Copper-catalyzed cross-coupling reactions of methyl 13-Iodo-O- methylpodocarpate and amides

Article abstract of DOI:10.1080/00397910802499526

Copper iodide was utilized as a relatively inexpensive catalyst (versus palladium) for the high-yield synthesis of amide derivatives of podocarpic acid. The reaction involved the one-step cross-coupling reaction of methyl 13-iodo-O-methylpodocarpate with amides.

Full text of DOI:10.1080/00397910802499526

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Copper-Catalyzed Cross-
Coupling Reactions of Methyl
13-Iodo-O-methylpodocarpate
and Amides
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: 14 Jul 2009.
To cite this article: Dao M. Nguyen & D. Howard Miles (2009) Copper-Catalyzed Cross-
Coupling Reactions of Methyl 13-Iodo-O-methylpodocarpate and Amides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:16, 2829-2836, DOI: 10.1080/00397910802499526
To link to this article: http://dx.doi.org/10.1080/00397910802499526
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Synthetic Communications1, 39: 2829–2836, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802499526
Copper-Catalyzed Cross-Coupling Reactions of
Methyl 13-Iodo-O-methylpodocarpate
and Amides
Dao M. Nguyen and D. Howard Miles
Natural Products Research Laboratory, Department of Chemistry,
University of Central Florida, Orlando, Florida, USA
Abstract: Copper iodide was utilized as a relatively inexpensive catalyst (versus
palladium) for the high-yield synthesis of amide derivatives of podocarpic acid.
The reaction involved the one-step cross-coupling reaction of methyl 13-iodo-
O-methylpodocarpate with amides.
Keywords: Aryl amides, copper(I) iodide, methyl O-methylpodocarpate,
podocarpic acid
INTRODUCTION
Amines and amides are of great interest in organic synthesis because
many compounds in this class have biological activity.[1,2] The synthesis
of amides is also an important step for many intermediate organic
molecules including natural product derivatives.[3] Metal catalysts have
been employed for synthesis of aryl amines. Wolfer and Buchwald first
synthesized aryl amines by the utilization of palladium-catalyzed
reactions of primary amines and aryl iodides.[4] These investigators later
utilized an 18-crown-6 catalyst to improve the yield of the amine
products.[5] Applications of the cross-coupling reaction between aryl
halides and amines have also been performed in the pharmaceutical
Received August 1, 2008.
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
2829

2830
D. M. Nguyen and D. H. Miles
industry through the utilization of a palladium catalyst.[6] It is logical
that metal-catalyzed cross-coupling reactions could be extended to
aryl halides and amides. Thus, this work involved the synthesis of
amide derivatives of podocarpic acid by an alternative methodology that
utilized an inexpensive copper-mediated catalyst.[7] The generality of the
methodology for the cross-coupling reaction of aryl iodides and amides
was demonstrated by its application to the synthesis of seven novel amide
derivatives of methyl O-methylpodocarpate.
RESULTS AND DISCUSSION
Methyl 13-iodo-O-methylpodocarpate (3) was synthesized in 71% overall
yield from podocarpic acid (1) (Scheme 1). This conversion involved the
methylation of podocarpic acid (1) in 82% yield by the utilization of
dimethyl sulfate in sodium hydroxide solution. The resulting product
was identical to methyl O-methylpodocarpate (2) upon comparison with
the melting point, IR, NMR, and mass spectra with an authentic sample
of compound 2.[8] Methyl O-methylpodocarpate (2) was iodinated in 86%
yield by treatment with iodine in mercury(II) acetate to give compound 3,
as was confirmed by NMR, IR, and high-resolution mass spectroscopic
(HRMS) analysis. The high-resolution mass spectrum showed a molecu-
lar ion at 428.0844, which was consistent with the assigned molecular
formula of C19H25IO3. The IR spectrum showed an additional absorp-
tion for a CꢀI bond in the fingerprint region at 650 cmꢀ1. Of special
significance was the disappearance of the proton attached to carbon 13
that was present in the starting material (compound 2) at 6.80 d
and the downfield shift of carbon 13 from 131 ppm to 140 ppm in the
13C NMR.
The seven novel amide derivatives of compound (3) (compounds
4–10 in Schemes 2 and 3) were synthesized by the reaction of methyl
Scheme 1. Synthesis of methyl 13-iodo-O-methylpodocarpate.

