 °C, 1 h. NH-1,2,3-Triazole was removed via Kugelrohr distillation. The oily residue was purified
by column chromatography using (50% EtOAc/hexanes − 100% EtOAc) to afford 3g as a beige solid (2.48
g, 65%): mp 62.5−64.0 °C; IR (υ[cm-1]) = 3126, 3102, 2980, 2925, 1732, 1483, 1452, 1291, 1210, 1159,
1
1085, 902, 815, 616; H NMR (CDCl3, 400 MHz): δ 7.65 (s, 1H), 7.60 (s, 1H), 5.23−5.17 (m, 1H),
13
2.82−2.70 (m, 2H), 2.60−2.24 (m, 4H); C NMR (CDCl3, 100 MHz): δ 213.5, 133.6, 122.6, 57.3, 44.4,
36.2, 30.0; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C7H10N3O, 152.0818; found, 152.0817.
3-(1H-1,2,3-Triazol-1-yl)cyclohexanone (3h)
Prepared using method A, cyclohex-2-enone (2h) (486 μL, 5 mmol), NH-1,2,3-triazole (1) (1.45 mL, 25
mmol), 80 °C. NH-1,2,3-Triazole was removed via Kugelrohr distillation. The oily residue was purified by
column chromatography (80−90% EtOAc/hexanes) to afford 3h as a white solid (0.60 g, 73%): mp
59.0−60.0 °C; IR (υ[cm-1]) = 3128, 3093, 2961, 2876, 1706, 1453, 1324, 1213, 1116, 1094, 1020, 826, 750,
705; 1H NMR (CDCl3, 500 MHz): δ 7.69 (d, J = 1.0, 1H), 7.58 (d, J = 1.0, 1H), 4.86 (dddd, J = 10.0, 10.0,
5.0, 4.0, 1H), 2.97 (ddd, J = 14.5, 5.3, 1.3, 1H), 2.92 (dddd, J = 14.5, 5.5, 1.5, 1.5, 1H) 2.52−2.26 (m 4H),
13
2.11−2.04 (m, 1H), 1.83−1.74 (m, 1H); C NMR (CDCl3, 125 MHz): δ 206.4, 133.6, 121.9, 58.6, 47.3,
40.4, 31.7, 21.6; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C8H12N3O, 166.0975; found, 166.0979.
Method B: General procedure for the synthesis of 2H-triazolyl-ketones using base catalysis.
α,β-Unsaturated ketone and NH-1,2,3-triazole (1, 1.05−1.20 equiv.) were dissolved in MeCN (0.5−1 M)
and treated with K2CO3, (0.1 equiv.). The reaction was heated (55−80 °C) and monitored by TLC or LC/MS.
When no further change in the N1/N2 ratio was observed, the solvent was removed under reduced pressure
and the products were purified by column chromatography over silica gel. Note: In every case, the
N2-product elutes long before the more polar N1-isomer.
Representative example for base-catalyzed synthesis of 2H-triazoles:
3-(2H-1,2,3-Triazol-2-yl)cyclohexanone (4h)
Cyclohex-2-enone (2h) (2.30 g, 24.0 mmol) and NH-1,2,3-triazole (1.46 mL, 25 mmol) were dissolved in
MeCN (48 mL) in a round bottom flask and treated with K2CO3, (0.33 g, 2.4 mmol, 0.1 equiv.). The

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reaction was then capped and heated to 55 °C for 13.5 h, and monitored by TLC (80% EtOAc/hexanes) and
LC/MS. When no further change in the product distribution was observed the reaction was cooled to room
temperature and concentrated under vacuum. The crude residue was purified by column chromatography
(40% EtOAc/hexanes − 100% EtOAc) to afford 4h as a pale yellow oil (3.15 g, 80%) along with 3h (0.33 g,
8.3%) as the minor product.
1
(4h): IR (υ[cm-1]) = 3155, 2956, 2874, 1713, 1418, 1343, 1223, 1107, 1015, 962, 818, 753; H NMR
(CDCl3, 500 MHz): δ 7.54 (s, 2H), 4.96−4.91 (m, 1H), 2.99 (dd, J = 14.8, 9.3, 1H), 2.80 (dd, J = 14.8, 5.3,
1H), 2.40−2.37 (dd, J = 8.0, 6.0, 2H), 2.27−2.16 (m, 2H), 1.95−1.88 (m, 1H), 1.75−1.67 (m, 1H); 13C NMR
(CDCl3, 125 MHz): δ 207.1, 133.9, 62.2, 46.2, 30.3, 30.8, 21.1; HRMS (ESI-TOF) (m/z): [M + H]+ calcd
for C8H12N3O, 166.0975; found, 166.0969.
