Pseudo-domino palladium-catalyzed allylic alkylation/Mizoroki-Heck coupling reaction: a key sequence toward (±)-podophyllotoxin

Article abstract of DOI:10.1016/j.tetlet.2007.11.202

A formal synthesis of podophyllotoxin was carried out in nine steps. The key pseudo-domino step was accomplished through the succession of an intermolecular palladium-catalyzed allylic alkylation and an intramolecular Mizoroki-Heck coupling reaction.

Full text of DOI:10.1016/j.tetlet.2007.11.202

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 760–763
Pseudo-domino palladium-catalyzed allylic
alkylation/Mizoroki–Heck coupling reaction:
a key sequence toward ( )-podophyllotoxin
Francesco Mingoia a, Maxime Vitale b, David Madec b,*, Guillaume Prestat b, Giovanni Poli b,*
a Istituto per lo Studio dei Materiali Nanostrutturati, Via Ugo La Malfa 153, 90146 Palermo, Italy
b Universite´ Pierre et Marie Curie-Paris 6, Laboratoire de Chimie Organique (UMR CNRS 7611), Institut de Chimie
Mole´culaire (FR 2769), Case 183, 4 Place Jussieu, F-75252 Paris Cedex 05, France
Received 16 November 2007; accepted 30 November 2007
Available online 5 December 2007
Abstract
A formal synthesis of podophyllotoxin was carried out in nine steps. The key pseudo-domino step was accomplished through the
succession of an intermolecular palladium-catalyzed allylic alkylation and an intramolecular Mizoroki–Heck coupling reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Podophyllotoxin; Catalysis; Domino; Palladium; Ring-closure
O
Podophyllotoxin (Fig. 1), the parent member of the aryl-
tetralin lignan lactone family1 was first isolated in 1880
from podophyllin,2 a resinous powder obtained by precip-
itating an alcoholic tincture of the American Mayapple rhi-
zome (Podophyllum peltatum). Although the medicinal
properties of podophyllotoxin have been known for thou-
sands of years, particular attention toward this molecule
arose from the discovery of its antimitotic activity3 as a
result of its high affinity for tubulin.4 While altering cellular
division during mitosis, podophyllotoxin triggers cellular
death.5 However, the use of this molecule as anticancer
agent is hampered due to its high toxicity associated with
numerous secondary effects such as nausea, diarrhea, vom-
iting, and injury of healthy tissues.6 Consequently, several
hemi-synthetic derivatives of podophyllotoxin, such as eto-
poside7 and teniposide8 have been developed and success-
fully used for the clinical treatment of several cancers,
including small cell lung carcinoma, testicular cancer and
R
O
O
O
C
OH
C
HO
OH
O
O
A
B
D
O
A
B
D
O
O
O
O
O
E
E
MeO
OMe
MeO
OMe
OMe
OH
(-)-Podophyllotoxin
R = Me,
R = 2-thienyl, Teniposide
Etoposide
Fig. 1. (À)-Podophyllotoxin, etoposide, and teniposide structures.
Kaposi’s sarcoma.9 Interestingly, and in contrast to podo-
phyllotoxin, these analogs do not inhibit tubulin polymer-
ization, but act as topoisomerase II inhibitors, a nuclear
enzyme involved in transitional breaks of DNA double-
strand, compulsory for transcription.10
In 1998, we reported a stereoselective approach toward
3,4-disubstituted c-lactams based on the intramolecular
palladium-catalyzed allylic alkylation of stabilized acetam-
ide enolate anions taking place exclusively via a 5-exo
mode of cyclization.11 A few years later, we disclosed the
*
Corresponding authors. Tel.: +33 1 44 27 55 72; fax: +33 1 44 27 75 67
(G.P.).
E-mail addresses: madec@ccr.jussieu.fr (D. Madec), giovanni.poli@
upmc.fr (G. Poli).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.202