Amide Derivatives of Methyl O-Methylpodocarpate
2831
Scheme 2. Synthesis of amide derivatives of methyl O-methylpodocarpate.
13-iodo-O-methylpodocarpate (3) with amides using copper(I) iodide
catalyst and potassium carbonate in dioxane under reflux at 100 ꢁC for
a period of 24 to 48h. The amides utilized were formamide, acetamide,
propionamide, butyramide, benzamide, benzylamide, and 2-pyrrolidinone.
N,N0-dimethylethylenediamine was used in this reaction as a ligand
in order to dissolve the copper(I) iodide catalyst. The yields for com-
pounds 4–10 were 82, 84, 81, 81, 80, 92, and 90% respectively.
The structures of the derivatives were determined through the utiliza-
tion of MS, IR, and NMR analysis. HRMS confirmed the molecular ions
of compounds 4–10 respectively as 345.1927, 359.2096, 373.2264,
387.2411, 421.2253, 435.2410, and 385.2253. These results were consistent
with the formulas of C20H27NO4, C21H29NO4, C22H31NO4, C23H33NO4,
C26H31NO4, C27H33NO4, and C23H31NO4 respectively. The IR spectra
for all of the derivatives (except compound 10, which is a tertiary amide)
showed (in addition to those absorptions shown in the starting com-
pound 3) a single absorption for a secondary amide at 3400 cmꢀ1 and
an absorption in the range of 1640–1680 cmꢀ1 for the amide carbonyl
group.
Scheme 3. Synthesis of methyl 13-pyrrolidinone-O-methlpodocarpate.

2832
D. M. Nguyen and D. H. Miles
1
The H NMR spectra for derivatives 4–9 indicated the presence of a
singlet secondary N–H proton as a singlet at 8.00 d in addition to the
signals shown for starting compound 3. This was consistent with the
formation of an amide moiety. The presence of the desired aldehyde func-
tionality in compound 4 was indicated by a one-proton singlet at 8.42 d.
Compound 5 possessed an additional (versus starting material) 3 proton
singlet at 2.20 d, which could be assigned to a carbonyl methyl group.
Compound 6 showed additional (versus starting material) overlapping
multiplets at 2.35 and 1.75 d, which integrated for a total of five protons.
This is consistent with the presence of an ethyl group. The additional
multiplets (versus starting material) in the proton NMR spectrum of
compound 7 at 2.22 and 1.30 d integrated for a total of seven protons,
which is consistent with the presence of a propyl group. Compound 8 dis-
played signals at 7.5 and 7.9 d, which is consistent with the presence of
five additional aromatic protons. Compound 9 showed signals that were
not present in compound 3, at 3.7 and 7.3 d, which integrated for two and
five protons respectively. This result was consistent with the presence of
two benzylic protons and five aromatic protons in compound 9.
Compound 10 possessed signals that were not present in the starting
compound 3, at 3.8 and 2.2 d, which integrated for six protons. This
is consistent with the presence of the desired pyrrolidinone moiety in
compound 10.
The 13C NMR spectra showed signals for the amide carbons (in com-
pounds 4–10) at 160, 168, 172, 171.5, 165, 169, and 176 ppm respectively.
In addition, the chemical shift of carbon 13 in all derivatives was down-
field versus that shown by carbon 13 in the 13C spectrum of the starting
compound 3.
In summary, amides derivatives of pododcarpic acid were synthe-
sized in high yield by utilizing copper-catalyzed cross-coupling reactions
between amides and methyl 13-iodo-O-methylpodocarpate. Thus this
work provides a new and efficient method of synthesizing amide deriva-
tives of podocarpic acid. In addition, seven novel amide derivatives of
podocarpic acid were prepared, and these derivatives will be evaluated
for their potential as new drug leads for the treatment of tuberculosis
and cancer.
EXPERIMENTAL
Podocarpic acid (1) was recrystallized from methanol and dried in vacuo.
IR spectra were recorded in chloroform with a Perkin-Elmer spectro-
meter; NMR spectra were recorded in deuterated chloroform with the
utilization of Mercury 300-MHz and Varian 500-MHz spectrometers.

