Copper(I)-catalyzed cycloaddition of methyl O-propargylpodocarpate and azides at room temperature

Article abstract of DOI:10.1080/00397911.2010.492081

Copper iodide was employed as an efficient catalyst for the synthesis of 1,2,3-triazole derivatives of podocarpic acid at room temperature through "click" chemistry cycloaddition reactions of methyl O-propargylpodocarpate and propargyl O-propargylpodocarpate with azides.

Full text of DOI:10.1080/00397911.2010.492081

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Copper(I)-Catalyzed Cycloaddition of
Methyl O-Propargylpodocarpate and
Azides at Room Temperature
Dao M. Nguyen a & D. Howard Miles a
a Natural Products Research Laboratory, Department of Chemistry,
University of Central Florida, Orlando, Florida, USA
Published online: 29 Apr 2011.
To cite this article: Dao M. Nguyen & D. Howard Miles (2011) Copper(I)-Catalyzed Cycloaddition of
Methyl O-Propargylpodocarpate and Azides at Room Temperature, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:12, 1759-1771,
DOI: 10.1080/00397911.2010.492081
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Synthetic Communications1, 41: 1759–1771, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.492081
COPPER(I)-CATALYZED CYCLOADDITION OF METHYL
O-PROPARGYLPODOCARPATE AND AZIDES AT
ROOM TEMPERATURE
Dao M. Nguyen and D. Howard Miles
Natural Products Research Laboratory, Department of Chemistry,
University of Central Florida, Orlando, Florida, USA
GRAPHICAL ABSTRACT
Abstract Copper iodide was employed as an efficient catalyst for the synthesis of
1,2,3-triazole derivatives of podocarpic acid at room temperature through ‘‘click’’
chemistry cycloaddition reactions of methyl O-propargylpodocarpate and propargyl
O-propargylpodocarpate with azides.
Keywords Azides; copper(I) iodide; methyl O-propargylpodocarpate; podocarpic acid
derivatives; 1,2,3-triazoles
INTRODUCTION
Triazoles are of great interest in organic synthesis because many compounds in
this class have displayed a broad spectrum of biological activity.[1–3] The synthesis of
1,2,3-triazoles by thermal heating of a terminal alkyne and an azide has been known
as the Huisgen 1,3-dipolar cycloaddition reaction since the 1960s.[4–6] However,
this reaction is rather slow and yields a mixture of 1,2-disubstituted and 1.4-
disubstituted 1,2,3-triazoles.
Received February 2, 2010.
Address correspondence to D. Howard Miles, Natural Products Research Laboratory, Department
of Chemistry, University of Central Florida, Orlando, FL 32816, USA. E-mail: dhmiles@pegasus.cc.
ucf.edu
1759

1760
D. M. NGUYEN AND D. H. MILES
Sharpless and coworkers have demonstrated that copper(I) salt–catalyzed 1,3-
dipolar cycloaddition reactions proceed efficiently in a polar medium such as a
mixture of tert-butyl alcohol and water.[7] As a result, the term ‘‘click reaction’’
was utilized.[8,9] Click chemistry reactions are more practical and reliable because
of thermodynamic driving forces of more than 20 Kcal molÀ1 [10]
The click reaction
.
between a terminal alkyne and an azide usually utilizes dimethylformamide
(DMF) [or a mixture of dimethylsulfoxide (DMSO)=H2O] at elevated temperatures
(60–80ꢀC) with a copper(I) catalyst that is generated in situ by employing copper(II)
sulfate and sodium ascorbate in aqueous media.[11] Moreover, a sterically hindered
base such as N,N-diisopropylethylamine or lutidine was required for optimal
results.[9,12]
The naturally occurring terpenoids, podocarpic acid and its derivatives, have
been known for their bioactive and antitumor properties.[13–15] This study reports
upon the synthesis of 1,2,3-triazole derivatives of podocarpic acid utilizing a click
chemistry approach that involved using copper(I) iodide in triethylamine as catalyst
for the cycloaddition of terminal alkynes with azides in dioxane at room tempera-
ture. The reaction provides methodology for the preparation of triazoles in good
yield and in a reasonable period of time (6–24 h), with a simple workup procedure.
Selected 1,2,3-triazole derivatives of podocarpic acid are being evaluated relative
to their potential as new drug leads for the treatment of cancer and other disease
targets.
RESULTS AND DISCUSSION
Methyl podocarpate (2) was synthesized (Scheme 1) in 81% yield from podo-
carpic acid (1). This conversion involved selective monomethylation of podocarpic
acid (1) by the utilization of a solution with 1 molar equivalent of dimethyl sulfate
in sodium hydroxide solution. The resulting product was identical upon comparison
of the mp, Infrared (IR), mass spectral (MS), and NMR data of 2 with an authentic
sample of methyl podocarpate (2).[16] Methyl podocarpate (2) was treated with
propargyl bromide and potassium carbonate in acetone to give methyl
O-propargylpodocarpate (3) in 88% yield. The structure of 3 was confirmed by
MS [high-resolution mass spectral (HRMS) analysis gave a molecular ion at
326.1886, which is consistent with a molecular formula of C21H26O3] and NMR
1
analysis (the H NMR of 3 showed a 2H signal at 4.65 d, which was not present
Scheme 1. Preparation of methyl O-propargylpodocarpate (3).