1,3-Diphenyl-3-(2H-1,2,3-triazol-1-yl)propan-1-one (4c)
Prepared using method B, chalcone (2c) (1.04 g, 5 mmol), NH-1,2,3-triazole (304 μL, 5.25 mmol), 70 °C.
Purified by column chromatography (20−50% EtOAc/hexanes) to afford the 4c as an off-white solid (0.84 g,
61%) along with 3c (0.21g, 15%) as the minor product.
(4c): mp 95.5−97.5 °C; IR (υ[cm-1]) = 3133, 3066, 1682, 1422, 1370, 1333, 1210, 1144, 962, 832, 749, 722,
1
687; H NMR (CDCl3, 500 MHz): δ 8.00−7.98 (m, 2H), 7.60 (s, 2H), 7.60−7.56 (m, 1H), 7.48−7.45 (m,
1H), 7.36−7.27 (m, 5H), 6.51 (dd, J = 9.0, 5.5, 1H), 5.52 (dd, J = 17.5, 9.0, 1H), 3.73 (dd, J = 17.8, 5.3, 1H);
13C NMR (CDCl3, 125 MHz): δ 195.7, 139.4, 136.4, 134.1, 133.4, 128.8, 128.7, 128.3, 128.2, 126.7, 64.0,
44.0; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H16N3O, 278.1288; found, 278.1291.
4-Phenyl-4-(2H-1,2,3-triazol-2-yl)butan-2-one (4d)
Prepared using method B, 4-phenylbut-3-en-2-one (2d) (731 mg, 5 mmol), NH-1,2,3-triazole (304 μL, 5.25
mmol), 65 °C. Purified by column chromatography (25% EtOAc/hexanes to 100% EtOAc) to afford 4d as
a pale yellow oil (0.68 g, 63%) along with 3d (0.17 g, 16%) as the minor product.
(4d): IR (υ[cm-1]) = 3129, 3062, 2958, 1719, 1455, 1417, 1353, 1165, 1142, 1024, 961, 818, 753, 698; 1H
NMR (CDCl3, 500 MHz): δ 7.60 (s, 2H), 7.33-7.24 (m, 5H), 6.25 (dd, J = 9.5, 5.0, 1H), 3.94 (dd, J = 17.5,
13
9.5, 1H), 3.18 (dd, J = 17.8, 5.3, 1H), 2.19 (s, 3H); C NMR (CDCl3, 125 MHz): δ 204.3, 139.1, 134.1,
128.8, 128.3, 126.5, 63.9, 48.4, 30.3; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C12H14N3O, 216.1131;
found, 216.1130.
1-Phenyl-3-(2H-1,2,3-triazol-2-yl)butan-1-one (4e)

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1151
Prepared using method B, 1-phenylbut-2-en-1-one (2e) (710 μL, 5 mmol), NH-1,2,3-triazole (304 μL, 5.25
mmol), 65 °C. Purified by column chromatography (15% EtOAc/hexanes to 100% EtOAc) to afford 4e as a
pale yellow oil (0.65 g, 61 %) along with 3e (0.11 g, 10%) as the minor product.
(4e): IR (υ[cm-1]) = 3062, 2986, 1685, 1597, 1448, 1369, 1217, 1147, 1001, 962, 817, 755, 689; 1H NMR
(CDCl3, 500 MHz): δ 7.97−7.94 (m, 2H), 7.58−7.55 (m, 3H), 7.47−7.44 (m, 2H), 5.46 (dqd, J = 7.0, 6.8, 6.5,
1H), 3.87 (dd, J = 17.5, 6.5, 1H), 3.45 (dd, J = 17.5, 7.0, 1H), 1.66 (d, J = 6.8, 3H); 13C NMR (CDCl3, 125
MHz): δ 196.5, 136.5, 133.8, 133.4, 128.6, 128.1, 57.0, 44.4, 21.0; HRMS (ESI-TOF) (m/z): [M + H]+ calcd
for C12H14N3O, 216.1131; found, 216.1130.