Amide Derivatives of Methyl O-Methylpodocarpate
Preparation of Methyl O-Methylpodocarpate (2)[8]
2833
Compound 1 (50 g of podocarpic acid) was placed in a 300-mL beaker,
and 50 g of ice and then 50 mL of methanol were added. This mixture
was stirred, and then 24 g of sodium hydroxide pellets were added. The
resulting solution was continually stirred until the podocarpic acid (1)
and sodium hydroxide were completely dissolved. The resulting mixture
was then cooled to 15 ꢁC in an ice-water bath. To this solution,
42.5 mL of dimethyl sulfate was added over an hour while the tempera-
ture was maintained at 15 ꢁC. The solution was then allowed to solidified
with stirring. One hundred mL of water were then added, and the result-
ing mixture was filtered under vacuum to obtain approximately 45 g of a
white solid (yield 82%). The resulting solid was recrystallized from 2-
propanol to obtain 20 g of methyl O-methylpodocarpate (2) as white
needles with mp 125 ꢁC. IR (CHCl3): 1720, 1600, 1540, 1490, 1460,
1
1200, 1190, 1150 cmꢀ1. HNMR (Mercury 300 MHz): 6.95 (d), 6.80 (d),
6.65 (d), 3.85 (s), 3.65 (d), 2.80 (m), 2.25 (m), 1.95 (m), 1.60 (m), 1.50
(m), 1.40 (m), 1.22 (m), 1.20 (s), 1.15 (m), 1.05 (m), 1.00 (s) ppm.
13CNMR (Mercury 300 MHz): 178, 158, 150, 130, 128, 114, 112, 56,
52, 51, 44, 39.5, 38, 32, 28, 25, 22.5, 20.5, 20 ppm. HRMS (Finnigan spec-
trometer): 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)
Compound 2 (3.025 g) was weighed and transferred into a 500-mL flask
and then dissolved in 60 mL of acetic acid. In a separate 250-mL beaker,
2 g of mercury(II) acetate was dissolved in 60 mL of acetic acid, which was
then poured into the flask containing compound 2. The resulting solution
was equipped with a magnetic stir bar and then stirred on a hot plate at
70 ꢁC for 15 min. A solution of iodine was prepared by dissolving
2.614 g of iodine in 240 mL of warm acetic acid in a 500-mL Erlenmeyer
flask. The iodine solution was then added dropwise, with stirring, over
a period of 45 min into the reaction flask while the temperature was main-
tained at 70 ꢁC. This solution was stirred for an additional hour, after
which it was cooled to 15 ꢁC in an ice-water bath and filtered. The filtrate
was then stirred into 500 mL of cold water in a 1-L beaker, and the result-
ing white precipitate was filtered to yield 3.70 g of crude product 3 (86%
yield). The product was recrystallized from acetic acid to obtain 3.0 g of
a white powder, mp 149 ꢁC. IR (CHCl3): 1720, 1600, 1495, 1470, 1440,
1
1200, 1150, 750, 650 cmꢀ1. H-NMR (300 MHz): 7.45 (s), 6.65 (s), 3.95
(s), 3.85 (s), 2.70 (m), 2.20 (m), 1.95 (m), 1.60 (m), 1.50 (m), 1.25 (s),