METHYL O-PROPARGYLPODOCARPATE
1761
Scheme 2. Preparation of azides 5a–g.
in 2). In addition, there was a singlet 1H signal at 2.45 d, which was consistent with
the presence of the terminal alkyne in the propargyl functionality of 3.
The seven novel 1,2,3-triazole derivatives of 3 (compounds 5a–g in Scheme 2)
were synthesized by the reaction of methyl O-propargylpodocarpate (3) with azides
4a–g by using copper(I) iodide catalyst and triethylamine in dioxane at room tem-
perature for a period of 6 to 24 h. The azides utilized were ethyl azidoacetate (4a),
1-azidobutane (4b), 1,1,1,2,2,3,3,4,4,5,5,6,6,-tridecafluoro-8-azidooctane (4c), 1,1,1,
2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-10-azidodecane (4d), azidobenzene (4e),
azidomethylbenzene (4f), and 1-(azidomethyl)-4-bromobenzene (4g). Compounds
4b and 4c contained fluoroalkyl groups, which were selected to investigate the possi-
bility of increased bioactivity due to fluorination.[17] Compounds 4a, 4f, and 4g were
synthesized in nearly quantitative yield via nucleophilic substitution of ethyl bro-
moacetate, benzyl chloride, and 1-(bromomethyl)-4-bromobenzene respectively with
sodium azide in acetonitrile at 80ꢀC with reaction times of from 4 to 20 h. Likewise,
compounds 4b, 4c, and 4d were synthesized by the reaction of 1-bromobutane,
1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-8-iodooctane, and 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-
heptadecafluoro-10-iododecane respectively with sodium azide in DMSO at 95 ꢀC
for 24 h. The NMR spectra of 4a, 4b, and 4f–g were identical upon comparison with
literature values for the respective compounds.[18–20] Compound 4e was synthesized
in 70% yield from phenyl hydrazine by a modified procedure reported by Lindsay
and Allen.[21] The NMR spectrum of compound 4e was identical upon comparison
with the NMR data reported in the literature.[22] The HRMS analysis of 4c gave a
molecular ion of 489.0115, which corresponded to a molecular formula of
C10H4F11N3. The IR of 4a–g showed strong absorption bands in the region of
2100–2200 cmÀ1 that are consistent with the presence of azide functionality.
The reaction of 3 with azides 4a–g utilized copper(I) iodide in triethylamine in
dioxane to obtain derivatives 5a–g in yields of 82, 84, 81, 80, 80, 92, and 90% respect-
ively. The HRMS confirmed the molecular ions of 5a–g as 455.2412, 425.2669,
715.1921, 815.1921, 445.2371, 459.2514, and 538.1689 respectively. These results
were consistent with the formulas of C25H33N3O5, C25H35N3O3, C29H30F13N3,
C31H30F17N3, C27H31N3O3, C28H33N3O3, and C28H32BrN3O3 respectively. The

1762
D. M. NGUYEN AND D. H. MILES
1H NMR spectra for 5a–g indicated a downfield shift to 7.45–8.05 d versus 2.5 d in
the starting 3. This result indicated that the alkyne proton in 3 had disappeared and
is consistent with the aromatic protons in the desired triazoles. A 2H signal was
present at 4.3–4.4 d in derivatives 5a–d, 5f, and 5g, which could be assigned to the
amino methylene group of the side chains. The presence of the desired alkyl and aryl
functionalities in 5a–g was indicated by additional signals in the aliphatic and aro-
matic regions respectively. Compound 5a possessed an additional 2H signal at
4.15 d, which could be assigned to the ethoxy group that was not present in 3. Com-
pound 5b showed additional multiplets at 1.85, 1.35, and 1 d, which integrated for a
total of seven protons. This was consistent with the presence of the n-butyl group.
1
The additional 2H multiplets at 2.85 d in the H NMR spectrum of 5c and 5d were
consistent with the presence of a methylene group attached next to a nitrogen atom
on the triazole rings. Signals were present in 5e at 7.45, 7.55, and 7.75 d, which
accounted for the five aromatic protons of the phenyl group. Likewise, signals were
present at 7.2 and 7.35 d in 5f, which integrated for 5H and could be assigned to the
aromatic protons that are present in a benzyl moiety. Compounds 5f and 5g showed
an additional 2H signal at 5.47 d, which is consistent with the presence of benzylic
protons in the assigned structures. Compound 5g also showed two 2H signals at
7.18 and 7.55 d that were not present in 3. This was consistent with the presence
of the four aromatic protons that are in the 4-bromophenyl group. The 13C NMR
spectra for 5a–g showed signals at 124 and 146 ppm, respectively, which is consistent
with the presence of the two carbons in the new 1,2,3-triazole moiety. In addition,
the disappearance of alkyne carbons at 76–78 ppm is consistent with the assigned
structures. Furthermore, additional signals (versus starting material compound 3)
for alkyl and aryl carbons were present in the 13C NMR spectrum of all derivatives.
Compound 5e showed aromatic carbon signals at 136.7, 129.8, 129.6, 128.4, 120.9,
and 120.6 ppm. Compound 5f showed aromatic carbon signals at 134.4, 130.0,
128.5, 128.3, 128.2, and 122.0 ppm as well as signals for a benzylic carbon at
54.3 ppm. Compound 5g showed aromatic carbon signals at 133.6, 132.4, 132.2,
129.6, 122.1, and 120.0 ppm as well as signals for a benzylic carbon signal at
53.5 ppm. Ester and ethoxy moieties were indicated in 5a by the signals at 171 and
62.5 ppm. Compounds 5a–d gave signals at 51.0, 49.0, 42.45, and 42.11 ppm, which
could be assigned to amino carbons.
Scheme 3 shows the utilization of click chemistry for synthesis of 1,2,3-triazole
derivatives of podocarpic acid (7) in 90% yield from 6. Compound 6 synthesized in
95% yield from by reacting methyl podocarpate (2) with propargyl chloroformate in
1
pyridine at 0 ꢀC. The H NMR of 6 showed a 2H singlet at 4.3 d for the propargyl
moiety and an additional 1H singlet proton at 2.2 d, which was indicative of an
alkyne functionality. In addition, compound 7 showed signals at 7.25 and 7.40 d,
which integrated for a total of five protons, which is consistent with the aromatic
protons that are present in a benzyl group. There was an additional 2H signal at
5.50 d, which could be assigned to the benzylic protons that were adjacent to the
triazole ring. The HRMS analysis of 6 and 7 gave molecular ions at 370.1774 and
503.2312, respectively, which were consistent with the formulas of C23H26O5 and
C29H33O5N3.
A 1,2,3-bis-triazole derivative of podocarpic acid (compound 9) was synthe-
sized in 70% yield from propargyl O-propargylpodocarpate (8), which had been