4-Methyl-4-(2H-1,2,3-triazol-2-yl)pentan-2-one (4f)
Prepared using method B, mesityl oxide (2f) (572 μL, 5 mmol), NH-1,2,3-triazole (304 μL, 5.25 mmol), 65
°C. Purified by column chromatography (50% EtOAc/hexanes to 100% EtOAc) to afford 4f as a pale
yellow oil (0.57 g, 68%) along with 3f (0.11 g, 13%) as the minor product.
(4f): IR (υ[cm-1]) = 3124, 2988, 2939, 1718, 2421, 1365, 1325, 1179, 1140, 962, 817; 1H NMR (CDCl3, 500
MHz): δ 7.59 (s, 2H), 3.15 (s, 2H), 1.98 (s, 3H), 1.75 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 205.4, 133.5,
63.5, 53.5, 31.1, 27.6; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C8H14N3O, 168.1131; found, 168.1127.
3-(2H-1,2,3-Triazol-2-yl)cyclopentanone (4g)
Prepared using method B, cyclopent-2-enone (2g) (419 μL, 5 mmol), NH-1,2,3-triazole (304 μL, 5.25
mmol), 65 °C. Purified by column chromatography (70% EtOAc/hexanes to 100% EtOAc) to afford 4g as a
pale yellow oil (0.63 g, 83%) along with the 3g (0.08 g, 11%) as the minor product.
(4g): IR (υ[cm-1]) = 3126, 3009, 1743, 1418, 1351, 1154, 1117, 963, 902, 819, 752; 1H NMR (CDCl3, 500
MHz): δ 7.58 (s, 2H), 5.36-5.31 (m, 1H), 2.91-2.87 (br dd, J = 18.5, 4.5, 1H), 2.74 (br dd, J = 18.8, 7.6, 1H),
2.57-2.46 (m, 3H), 2.36-2.26 (m, 1H); 13C NMR (CDCl3, 125 MHz): δ 214.7, 134.2, 61.5, 44.2, 36.1, 29.7;
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C7H10N3O, 152.0818; found, 152.0817.
3-(2H-1,2,3-Triazol-2-yl)cycloheptanone (4i)
Prepared using method B, cyclohept-2-enone (2i) (223 μL, 2 mmol), NH-1,2,3-triazole (139 μL, 2.4 mmol),
70 °C. Purified by column chromatography (50%−90% EtOAc/hexanes) to afford 4i as a colorless oil (0.23
g, 65%) along with 3i (0.045 g, 13%) as the minor product:
(4i): IR (υ[cm-1]) = 3131, 2935, 2863, 1699, 1448, 1418, 1342, 1162, 1130, 961, 818, 736; 1H NMR (CDCl3,
500 MHz): δ 7.50 (s, 2H), 4.86−4.81 (m, 1H), 3.26 (dd, J = 15.1, 10.5, 1H), 2.86 (app dd, J = 15.2, 2.7, 1H),
13
2.57−2.43 (m, 2H), 2.20−2.16 (m, 2H), 1.88−1.81 (m, 2H), 1.73−1.65 (m, 1H), 1.60−1.52 (m, 1H); C

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NMR (CDCl3, 125 MHz): δ 209.6, 133.7, 61.2, 48.8, 43.9, 36.7, 26.1, 23.5; HRMS (ESI-TOF) (m/z): [M +
H]+ calcd for C9H14N3O, 180.1131; found, 180.1129.
(3i): IR (υ[cm-1]) = 3122, 2926, 2862, 1699, 1447, 1220, 1112, 1072, 1027, 791, 757, 730; 1H NMR (CDCl3,
500 MHz): δ 7.67 (s, 1H), 7.56 (s, 1H), 4.83 (tt, J = 10.8, 3.3, 1H), 3.28 (dd, J = 14.5, 11.0, 1H), 2.92 (ddd,
J = 14.8, 2.5, 2.0, 1H), 2.66−2.61 (m, 1H), 2.53 (ddd, J = 16.0, 11.3, 4.0, 1H), 2.30−2.26 (m, 1H), 2.18 (tdd,
J = 14.0, 11.3, 2.8, 1H), 2.07−1.96 (m, 2H), 1.80−1.72 (m, 1H), 1.64−1.56 (m, 1H); 13C NMR (CDCl3, 125
MHz): δ 209.0, 133.7, 121.5, 57.6, 49.8, 43.9, 37.7, 26.4, 23.5; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C9H14N3O, 180.1131; found, 180.1128.