2834
D. M. Nguyen and D. H. Miles
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, 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),
227 (15), 211 (4), 172 (6), 140 (5), 129 (8), 115 (6), 101 (3), 91 (2).
General Procedure for the Preparation of Amides 4–10
To 1.5 molar equivalents of each amide in a 100-mL flask, 0.1 g of copper(I)
iodide, 3.46g of potassium carbonate, 0.1 g of N,N0-dimethylethylenedia-
mine, and 15mL of dioxane were added. This was followed by the addition
of 2.15g of compound 3. After attaching a condenser, the mixture was
stirred (with a magnetic stirring bar) under nitrogen while heating at
100 ꢁC for 24h. After cooling to room temperature, a precipitate was
obtained, which was filtered and washed with 100 mL of ethyl acetate.
The filtrate was evaporated under reduced pressure to yield a solid material
which was further purified by open column chromatography with 63- to
200-mesh silica gel. Hexane and ethyl acetate (1:1) were used as the eluents.
Preparation of Methyl 13-Formamido-O-methylpodocarpate (4)
Formamide (0.34 g) was utilized, according to the general procedure out-
lined previously, to obtain 1.40 g of 13-formamido methyl O-methylpo-
docarpate (4) with mp 145 ꢁC (yield 82%). IR (CHCl3): 3410, 1700,
1640, 1620, 1520, 1480, 1460, 1420, 1220, 1150 cmꢀ1
.
1H NMR
(300 MHz): 8.42 (s), 8.02 (s), 7.80 (s), 6.80 (m), 3.95 (s), 3.85 (s), 2.80
(m), 2.30 (m), 1.95 (m), 1.65 (m), 1.6 (m), 1.4 (m), 1.30 (s), 1.20 (s)
ppm. 13C NMR (300 MHz): 178, 160, 147, 145, 128, 124.5, 120.5,
117.5, 56, 53, 44.5, 40, 39, 38, 32, 29, 23, 21.5, 20 ppm. HRMS: 346
(48), 345 (12), 302 (82), 300 (43), 219 (24), 154 (100).
Preparation of Methyl 13-Acetamido-O-methylpodocarpate (5)
Acetamide (0.45 g) was utilized, according to the general procedure
outlined previously, to provide 1.50 g of methyl 13-acetamido-O-
methylpodocarpate (5) with mp 157 ꢁC in 84% yield. IR (CHCl3): 3400,
1710, 1680, 1600, 1580, 1520, 1470, 1450, 1240, 1220, 1180, 1140,
1
1070 cmꢀ1. H NMR (300 MHz): 8.00 (s), 7.65 (s), 6.70 (s), 3.95 (s), 3.85
(s), 2.80 (m), 2.20 (m), 1.95 (m), 1.65 (m), 1.50 (m), 1.35 (m), 1.22 (m),
1.05 (m), 1.00 (s) ppm. 13C NMR (300 MHz): 178, 168, 146.5, 144, 128,
125.5, 120, 107, 56, 53, 44, 40, 39.5, 39, 32, 29, 25, 24, 22, 20.5 ppm. HRMS:
360 (22), 302 (24), 284 (90), 219 (10), 242 (100), 154 (100).

Amide Derivatives of Methyl O-Methylpodocarpate
2835
Preparation of Methyl 13-Propionamido-O-methylpodocarpate (6)
Propionamide (0.55 g) was utilized, according to the general procedure
given previously, to obtain 1.51 g of 13-propionamido methyl O-methyl-
podocarpate (6) with mp 159 ꢁC (81% yield). IR (CHCl3): 3400, 1720,
1
1680, 1610, 1595, 1520, 1490, 1470, 1220, 1130, 1070, 1020 cmꢀ1. H
NMR (300 MHz): 8.02 (s), 7.65 (s), 6.65 (s), 3.95 (s), 3.85 (s), 2.80 (s),
2.35 (s), 2.20 (m), 1.95 (m), 1.75 (m), 1.60 (m), 1.50 (m), 1.30 (s), 1.20
(s), 1.05 (s) ppm. 13C NMR (300 MHz): 178.2, 172, 146, 143.6, 128,
120, 107.8, 56, 54, 52, 44, 40, 38.6, 38, 32, 31.6, 28.8, 20, 10 ppm. HRMS:
374 (42), 358 (5), 350 (8), 302 (56), 300 (30), 219 (18), 154 (100).
Preparation of Methyl 13-Butyramido-O-methylpodocarpate (7)
Butyramide (0.66 g) was utilized, according to the general procedure pre-
viously given, to obtained 1.57 g of compound 7 with mp 162 ꢁC (81%
yield). IR (CHCl3): 3395 1710, 1680, 1600, 1590, 1510, 1480, 1460,
1
1260, 1210, 1140 cmꢀ1. H NMR (300 MHz): 8.00 (s), 7.62 (s), 6.65 (s),
3.92 (s), 3.82 (s), 2.80 (m), 2.22 (m), 2.15 (m), 1.95 (m), 1.6 (m), 1.50
(m), 1.30 (m), 1.20 (s), 1.00 (m) ppm. 13C NMR (300 MHz): 178, 171.5,
146.5, 143.2, 128, 126, 120, 107, 56, 53, 52, 44, 40.5, 38.8, 32, 29, 23,
22, 20.5, 19.5, 14 ppm. HRMS: 388 (30), 302 (35), 219 (10), 154 (100).
Preparation of Methyl 13-Phenylamido-O-methylpodocarpate (8)
Benzamide (0.9 g) was utilized, according to the general procedure pre-
viously outlined (with the exception of heating for 48 h) to obtain 1.7 g
of compound 8 with mp 128 ꢁC (80% yield). IR: 3400, 1740, 1700,
,
1520, 1490, 1400, 1250, 1200, 1100, 1000 cmꢀ1 1H NMR(300 MHz):
8.5 (s), 8.2 (s), 7.9 (m), 7.5 (m), 6.8 (s), 3.9 (s), 3.7 (s), 2.8 (m), 2.3 (m),
2.0 (m), 1.6 (m), 1.4 (m), 1.3 (s), 1.1 (s). 13C NMR: 178, 165, 147, 144,
135, 132, 129, 128, 127, 125, 120, 107, 56, 53, 51, 44, 40, 39, 38, 32, 28,
23, 21, 20. HRMS: 423 (26), 422 (100), 421 (69), 420 (8).
Preparation of Methyl 13-Benzylamido-O-methylpodocarpate (9)
Benzylamide (0.82 g) was utilized, according to the general procedure
given previously, to obtain 2 g of compound 9 with mp 139 ꢁC (yield
92%). IR: 3415, 1721, 1669, 1520, 1477, 1410, 1257, 1225, 1141, 1062,
1
1038 cmꢀ1. H NMR (500 MHz): 8.0 (s), 7.7 (s), 7.3 (s), 6.6 (s), 3.7 (m),

