Copper-catalyzed cross-coupling reactions of methyl 13-iodo-o- methylpodocarpate and alcohols

Article abstract of DOI:10.1080/00397910903134642

Copper iodide was utilized as a relatively inexpensive catalyst for the synthesis of podocarpic acid ether derivatives in excellent yields through the one-step cross-coupling reaction of methyl 13-iodo-O-methylpodocarpate with alcohols. Copyright

Full text of DOI:10.1080/00397910903134642

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Copper-Catalyzed Cross-Coupling
Reactions of Methyl 13-Iodo-O-
methylpodocarpate and Alcohols
Manjeera Yalavarty a , Courtney M. Paradise a , Travis A. L. Klein a &
D. Howard Miles a
a Natural Products Research Laboratory, Department of Chemistry,
University of Central Florida, Orlando, Florida, USA
Version of record first published: 06 May 2010
To cite this article: Manjeera Yalavarty, Courtney M. Paradise, Travis A. L. Klein & D. Howard Miles
(2010): Copper-Catalyzed Cross-Coupling Reactions of Methyl 13-Iodo-O-methylpodocarpate and
Alcohols, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:11, 1625-1630
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Synthetic Communications1, 40: 1625–1630, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903134642
COPPER-CATALYZED CROSS-COUPLING REACTIONS
OF METHYL 13-IODO-O-METHYLPODOCARPATE AND
ALCOHOLS
Manjeera Yalavarty, Courtney M. Paradise,
Travis A. L. Klein, and D. Howard Miles
Natural Products Research Laboratory, Department of Chemistry,
University of Central Florida, Orlando, Florida, USA
Copper iodide was utilized as a relatively inexpensive catalyst for the synthesis of podocarpic
acid ether derivatives in excellent yields through the one-step cross-coupling reaction of
methyl 13-iodo-O-methylpodocarpate with alcohols.
Keywords: Aryl ethers; copper(I) iodide; methyl 13-iodo-O-methylpodocarpate; podocarpic acid
INTRODUCTION
The goal of this work was to synthesize novel ether derivatives of podocarpic
acid at the C-13 aromatic position. In regard to the synthesis of aryl ethers, it is
known that aromatic ethers can be prepared from aryl halides.[1] The most general
synthesis of diaryl ethers, which has the disadvantage of requiring strong reaction
conditions, has been the copper-mediated Ullmann coupling of aryl bromides and
aryl iodides with phenols.[2] Goldberg[3] also used a copper catalyst to study the
formation of ethers from aryl bromides. However, the yields were poor, separations
were difficult, and high temperatures were required (200 ꢀC). Thus, a search for more
optimal reaction conditions was needed.
Palladium has been utilized as a catalyst for the formation of ethers at moder-
ate temperatures and has resulted in relatively good product yield.[4] However, the
palladium catalyst is expensive, and for this reason, a search was conducted for an
inexpensive copper catalyst[5,6] for the coupling of an aryl halide with an alcohol that
would yield an aryl ether. The advantages of a copper catalyst are that it is not only
cheap but also can be used in versatile conditions such as in the presence of moisture
or oxygen. For these reasons, this study utilized a copper catalyst for the synthesis of
novel ether derivatives of podocarpic acid.
Received May 2, 2009.
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
1625