F. Mingoia et al. / Tetrahedron Letters 49 (2008) 760–763
761
As two efficient syntheses of aryltetralin lignan lactones
reported in the literature entail keto diester A as an
advanced intermediate,16 we focused on the latter structure
as our synthetic goal. We report herein a formal synthesis
of ( )-podophyllotoxin according to the retrosynthetic
path depicted in Scheme 2. Key precursor A would arise
via oxidative cleavage of tetracyclic diester B, which could
in turn derive from an intramolecular palladium-catalyzed
Mizoroki–Heck coupling reaction of the bromoaryl alkene
C. A palladium-catalyzed allylation may then allow the
preparation of C from D. Finally, alkylation of a malonate
diester with the suitably functionalized benzhydrol E con-
cludes the retrosynthesis.
O
O
O
O
.
BF3 OEt2
Br
OH Br
+
MeO2C
OAc
OAc
MeO2C
N
Bn
O
O
N
Bn
Pseudo-domino
allylic alkylation/
Mizoroki-Heck
Pd(0)
base
O
O
O
O
Accordingly, Lewis acid promoted benzhydrylation of
dimethyl malonate with benzhydrol 1a17 was first attempted
(Scheme 3). Neither BF3ÁOEt2 nor TiCl4 proved to be suc-
cessful in generating the desired adduct 2. After some exper-
imentation, 2 could be cleanly obtained (86% yield)
by treatment of dimethyl malonate with the benzhydryl
acetate 1b in the presence of TiCl4 in toluene at room
temperature.18
OH
MeO2C
O
O
N
Bn
N
Bn
( )-demethoxy-
epiisopicropodophyllin
N-benzyl lactame
Scheme 1. Synthesis of an aza-analog of podophyllotoxin.13
Intermolecular palladium-catalyzed allylic alkylation of
diester 2 was next studied (Scheme 4). Treatment of 2 with
allyl acetate (2.5 equiv) in presence of the catalytic system
[Pd(OAc)2 (10 mol %), dppe (20 mol %)], NaH as the base
(1.2 equiv) in DMF gave, after 2 h at room temperature the
allylated diester 3 in 92% yield.19
synthesis of a novel aza-analog of podophyllotoxin exploit-
ing a pseudo-domino12 palladium-catalyzed intramolecular
allylic alkylation/Mizoroki–Heck sequence,13 the cycliza-
tion precursor being assembled through an acid-mediated
benzhydrylation protocol, previously discovered in our
group (Scheme 1).14
From this result, we next envisioned to exploit the
pseudo-domino palladium-catalyzed allylic alkylation/
Mizoroki–Heck sequence process for the synthesis of the
parent member, podophyllotoxin.15
Then, exposure of 3 to the identical catalytic system as
previously used in the allylation step [Pd(OAc)2
(10 mol %), dppe (20 mol %)], in the presence of n-Bu4NOAc
(2 equiv) in DMF afforded, after 2 h at 100 °C, the expected
cyclized product 4 in 93% yield.20 These two successful
experiments occurring under similar reaction conditions
prompted us to investigate the one-pot pseudo-domino
palladium-catalyzed allylic alkylation/Mizoroki–Heck
sequence. In the event, treatment of precursor 2 with
Pd(OAc)2 (10 mol %), dppe (20 mol %), NaH (1.2 equiv),
allyl acetate (2.5 equiv) and n-Bu4NOAc (2 equiv) in
DMF gave, after 2 h at 100 °C, the product of domino reac-
tion 4 in 65% yield.21,22 Oxidative cleavage of the vinylidene
moiety to give ketone 5a completed the formal synthesis of
podophyllotoxin (Scheme 5). This was obtained via
osmium-catalyzed cis-dihydroxylation of 4 followed by
periodate mediated cleavage of the crude diol (75% yield).23
Compound 5a was thus obtained in four steps and 42%
O
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
ref.16
OH
O
RO2C CO2R
O
O
A
O
O
O
O
MeO
MeO
MeO
Br
MeO
MeO
MeO
Mizoroki-
Heck
RO2C CO2R
RO2C CO2R
C
O
B
Pd-catalyzed
O
O
allylic alkylation
MeO
MeO
Br
O
O
O
MeO
MeO
MeO
Br
a), b)
O
O
MeO
MeO
MeO
Br
CO2Me
MeO
MeO
MeO
Br
MeO MeO2C
OR
1 (a: R = H, b: R = Ac)
OR'
2
CO2R
RO2C
Scheme 3. Reagents and conditions: (a) Ac2O (1.2 equiv), Et3N
(1.2 equiv), DMAP cat., CH2Cl2, rt, 1 h, quantitative yield; (b) dimethyl-
malonate (2 equiv), TiCl4 (1.2 equiv), toluene, 0 °C then rt, 16 h, 86%.
D
E
Scheme 2. Retrosynthetic approach to podophyllotoxin.