3-Methyl-4-(2H-1,2,3-triazol-2-yl)pentan-2-one (4j)
Prepared using method B, 3-methylpent-3-en-2-one (2j) (491 mg, 5 mmol), NH-1,2,3-triazole (304 μL,
5.25 mmol), 65 °C. Purified by column chromatography (50% EtOAc/hexanes to 100% EtOAc) to afford 4j
as a colorless oil (0.45 g, 54%) and 3j (0.15 g, 18%) as the minor product:
(4j) (isolated as a 1:1 mixture of diastereomers): IR (υ[cm-1]) = 3123, 2986, 2940, 1712, 1452, 1420, 1339,
1152, 1081, 961, 818; Diastereomer A: 1H NMR (CDCl3, 500 MHz): δ 7.60 (s, 1H), 5.01 (dq, J = 8.5, 6.8,
1H), 3.35 (dq, J = 8.5, 7.5, 1H), 2.08 (s, 3H), 1.55 (d, J = 6.5, 3H), 1.18 (d, J = 7.0, 3H); 13C NMR (CDCl3,
1
125 MHz): δ 209.6, 133.8, 61.8, 51.3, 28.8, 17.5, 13.2; Diastereomer B: H NMR (CDCl3, 500 MHz): δ
7.56 (s, 1H), 4.96 (dq, J = 9.3, 6.8, 1H), 3.20 (dq, J = 9.3, 7.3, 1H), 2.22 (s, 3H), 1.53 (d, J = 6.5, 3H), 0.81
(d, J = 7.0, 3H); 13C NMR (CDCl3, 125 MHz): δ 209.5, 133.7, 62.5, 53.0, 29.7, 19.2, 14.0; HRMS
(ESI-TOF) (m/z): [M + H]+ calcd for C8H14N3O, 168.1131; found, 168.1126.
(3j) (isolated as a 1:1 mixture of diastereomers): IR (υ[cm-1]) = 3128, 2983, 2941, 1709, 1453, 1360, 1224,
1115, 1077, 953, 792; Diastereomer A: 1H NMR (CDCl3, 500 MHz): δ 7.69 (d, J = 1.0, 1H), 7.55 (d, J = 1.0,
1H), 4.88-4.82 (m, 1H), 3.29 (dq, J = 8.8, 7.3, 1H), 2.04 (s, 3H), 1.58 (d, J = 7.0, 3H), 1.21 (d, J = 7.0, 3H);
13C NMR (CDCl3, 125 MHz): δ 209.8, 133.3, 123.1, 57.8, 51.7, 29.2, 18.3, 13.8; Diastereomer B: 1H NMR
(CDCl3, 500 MHz): δ 7.63 (d, J = 1.0, 1H), 7.53 (d, J = 1.0, 1H), 4.88-4.82 (m, 1H), 3.18 (dq, J = 8.8, 7.3,
1H), 2.22 (s, 3H), 1.57 (d, J = 6.5, 3H), 0.88 (d, J = 7.0, 3H); 13C NMR (CDCl3, 125 MHz): δ 209.5, 133.1,
123.5, 58.1, 52.7, 29.7, 19.7, 14.0; HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C8H14N3O, 168.1131;
found, 168.1128.
ACKNOWLEDGEMENTS
The authors thank Drs. S. M. Pitram and J. C. Tripp and Ms. J. Raushel for assisting in the preparation of
this manuscript. Financial support for this work was provided by the National Institute of General Medical
Sciences, National Institute of Health (GM28384), the Skaggs Institute for Chemical Biology, and the W.
M. Keck Foundation (K.B.S.). We also thank the Skaggs Foundation for a graduate student fellowship

HETEROCYCLES, Vol. 76, No. 2, 2008
1153
(S.W.K.) and Natural Science and Engineering Research Council of Canada for a postdoctoral fellowship
(J.E.H.).
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14. Reaction of 2h at 80 °C for 6 h gave a mixture of N1- (36%) and N2- (14%) isomers. Improved yield
was observed at 50 °C (see experimental section).
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