1626
M. YALAVARTY ET AL.
RESULTS AND DISCUSSION
The first step toward achieving the goal of the synthesis of novel C-13 ether
derivatives of podocarpic acid involved the methylation of podocarpic acid (1)[6]
(Scheme 1) to form methyl O-methylpodocarpate (2). This process resulted in the
formation of the desired compound 2 in 84% yield with a melting point of 127 ꢀC.
The infrared (IR), NMR, and mass spectra (MS) of compound 2 were identical with
those of an authentic sample of methyl O-methylpodocarpate (2).[7]
The formation of methyl 13-iodo-O-methylpodocarpate (3) in 94% yield
(melting point of 149 ꢀC) was achieved by the reaction of iodine with methyl
O-methylpodocarpate (2) as shown in Scheme 2. The IR, NMR, and MS data of
compound 3 were identical with those of an authentic sample of methyl 13-iodo-O-
methylpodocarpate (3).[8]
As shown in Scheme 3, the novel derivatives of compound 3 (compounds 4, 5,
and 6) were synthesized via the reaction of methyl 13-iodomethylpodocarpate (3)
with aliphatic alcohols using copper(I) iodide catalyst. The general procedure
involved the utilization of 1 molar equivalents of compound 3 with 1.5 molar equiva-
lents of the corresponding alcohol, 0.1 molar equivalents of copper(I) iodide, and 2
molar equivalents of potassium carbonate. This mixture was then refluxed in
N,N-dimethylformamide for 4 h. The alcohols utilized were methanol, ethanol,
and 1-propanol, and the resulting yields for compounds 4, 5, and 6 were 84, 88,
and 84% respectively.
The structures of derivatives 4, 5, and 6 were determined through the utilization
of MS, IR, and NMR analysis. The IR spectrum of compounds 4, 5, and 6 gave
signals at 1730 cmÀ1, which corresponded to the methyl ester they all have in
common. The signals at 1450, 1490, and 1600 cmÀ1 confirmed the presence of an aro-
matic ring in the aryl ether derivatives, whereas a signal at 1200cmÀ1 corresponded to
the C-O bond present in the ether and ester functionalities that are present in all three
compounds. High-resolution mass spectra (HRMS) confirmed the molecular ions of
compounds 4, 5, and 6 to be, respectively, 332.4243, 346.4404, and 360.4756. These
results are consistent with the formulas of C20H28O4(332.4240), C21H30O4 (346.4500),
and C22H32O4 (360.4760) respectively.
Scheme 1. Formation of methyl O-methylpodocarpate.

C-13 ETHER DERIVATIVES OF PODOCARPIC ACID
1627
Scheme 2. Formation of methyl 13-iodo-O-methylpodocarpate.
In comparison to the data of compound 3, the 1H NMR spectra of compound
4 indicated that the C-13 aryl hydrogen had disappeared and that an additional 3H
peak was present at d 3.62 ppm as a singlet. This information corresponds to the
presence of the desired methoxy group at the C-13 position of compound 4. Also,
in comparison with the NMR data for compound 3, the spectra of compound 5 gave
a new signal at d 3.98 ppm (q), which could be assigned to the CH2-O moiety that is
present in compound 5 at the C-13 aryl position. Additionally, a methyl group
appeared as a triplet at d 1.33 ppm. Thus, the presence of a triplet and
quartet along with the chemical shift value of the quartet indicated that the desired
ethoxy group was present. The NMR for compound 6 (in comparison with
compound 3) indicated that a propoxy group was present at the C-13 position. This
is supported both by the absence of the C-13 aromatic proton and the presence of the
signals expected for a propoxy group (3H signal at 1.10 ppm as a triplet, 2H signal at
1.75 ppm as a sextet, and a 2H signal at d 1.10 ppm as a triplet).
The 13C NMR spectrum of compound 4 gave a signal at d 57.2 ppm corre-
sponding to the methoxy group at C-13 of compound 4. The spectrum for compound
5 showed new signals at d 65.0 ppm and d 14.8 ppm, which corresponded to the
CH2-O and CH3 moieties of the ethoxy group. The C-13 NMR spectrum of
Scheme 3. General reaction for the formation of novel ethers of podocarpic acid.