METHYL O-PROPARGYLPODOCARPATE
1763
Scheme 3. Preparation of triazole 7.
prepared by reacting podocarpic acid (1) with a two-fold excess of propargyl bro-
1
mide in potassium carbonate in acetone (Scheme 4). The H NMR analysis of 8
showed a 4H multiplet at 4.65 d, which was consistent with the presence of two pro-
pargyl groups. Compound 8 showed two additional 1H signals at 2. 35 and 2.40 d,
which account for the two terminal alkynes moieties. Click chemistry was further
explored in a reaction of a bis-alkyne functionality in 8 with phenyl azide catalyzed
by copper(I) in dioxane at room temperature to obtain 9. The 1H NMR of 9 showed
signals at 7.45, 7.55, and 7.75 d, which integrated for a total of 10 protons and is
consistent with the presence of the aromatic protons in the two benzyl groups.
The benzylic protons that were adjacent to the triazoles rings were observed as
two 2H signals at 5.25 and 5.35 d respectively. Further evidence that 9 had been
formed involved the disappearance of the two terminal alkyne protons that were
present in the starting 8. The HRMS analysis of 8 and 9 gave molecular ions at
350.1893 and 588.2843 that were consistent with the formulas of C23H26O3 and
C35H36O3N6, respectively.
In summary, 1,2,3-triazole derivatives of podocarpic acid (compounds 5a–g, 7,
and 9) were synthesized in good yield by the copper(I) iodide–catalyzed cycloaddi-
tion of methyl O-propargylpodocarpate and propargyl O-propargylpodocarpate
with alkyl and aryl azides at room temperature. Thus, this work provides efficient
methodology for the synthesis of novel 1,2,3-triazole derivatives of podocarpic
acid. Furthermore, their potential as new drug leads is indicated by the fact that
evaluation of the activity of compounds 5b, 5e, and 5f against 60 human cancer
Scheme 4. Preparation of bis-triazole 9.

1764
D. M. NGUYEN AND D. H. MILES
cell lines by NIH=NCI Developmental Therapeutics Program (DTP) demonstrated
that compound 5b had significant activity (70%) relative to inhibiting the growth
of melanoma SK-MEL-5 cells.
EXPERIMENTAL
Podocarpic acid (1) was recrystallized from methanol and dried under vacuum.
IR spectra were recorded with a Perkin-Elmer spectrometer. NMR spectra were
recorded with Mercury 300-MHz and Varian 500-MHz spectrometers in deuterated
chloroform. Precaution was taken when azides were synthesized because they are
potentially explosive. This was performed by heating at moderate temperatures
and by working on a small scale.
Preparation of Methyl Podocarpate (2)
Podocarpic acid (1) (50 g, 0.18 mol) was dissolved in methanol (300 mL) in a
600 mL beaker. A solution of sodium hydroxide (7.3 g, 0.18 mol) in water
(200 mL) was then added. The resulting solution was continually stirred until the
podocarpic acid (1) was completely dissolved in the mixture. To this solution,
dimethyl sulfate (19 mL, 0.18 mol) was added dropwise over a 30-min period at room
temperature. For an additional 30 min, the solution was then allowed to solidify with
stirring. At the end of this period, the solution was heated to boiling for 15 min and
then allowed to cool to room temperature. A white precipitate formed and was
removed (after cooling in an ice bath) by vacuum filtration to yield 2 (42 g,
0.15 mol) as a white solid (yield 80%). The resulting solid was recrystallized from
methanol and dried under vacuum to obtain methyl podocarpate (2) as white needÀle1s
with mp 206–208 ꢀC. IR: 1720, 1600, 1540, 1490, 1460, 1200, 1190, 1150 cm
.
1H NMR (CDCl3, 300 MHz): 6.95 (d, 1H), 6.80 (s, 1H), 6.65 (d, 1H), 3.58 (s, 3H),
2.80 (m, 2H), 2.25 (m, 3H), 1.95 (m, 2H), 1.40–1.60 (m, 4H), 1.28 (s, 3H), 1.05
(m, 1H), 1.00 (s, 3H) ppm. 13C NMR (CDCl3, Mercury 500 MHz): 178, 153.5,
149.6, 130.1, 127.6, 113, 112.1, 52.8, 51.3, 44, 39.4, 38.6, 37.6, 31.2, 28.6, 22.9,
21.1, 20 ppm.
Preparation of Methyl O-Propargylpodocarpate (3)
Compound 2 (4.6 g, 0.016 mol) was weighed and dissolved in acetone (60 mL)
in a 200-mL flask. To this solution, potassium carbonate (6.6 g, 0.048 mol) and 18
crown 6 ether (50 mg) were added. Then a solution of 80% of propargyl bromide
in toluene (3.1 g) was added, and the resulting solution was stirred using a magnetic
stirring bar. The solution was then refluxed under a nitrogen atmosphere at 70 ꢀC for
20 h. At the end of this period, the solution was allowed to cool to room tempera-
ture. The resulting solution was filtered and washed with ethyl acetate (60 mL),
and the filtrate was evaporated in vacuo to obtain crude product 3. The crude pro-
duct was purified on a silica-gel column by using hexane and ethyl acetate (70:30) as
eluents to obtain pure 3 (4.0 g, 0.012 mol) in 76% yield as a white powder with mp
89 ꢀC. IR: 3267, 2987, 2852, 2172, 1713, 1605, 1581, 1502, 1459, 1380, 1304, 1241,
1
1191, 1072 cmÀ1. H NMR (CDCl3, 300 MHz): 7.00 (m, 1H), 6.90 (s, 1H), 6.75