2836
D. M. Nguyen and D. H. Miles
3.65 (m), 2.6 (m), 2.2 (m), 2.0 (m), 1.9 (m), 1.6 (m), 1.2 (s), 1.0 (s).
13C NMR: 178, 169, 146, 143, 135, 130, 129, 128, 127, 126, 120, 107,
56, 53, 51, 45, 44, 40, 39, 38, 32, 28, 23, 21, 20. HRMS: 437 (30), 435
(69), 436 (100), 434 (7).
Preparation of Methyl 13-Pyrrolidinone-O-methylpodocarpate (10)
2-Pyrrolidinone (0.55 g) was utilized according to the general procedure
given previously, to obtain 1.7 g of compound 10 with mp 114 ꢀC (yield
.
90%). IR: 1722, 1697, 1511, 1414, 1287, 1233, 1190 cmÀ1 1H NMR
(500 MHz): 6.95 (s), 6.85 (s), 3.8 (s), 3.7 (s), 2.8 (s), 2.6 (s), 2.2 (s), 2.0
(s), 1.6 (m), 1.3 (s), 1.2 (s), 1.1 (s). 13C NMR: 178, 175, 153, 148, 129,
128, 125, 109, 55.73, 55.71, 53, 51.31, 51.28, 50.14, 44, 39.49, 38.75,
37.59, 31.27, 31.05, 29, 23, 21, 20, 19. HRMS: 387 (25), 385 (54), 386
(100), 384 (11).
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.
REFERENCES
1. Srivastava, S. K. Synthesis of some new bioactive aryl amides. J. Ind. Chem.
Soc. 1991, 68 (6), 358–359.
2. Schmeller, T.; Wink, M. Utilization of alkaloids in modern medicine. Alkaloids
1998, 435–459.
3. Hayashi, Y.; Matsumoto, T.; Nishizawa, M. Total synthesis of nagilactone F,
a biologically active norditerpenoid dilactone isolated from podocarpus nagi.
J. Org. Chem. 1982, 47, 3428–3433.
4. Wolfe, J. P.; Buchwald, S. L. Palladium-catalyzed amination of aryl iodides.
J. Org. Chem. 1996, 61, 1133–1135.
5. Wolfe, J. P.; Buchwald, S. L. Room temperature catalytic amination of aryl
iodides. J. Org. Chem. 1997, 62, 6066–6068.
6. Richardson, C. F.; Schuster, D. I.; Wilson, S. R. Synthesis and characteriza-
tion of water-soluble amino fullerene derivatives. Org. Letts. 2000, 2 (8),
1011–1014.
7. Antilla, J. C. The copper-catalyzed N-arylation of indoles. J. Am. Chem. Soc.
2002, 124 (39), 11684–11688.
8. Miles, D. H. The synthesis of tetracyclic diterpenoid alkaloids and related
diterpenoids. Thesis. Georgia Institute of Technology, Atlanta, GA, 1969.