1628
M. YALAVARTY ET AL.
compound 6 showed signals at d 73.5, 22.7, and 14.2 ppm for the carbons in the
desired propoxy group.
In summary, the reaction of methyl 13-iodo-O-methylpodocarpate (3) with
aliphatic alcohols gave ether derivatives of podocarpic acid in good yield. Thus, this
work provides a new and efficient method of synthesizing ether derivatives of
podocarpic acid that will be evaluated for their potential as new drug leads for the
treatment of tuberculosis and cancer.
EXPERIMENTAL
Preparation of Methyl-O-methylpodocarpate (2)
Podocarpic acid (25 g) was weighed into a 300-mL beaker to which 25 g of ice
were added. Methanol (25 ml) was then added to the beaker, and the resulting mixture
was stirred while 12 g of sodium hydroxide pellets were added. After continually
stirring this solution to completely dissolve the podocarpic acid and sodium hydrox-
ide, it was cooled to 15 ꢀC in an ice bath. Next, 21.5 mL of dimethyl sulfate was added
to the cooled solution over a period of 1 h.[4] The solution solidified, but stirring was
continued for an additional 30 min. Additional water (50 mL) was added, and the solid
material was removed by filtration. The solid was then dried to obtain 22 g of a white
solid. This solid was recrystallized to obtain 20 g of methyl O-methylpodocarpate (2)
with a melting point of 125 ꢀC (82% yield). IR (CHCl3): 3000, 2950, 2900, 2860, 1720,
1600, 1540, 1490, 1460, 1400, 1360, 1300, 1240, 1200, 1190, 1150, 1060, 1020, 950, 760,
740. 1H NMR: (300 MHz): 6.95 (d), 6.8 (s), 6.65 (d), 3.85 (s), 3.65 (s), 2.8 (m), 2.25 (m),
1.95 (m), 1.6 (m), 1.5 (m), 1.4 (m), 1.22 (m), 1.2 (s), 1.15 (m), 1.05 (m), 1.00 (s) ppm. 13
C
NMR (300 MHz): 178, 158, 150, 130, 128, 114, 112, 56, 52, 51, 44, 39.5, 38, 31, 28, 25,
22.5, 20.5, 20 ppm. MS: 302 (44), 287 (6), 228 (16), 227 (100), 173 (6), 170 (23), 147 (10),
121 (6), 91 (4).
Preparation of Methyl 13-Iodo-O-methylpodocarpate (3)
Three g of methyl-O-methylpodocarpate (2) were weighed, transferred into a
500-mL volumetric flask, and then dissolved in 60 mL of acetic acid. In a separate
beaker, 2 g of mercury(II) acetate were weighed and dissolved in 60 mL of acetic
acid. This solution was then added to the flask containing compound 2. The result-
ing solution was heated to 70 ꢀC and stirred for 15 min. A solution of iodine was
prepared by dissolving 7.6 g of iodine in 240 mL of warm acetic acid. This iodine
solution was then added dropwise over a period of 45 min into the flask while the
temperature was maintained at 70 ꢀC. The solution was then filtered, and the
resulting filtrate was added into 500 mL of cold water in a 1-L beaker. A precipi-
tate formed and was removed by filtration to give 3 g of crude product 3. This
material was recrystallized from acetone to obtain 2 g of pure compound 3 with
a melting point of 149 ꢀC and yield of 95%. IR: 3000, 2940, 2850, 2400, 1720,
1600, 1495, 1470, 1440, 1390, 1350, 1300, 1250, 1200, 1150, 1050, 950, 900, 800,
750, 650 cmÀ1 1H NMR (300 MHz): 7.45 (s), 6.65 (s), 3.95 (s), 3.85 (s), 2.70
.
(m), 2.20 (m), 1.95 (m), 1.6 (m), 1.5 (m), 1.25 (s), 1.15 (m), 1.02 (s), 0.95 (m)
ppm. 13C NMR (300 MHz): 178, 156, 150, 140, 131, 108, 83, 56.5, 52.5, 52, 44,