METHYL O-PROPARGYLPODOCARPATE
1765
(m, 1H), 4.66 (s, 2H), 3.67 (s, 3H), 2.65–2.85 (m, 2H), 2.50 (s 1H), 2.2–2.3 (m, 2H),
1.95–2.05 (m, 2H), 1.42–1.65 (m, 4H), 1.28 (s, 3H), 1.04–1.10 (m, 4H) ppm. 13C
NMR (CDCl3, 300 MHz): 177.90, 155.70, 149.38, 129.86, 128.65, 112.36, 112.13,
78.89, 75.31, 55.87, 52.75, 51.29, 44.00, 39.35, 38.67, 37.61, 31.26, 28.56, 22.89,
21.06, 19.98 ppm. HRMS calcd. for C21H26O3 326.4346; found 326.1886.
Synthesis of Ethyl Azidoacetate (4a)
Ethyl bromoacetate (5 g, 0.03 mol) was weighed and dissolved in acetonitrile
(150 mL) in a 500-mL flask. To this solution, sodium azide (2.35 g, 0.036 mol) was
added. The resulting mixture was stirred using a magnetic stirring bar and then
refluxed under nitrogen at 80 ꢀC for 4 h. At the end of this period, the solution
was allowed to cool to room temperature and then filtered. The filtrate was evapo-
rated under reduced pressure to obtain a crude product, which was further purified
on a silica-gel column using hexane as the eluent to obtain ethyl azidoacetate (4a)
(3.5 g, 0.027 mol) as a pure colorless liquid (90% yield). IR: 2986, 2106, 1744,
1
1426, 1373, 1288, 1195, 1024 cmÀ1. H NMR (CDCl3, 500 MHz): 4.26–4.30 (m,
2H), 3.87 (s, 2H), 1.30–1.36 (m, 3H) ppm. 13C NMR (CDCl3, 500 MHz): 168.30,
61.88, 50.37, 14.06 ppm.
Synthesis of Butyl Azide (4b)
1-Bromobutane (5.5 g, 0.04 mol) was weighed and dissolved in DMSO (50 mL)
at room temperature in a 200 mL flask to which was added sodium azide (3.9 g,
0.06 mol). The solution was then refluxed under nitrogen at 95 ꢀC for 24 h. At the
end of this period, the solution was allowed to cool to room temperature. A white
precipitate formed, and the resulting mixture was transferred into water (100 mL)
in a separatory flask to which diethyl ether (50 mL) was added. The organic phase
was then removed. The aqueous phase was then extracted three times with portions
of ether (100 mL). The ether phases were then combined, washed with water, dried
with sodium sulfate, and then evaporated in vacuo to yield butyl azide 9a (3 g,
0.03 mol) in 80% yield as a colorless liquid. IR: 2090 cmÀ1 1H NMR (CDCl3,
.
500 MHz): 3.18–3.21 (m, 2H), 1.49–1.55 (m, 2H), 1.30–1.37 (m, 2H), 0.86–0.89 (m,
3H) ppm. 13C NMR (CDCl3, 500 MHz): 39.97, 29.82, 18.87, 12.60 ppm.
Synthesis of 1,1,1,2,2,3,3,4,4,5,5,6,6,-Tridecafluoro-8-
azidooctane (4c)
1,1,1,2,2,3,3,4,4,5,5,6,6,-Tridecafluoro-8-iodooctane (4.8 g, 0.010 mol) was
weighed and dissolved in DMSO (25 mL), to which sodium azide (1.0 g, 0.015 mol)
was added. The resulting mixture was heated to 95 ꢀC for 24 h and then worked
up as described in the procedure for 4b to obtain 4c (3.1 g, 0.007 mol) as a white solid
1
(70% yield). IR: 2106, 1233, 1190, 1122, 1075 cmÀ1. H NMR (CDCl3, 500 MHz):
3.40 (m, 2H), 2.27–2.37 (m, 2H) ppm. 13C NMR (CDCl3, 500 MHz): 41.40,
29.06 ppm. HRMS calcd. for C10H4F11N3 489.1345; found 489.0115.