C-13 ETHER DERIVATIVES OF PODOCARPIC ACID
1629
39, 38.5, 32, 31.5, 29.5, 23, 21, 20 ppm. HRMS: 428 (100), 413 (8), 381 (3), 368 (3),
353 (77), 313 (4), 287 (6), 272 (6), 227 (15), 211 (4), 172 (6), 140 (5), 129 (8), 115
(6), 101 (2), 91 (2).
General Procedure for the Preparation of Ethers 4–6
Methyl 13-iodo-O-methylpodocarpate (2.14 g) was weighed into a 100-mL,
round-bottom flask and dissolved in 0.32 g of N,N-dimethylformamide. In
addition, 0.405 g of sodium methoxide was added to 1.5 molar equivalents of the
three respective alcohols in a separate beaker. The solution in the beaker was then
added to the solution in the round-bottom flask. The resulting solution in the
round-bottom flask was heated using a heating mantle with continuous stirring
until the temperature of the solution reached 110 ꢀC, at which time 0.1 g copper(I)
iodide was added. A condenser was connected, and the solution was refluxed at
110 ꢀC for 4 h while monitoring the reaction with thin-layer chromatography
(TLC). After the completion of the reaction, the solution was allowed to cool.
The precipitate formed and was filtered. The precipitate was washed with
100 mL ethyl acetate. The filtrate was evaporated to obtain either solid compound
4, 5, or 6.
The first aryl ether derivative (4) was obtained in 84% yield (1.30 g) with a
melting point of 143 ꢀC. IR: 3000, 2940, 2850, 2400, 1720, 1600, 1495, 1470, 1440,
1
1390, 1350, 1300, 1250, 1200, 1150, 1050 cmÀ1. H NMR (300 MHz): 7.52 (s), 7.32
(s), 6.73 (s), 3.95 (s), 3.85 (s), 3.62 (s), 2.80 (m), 2.28 (m), 2.02 (m), 1.64 (m), 1.30
(s), 1.22 (s), 0.81 (s) ppm. 13C NMR (300 MHz): 178, 158, 151, 148, 146.1, 132,
110.5, 57.2, 52, 50.2, 44.3, 38, 36, 30, 28, 22, 20, 18 ppm. MS: 333.4 (30), 332 (14),
302.4 (82), 220.3 (18), 155.1 (100).
Compound 5 was obtained in 88% yield (1.42 g) with a melting point of
146 ꢀC. IR: 3000, 2940, 2850, 2400, 1720, 1600, 1495, 1470, 1440, 1390, 1350,
1
1300, 1250, 1200, 1150, 1050 cmÀ1. H NMR (300 MHz): 7.45 (s), 7.25 (s), 4.04
(m), 3.95 (s), 3.85 (s), 2.80 (m), 2.28 (m), 2.02 (m), 1.64 (m), 1.30 (s), 1.22 (s),
0.81 (s) ppm. 13C NMR (300 MHz): 178, 150, 142, 140, 132, 108, 106, 65.2, 56,
52.2, 44.3, 40, 36, 30, 28, 22, 20, 18, 14 ppm. MS: 347.4 (25), 346 (10), 302.4
(58), 220.3 (18), 155.1 (100).
Compound 6 was obtained in 84% yield (1.41 g) with a melting point of
148 ꢀC. IR: 3000, 2940, 2850, 2400, 1720, 1600, 1495, 1470, 1440, 1390, 1350,
1
1300, 1250, 1200, 1150, 1050 cmÀ1. H NMR (300 MHz): 6.82 (s), 6.73 (s), 4.01
(m), 3.95 (s), 3.85 (s), 3.12 (m), 1.80 (m), 1.60 (m), 1.40 (s), 1.02 (s), 0.81 (s)
ppm. 13C NMR (300 MHz): 178, 146, 144, 142, 132, 110.5, 108.2, 70.4, 58, 53.8,
52, 44.3, 38, 36, 32, 30, 28, 22, 20, 19, 18, 14 ppm. MS: 361.2 (16), 360 (5), 302
(68), 220.3 (18), 155.1 (100).
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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M. YALAVARTY ET AL.
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