1766
D. M. NGUYEN AND D. H. MILES
Synthesis of 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-Heptadecafluoro-10-
azidodecane (4d)
1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-Heptadecafluoro-8-iodooctane (5.74 g, 0.010 mol)
was weighed and dissolved in DMSO (25 mL) to give a solution to which sodium azide
(1 g, 0.015 mol) was added. The resulting mixture was heated to 95 ꢀC for 24 h and then
worked up as described for 4b to give 4d (4.2 g, 0.009 mol) in 85% yield as a white solid.
1
IR: 2107, 1200, 1146, 962 cmÀ1. H NMR (CDCl3, 500 MHz): 3.50–3.60 (m, 2H),
2.20–2.35 (m, 2H) ppm. 13C NMR (CDCl3, 500 MHz): 43.29, 30.79 ppm.
Synthesis of Phenyl Azide (4e)
Phenyl hydrazine (3.4 g, 0.031 mol) was weighed into a 30-mL beaker and then
was added into a solution of hydrochloric acid (6 mL) and water (30 mL) at 0–5 ꢀC in
an ice bath. The resulting solution was stirred and maintained at this temperature.
Diethyl ether (10 mL) was then added, which was followed by the dropwise addition
of a solution of sodium nitrite (2.5 g, 0.042 mol) in water (5 mL). The resulting mix-
ture was allowed to stand at this temperature for an additional 15 min, and then
diethyl ether (10 mL) was added. It was poured into a 100-mL separatory flask
and extracted with portions of diethyl ether (50 mL). The organic layers were com-
bined, dried over sodium sulfate, and evaporated in vacuo to obtain a crude product.
The crude product was purified on a silica-gel column using hexane as eluent to
obtain a colorless liquid 4e (2.2 g, 0.018 mol) in 60% yield. IR: 2125, 2094, 1594,
1
1492, 1294, 1281 cmÀ1. H NMR (CDCl3, 500 MHz): 7.36–7.39 (m, 2H), 7.05–7.18
(m, 3H) ppm. 13C NMR (CDCl3, 500 MHz): 140.0, 129.78, 124.89, 119.04 ppm.
Synthesis of Azidomethylbenzene (4f)
Benzyl chloride (3.8 g, 0.03 mol) was dissolved in acetonitrile (150 mL) to which
2.9 g of sodium azide (2.9 g, 0.045 mol) was added and then heated to 80 ꢀC for 20 h.
The crude product was purified on a silica-gel column using hexane as eluent to
obtain azidomethylbenzene (4f) (3.0 g, 0.023 mol) as a colorless liquid (75% yield).
IR: 2150 cmÀ1 1H NMR (CDCl3, 500 MHz): 7.35–7.43(m), 4.37(s) ppm. 13C
.
NMR (CDCl3, 500 MHz): 135.39, 128.93, 128.88, 128.40, 128.31, 128.26, 54.82 ppm.
Synthesis of 1-(Azidomethyl-4-bromobenzene) (4g)
4-Bromobenzylchloride (6.6 g, 0.030 mol) was utilized in a procedure that was
identical to that used for the synthesis of 4f to obtain 4g (5.5 g, 0.026 mol) as a color-
less liquid (85% yield). IR: 2932, 2095, 1592, 1488, 1456, 1406, 1341, 1283, 1195,
1
1070, 1012, 883 cmÀ1. H NMR (CDCl3, 500 MHz): 7.50–7.52 (m, 2H), 7.18–7.21
(m, 2H), 4.31 (s, 2H) ppm. 13C NMR (CDCl3, 500 MHz): 134.39, 132.10, 131.91,
129.92, 129.70, 122.35, 54.09 ppm.
General Procedure for the Preparation of 1,2,3-Triazole 5a–g
Copper(I) iodide (0.05 g, 0.003 mol) and triethylamine (2 mL) were added to a
weighed amount (1.5 molar equivalent) of each azide dissolved in dioxane (10 mL) in

METHYL O-PROPARGYLPODOCARPATE
1767
a 100-mL flask. This was followed by the addition of 3 (1.0 g, 0.003 mol). The result-
ing solution was stirred using a magnetic bar under a nitrogen atmosphere at room
temperature for a period from 6 to 24 h. The resulting solution was filtered and
washed with portions of ethyl acetate (60 mL). The filtrate was evaporated in vacuo
to give a solid material, which was further purified by open column chromatography
with 63- to 200-mesh silica gel. Hexane and ethylacetate (1:1) were used as the
eluents to obtain the pure 1,2,3-triazole derivatives of podocarpic acid.
Data for Compounds 5a–g
Compound 5a. Ethyl azidoacetate (0.6 g) was utilized with the reaction time
of 6 h to obtain 5a (1.1 g, 0.0023 mol) as a white solid with mp 145 ꢀC (82% yield). IR
(CHCl3): 2954, 2848, 1750, 1723, 1608, 1575, 1501, 1468, 1373, 1328, 1281, 1239,
1
1210, 1150, 1097, 1022, 972 cmÀ1. H NMR (CDCl3, 500 MHz): 7.80 (s, 1H), 7.00
(m, 1H), 6.92 (s, 1H), 6.78 (m, 1H), 5.16–5.20 (m, 2H), 4.35 (m, 2H), 4.25 (m,
2H), 3.66 (s, 3H), 2.65–2.85 (m, 2H), 2.18–2.30 (m, 3H), 1.90–2.02 (m, 2H),
1.50–1.62 (m, 2H), 1.25–1.42 (m, 7H), 1.05 (m, 1H), 1.02 (s, 3H) ppm. 13C NMR
(CDCl3, 300 MHz): 177.89, 171.15, 166.18, 156.36, 149.44, 145.0, 130.05, 128.31,
124.01, 111.96, 62.48, 60.15, 52.25, 51.11, 50.91, 43.98, 39.38, 38.67, 37.75, 31.22,
28.36, 22.77, 21.06, 19.97, 14.08 ppm. HRMS calcd. for C25H33N3O5 455.5528;
found 455.2412.
Compound 5b. Azidobutane (0.45 g) was utilized with the reaction time of
24 h to obtain an oily liquid 5b (1.0 g, 0.0024 mol) in 84% yield. IR: 2956, 2872,
1721, 1608, 1574, 1501, 1465, 1379, 1327, 1282, 1245, 1211, 1190, 1149, 1098,
1
1033, 834 cmÀ1. H NMR (CDCl3, 300 MHz): 7.60 (s, 1H), 7.00 (m, 1H), 6.90 (s,
1H), 6.80 (m, 1H), 5.22 (s 1H), 4.40 (m, 2H), 3.66 (s, 3H), 2.65–2.85 (m, 2H),
2.20–2.35 (m, 3H), 1.90–2.00 (m, 4H), 1.50–1.65 (m,2H), 1.35–1.40 (m, 6H), 1.28
(s, 3H), 0.96–1.02 (m, 7H) ppm. 13C NMR (CDCl3, 300 MHz): 177.85, 156.42,
149.43, 144.15, 130.01, 128.26, 122.23, 112.31, 112.05, 62.03, 52.23, 51.32, 48.95,
44.00, 39.57, 38.68, 37.63, 32.21, 31.24, 28.62, 22.86, 21.09, 21.00, 19.70,
13.49 ppm. HRMS calcd. for C25H35N3O3 425.5698; found 425.2669.
Compound 5c. Compound 4c (1.75 g) was utilized with the reaction time of
24 h to obtain 1.7 g of 5c (1.7 g, 0.0024 mol) as a white solid with mp 60 ꢀC (81%
1
yield). IR: 2951, 1722, 1610, 1501, 1236, 1144 cmÀ1. H NMR (CDCl3, 500 MHz):
7.70 (s, 1H), 7.00 (m, 1H), 6.90 (s, 1H), 6.78 (m, 1H), 5.20 (s, 2H), 4.65 (m, 2H),
3.66 (s, 3H), 2.70–2.90 (m, 4H), 2.20–2.35 (m, 3H), 1.92–2.05 (m, 2H), 1.60 (m,
1H), 1.54 (m, 1H), 1.40 (m, 1H), 1.28 (s, 3H), 1.02–1.10 (m, 4H) ppm. 13C NMR
(CDCl3, 500 MHz): 177.88, 156.22, 149.51, 145.10, 129.98, 128.44, 123.18, 112.18,
111.92, 62.06, 52.75, 51.30, 43.98, 42.45, 39.40, 38.68, 37.58, 31.81, 31.23, 28.56,
22.92, 21.04, 19.95 ppm. HRMS calcd. for C29H30F13N3O3 715.5535; found
715.1921.
Compound 5d. Compound 4d (2.2 g) was utilized with the reaction time of
24 h to obtained 1.9 g of 5d (1.9 g, 0.0023 mol) as a white solid with mp 70 ꢀC
1
(80% yield). IR: 2956, 1723, 1609, 1501, 1450, 1250, 1203, 1146, 1071 cmÀ1. H
NMR (CDCl3, 500 MHz): 7.63 (s, 1H), 7.00 (m, 1H), 6.90 (s, 1H), 6.75 (m, 1H),

1768
D. M. NGUYEN AND D. H. MILES
4.70 (m, 2H), 3.66 (s, 3H), 2.70–2.90 (m, 4H), 2.18–2.30 (m, 3H), 1.90–2.02 (m, 2H),
1.60 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.28 (s, 3H), 1.03–1.10 (m, 4H) ppm. 13C
NMR (CDCl3, 500 MHz): 177.83, 156.31, 149.53, 145.10, 130.00, 128.44, 123.12,
112.25, 111.98, 62.04, 52.71, 51.30, 44.00, 42.11, 39.25, 38.68, 37.61, 31.85, 31.22,
28.60, 28.46, 22.97, 22.85, 20.43, 19.87 ppm. HRMS calcd. for C31H30F17N3O3,
815.5670; found 815.1921.
Compound 5e. Azidobenzene (0.54 g) was utilized with a reaction time of
24 h to obtain 1 g of 5e (1.0 g, 0.0022 mol) in 80% yield as a white solid with mp
118 ꢀC IR: 2950, 2848, 1720, 1607, 1574, 1501, 1467, 1437, 1379, 1282, 1243, 1190,
1
1151, 1137, 1098, 989 cmÀ1. H NMR (CDCl3, 500 MHz): 8.02 (s, 1H), 7.75 (m,
2H), 7.65 (m, 2H), 7.50 (m, 1H), 7.00 (m, 1H), 6.95 (s, 1H), 6.80 (m, 1H), 5.28
(m, 2H), 3.67 (s, 3H), 2.85 (m, 1H), 2.75 (m, 1H), 2.20–2.30 (m, 3H), 1.90–2.05
(m, 2H), 1.60 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.28 (s, 3H), 1.04–1.10 (m, 4H)
ppm. 13C NMR (CDCl3, 500 MHz): 177.89, 156.34, 149.52, 145.63, 136.70, 129.99,
129.79, 129.59, 128.86, 128.44, 120.88, 120.61, 112.23, 111.96, 62.09, 52.75, 51.28,
43.99, 39.41, 38.70, 37.60, 31.25, 28.57, 22.95, 21.06, 19.98 ppm. HRMS calcd. for
C27H31N3O3 445.5602; found 445.2371.
Compound 5f. Azidomethylbenzene (0.6 g) was utilized with a reaction time
of 24 h to obtain an oily liquid 5f (1.2 g, 0.0026 mol) in 92% yield. IR: 2954, 2852,
1722, 1610, 1576, 1500, 1458, 1439, 1382, 1284, 1193, 1123, 1072, 1035, 928 cmÀ1
.
1H NMR (CDCl3, 500 MHz): 7.45 (s, 1H), 7.28–7.32 (m, 2H), 7.18–7.20 (m, 2H),
6.89 (m, 1H), 6.78 (s, 1H), 6.64 (m, 1H), 5.45 (s, 2H), 5.07 (s, 2H), 3.63 (s, 3H),
2.80 (m, 1H), 2.62–2.70 (m, 1H), 2.10–2.20 (m, 3H), 1.90–1.95 (m, 2H), 1.62 (s,
1H), 1.58 (m, 1H), 1.44 (m, 1H), 1.24 (m, 1H), 1.19 (s, 3H), 0.96–1.02 (m, 1H),
0.92 (s, 3H) ppm. 13C NMR (CDCl3, 500 MHz): 177.89, 156.36, 149.41, 145.10,
134.46, 130.00, 129.01, 128.88, 128.45, 128.30, 128.15, 122.13, 122.02, 112.26,
111.99, 62.19, 54.25, 52.35, 51.35, 43.98, 38.96, 38.66, 37.59, 31.24, 28.61, 22.94,
21.08, 19.99 ppm. HRMS calcd. for C28H33N3O3 459.5870; found 459.2514.
Compound 5g. Compound 4g (0.95 g) was utilized with the reaction time of
6 h to obtain 1.4 g of 5g (1.4 g, 0.0026 mol) as a white solid with mp 45 ꢀC (yield 90%).
1
IR: 2950, 1720, 1605, 1500, 1470, 1450, 1280, 1210, 1180 cmÀ1. H NMR (CDCl3,
500 MHz): 7.55–7.60 (m, 3H), 7.18 (m, 2H), 6.95 (m, 1H), 6.85 (s, 1H), 6.75 (m,
1H), 5.47 (s, 2H), 5.16 (s, 2H), 3.66 (s, 3H), 2.65–2.75 (m, 2H), 2.05–2.15 (m, 3H),
1.95–2.00 (m, 2H), 1.75 (s, 1H), 1.60 (m, 1H), 1.50 (m, 1H), 1.20–1.30 (s, 3H),
1.00–1.10 (m, 4H) ppm. 13C NMR (CDCl3, 500 MHz): 177.83, 156.34, 149.45,
145.76, 133.56, 132.41, 132.18, 129.82, 129.56, 128.34, 122.35, 122.10, 119.95,
112.07, 112.06, 62.18, 53.49, 52.35, 51.37, 44.00, 39.07, 38.67, 37.75, 31.23, 28.12,
22.36, 21.08, 20.01 ppm. HRMS calcd. for C28H32BrN3O3, 538.4841; found
538.1689.
Preparation of Compound 6
Methyl podocarpate (2) (2.88 g, 0.010 mol) was weighed and dissolved in pyri-
dine (10 mL) and THF (10 mL) at 0 ꢀC. To this solution, propargyl chloroformate
(1.8 g, 0.015 mol) was added dropwise over a period of 15 min. The resulting solution

METHYL O-PROPARGYLPODOCARPATE
1769
was stirred at this temperature for an additional 3 h and then poured into a cold
solution of hydrochloric acid (9 mL) in water (50 mL). The resulting solution was
transferred into a separatory flask and then extracted with diethyl ether (50 mL)
three times. The organic phases were combined and washed with a solution of 5%
sodium bicarbonate and then water. This solution was dried over sodium sulfate
and evaporated in vacuo obtain a white solid. The crude product was further purified
on a silica-gel column by using hexane and ethyl acetate (7:3) as eluents to obtain 6
(3.3 g, 0.009 mol), a white solid with a mp of 125–126 ꢀC in 90% yield. IR: 3235, 2950,
1
2836, 1762, 1708, 1607, 1493, 1467, 1435, 1329, 1278, 1231, 1191, 1100 cmÀ1. H
NMR (CDCl3, 500 MHz): 6.96–7.02 (m, 2H), 6.81–6.84 (m, 1H), 4.76 (s, 2H), 3.60
(s, 3H), 2.81–2.85 (m, 1H), 2.66–2.73 (m, 1H), 2.50 (s, 1H), 2.10–2.20 (m, 3H),
1.85–1.95 (m, 2H), 1.52–1.58 (m, 1H), 1.44–1.46 (m, 1H), 1.30–1.36 (m, 1H), 1.20
(s, 3H), 1.02–1.05 (m, 1H), 1.01 (s, 3H) ppm. 13C NMR (CDCl3, 500 MHz):
177.76, 153.32, 149.56, 149.16, 133.41, 129.99, 118.0, 76.66, 76.09, 55.77, 52.42,
51.31, 43.96, 39.25, 38.64, 37.54, 31.45, 28.50, 22.95, 20.83, 19.86 ppm. HRMS calcd.
for C22H26O5 370.4444; found 370.1774..
Preparation of Compound 7
Azidomethylbenzene (0.6 g, 0.0045 mol) was weighed and dissolved in dioxane
(10 mL) in a 100-mL flask to which a solution of copper(I) iodide (0.05 g) and 6
(1.1 g, 0.003 mol) in triethylamine (2 mL) was added. The mixture was stirred (with
a magnetic stirring bar) under a nitrogen atmosphere at room temperature for
24 h. The resulting solution was filtered and washed with portions of ethyl acetate
(60 mL). The filtrate was evaporated in vacuo to give a solid material, which was
further purified by open column chromatography with 63- to 200-mesh silica gel.
Hexane and ethylacetate (1:1) were used as the eluents to obtain 7 (1.3 g,
0.0026 mol) in 90% yield as a white crystal with mp 90 ꢀC. IR: 2952, 1758, 1721,
1500, 1454, 1227, 1145, 1047 cmÀ1 1H NMR (500 MHz, CDCl3): 7.80 (s, 1H),
.
7.60 (m, 3H), 7.50 (m, 2H), 7.00 (m, 2H), 6.80 (m, 1H), 5.77 (s, 2H), 5.32 (s, 2H),
3.62 (s, 3H), 2.85 (m, 1H), 2.75 (m, 1H), 2.25 (m, 1H), 2.10–2.19 (m,
2H), 1.92–2.00 (m, 2H), 1.60 (m, 1H), 1.50 (m, 1H), 1.40 (m, 1H), 1.25 (s, 3H),
1.02–1.08 (m, 1H), 1.00 (s, 3H) ppm. 13C NMR (500 MHz, CDCl3): 177.77,
153.88, 149.53, 149.10, 142.01, 134.27, 133.37, 129.97, 129.20, 128.93, 128.63,
128.20, 124.00, 118.05, 117.91, 61.41, 54.32, 52.40, 51.75, 43.95, 39.22, 38.62,
37.53, 31.45, 28.51, 22.95, 20.82, 19.86 ppm. HRMS calcd. for C29H33N3O5
503.5968; found 503.2312.
Preparation of Propargyl O-Propargylpodocarpate (8)
Podocarpic acid (2.75 g, 0.01 mol) was weighed and dissolved in acetone
(60 mL) in a 200-mL flask. To this solution, 12 g of potassium carbonate (12 g,
0.087 mol), 18 crown 6 ether (50 mg), and a solution of 80% propargyl bromide in
toluene (4.5 g) were added. The resulting solution was then connected to a condenser
under a nitrogen atmosphere and stirred on a hotplate at 70 ꢀC for 20 h. At the end
of this period, the solution was allowed to cool to room temperature. The resulting
solution was filtered and washed with ethyl acetate (60 mL), and the filtrate was

1770
D. M. NGUYEN AND D. H. MILES
evaporated in vacuo to obtain a crude product 8. The product was purified on a
silica-gel column using hexane and ethyl acetate (70:30) as eluents to obtain 8
(2.5 g, 0.007 mol) as a white powder with mp 99 ꢀC in 70% yield. IR: 3300, 3275,
2955, 2205, 2167, 2034, 1994, 1970, 1719, 1606, 1571, 1282, 1231, 1179, 1136,
1
1038 cmÀ1. H NMR (CDCl3, 300 MHz): 7.00 (m, 1H), 6.93 (s, 1H), 6.85 (m, 1H),
4.65–4.70 (m, 4H), 2.65–2.95 (m, 2H), 2.50 (s, 1H), 2.45 (s, 1H), 2.20–2.30 (m,
3H), 2.00–2.10 (m, 2H), 1.55–1.65 (m, 2H), 1.40–1.42 (m, 1H), 1.35 (s, 3H),
1.05–1.10 (m, 4H) ppm. 13C NMR (CDCl3, 300 MHz): 176.51, 155.72, 149.30,
129.87, 128.63, 112.36, 112.17, 78.50, 77.68, 75.34, 74.67, 55.87, 52.79, 51.56,
44.14, 39.29, 38.77, 37.58, 31.27, 28.46, 23.22, 21.02, 19.90 ppm. HRMS calcd. for
C23H26O3 350.4566; found 350.1893.
Preparation of Compound 9
Copper(I) iodide (0.05 g), triethylamine (2 mL), and 8 (1.05 g, 0.003 mol) were
added to azidobenzene (0.54 g, 0.0045 mol), which had been weighed and then dis-
solved in dioxane (10 mL) in a 100-mL flask. The mixture was stirred (with a mag-
netic stirring bar) under a nitrogen atmosphere at room temperature for 24 h. The
resulting solution was filtered and washed with several portions of ethyl acetate
(60 mL). The filtrate was evaporated in vacuo to give a solid material, which was
further purified by using open column chromatography with 63- to 200-mesh silica
gel. Hexane and ethyl acetate (1:1) were used as the eluents to obtain 9 (1.2 g,
0.002 mol) in 70% yield as a white solid with mp 85–87 ꢀC. IR: 2931, 1717, 1607,
1
1506, 1465, 1246 cmÀ1. H NMR (500 MHz, CDCl3): 8.05 (s, 2H), 7.70–7.74 (m,
4H), 7.52–7.54 (m, 6H), 6.95 (m, 1H), 6.85 (s, 1H), 6.80 (m, 1H), 5.25–5.32 (m,
4H), 2.85 (m, 1H), 2.75 (m, 1H), 2.30 (m, 1H), 2.15–2.20 (m, 2H), 2.00 (m, 2H),
1.75–1.85 (m, 2H), 1.38–1.40 (m, 1H), 1.29 (s, 3H), 1.15 (m, 1H), 0.92 (s, 3H)
ppm. 13C NMR (500 MHz, CDCl3): 177.90, 156.15, 149.87, 145.10, 143.54, 137.25,
130.00, 129.82, 129.79, 129.00, 128.87, 128.21, 128.11, 122.23, 120.89, 120.61,
112.19, 112.01, 62.00, 57.05, 52.82, 44.13, 39.02, 38.75, 37.51, 31.00, 28.07, 23.03,
20.77, 19.98 ppm. HRMS calcd. for C35H36O3N6, 588.7066; found 588.2843.
ACKNOWLEDGMENTS
This work was supported by the Chemistry Department of the University of
Central Florida. The authors thank the Nebraska Center for Mass Spectrometry
for providing the MS data.
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