762
F. Mingoia et al. / Tetrahedron Letters 49 (2008) 760–763
vative Catalysis: New Processes and Selectivities’ is kindly
acknowledged.
O
O
O
O
MeO
MeO
MeO
MeO
MeO MeO2C
Br
a)
References and notes
CO2Me
MeO MeO2C CO2Me
1. (a) Sellars, J. D.; Steel, P. G. Eur. J. Org. Chem. 2007, 3815–3828; (b)
Ward, R. S. Nat. Prod. Rep. 1999, 16, 75–96; (c) Ward, R. S. Nat.
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183–205; (e) Ward, R. S. Nat. Prod. Rep. 1993, 10, 1–28.
4
2
O
b)
c)
O
MeO
Br
2. Podwyssotzki, V. Arch. Exp. Pathol. Pharmakol. 1880, 13, 29–52.
3. King, L.; Sullivan, M. Science 1946, 104, 244.
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1998, 5, 205–252; (b) Zhang, Y.; Lee, K.-H. Chin. Pharm. J. 1994, 46,
MeO
MeO MeO2C CO2Me
3
´
´
319–369; (c) Ramos, A. C.; Pelaez-Lamamie de Clairac, R.; Medarde,
M. Heterocycles 1999, 51, 1443–1470; (d) Ward, R. S. Chem. Soc. Rev.
1982, 75–125; (e) Ward, R. S. Synthesis 1992, 719–730; (f) Castro, M.
Scheme 4. Reagents and conditions: (a) Pd(OAc)2 (10 mol %), dppe
(20 mol %), n-Bu4NOAc (2 equiv), NaH (1.2 equiv), allyl acetate
(2.5 equiv), DMF, 100 °C, 2 h, 65%; (b) Pd(OAc)2 (10 mol %), dppe
(20 mol %), NaH (1.2 equiv), allyl acetate (2.5 equiv), DMF, rt, 2 h, 92%;
(c) Pd(OAc)2 (10 mol %), dppe (20 mol %), n-Bu4NOAc (2 equiv), DMF,
100 °C, 2 h, 93%.
´
A.; Gomez-Zurita, M. A. Toxicon 2004, 44, 441–459.
5. (a) Cortese, F.; Bhattacharyya, B.; Wolff, J. J. Biol. Chem. 1977, 252,
1134–1140; (b) Andreu, J. M.; Timasheff, S. N. Biochemistry 1982, 21,
6465–6476; (c) Sackett, D. L. Pharm. Ther. 1993, 59, 163–228.
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7. Sta¨helin, H. Eur. J. Cancer 1973, 9, 215–221.
O
O
O
O
8. Sta¨helin, H. Eur. J. Cancer 1970, 6, 303–311.
9. Gordaliza, M.; Castro, M. A.; Miguel del Corral, J. M.; San
Feliciano, A. Curr. Pharm. Des. 2000, 6, 1811–1839.
MeO
MeO
MeO
MeO
MeO
a)
10. MacDonald, T. L.; Lehnert, E. K.; Loper, J. T.; Chow, K. C.; Ross,
W. E. On the Mechanism of Interaction of DNA topoisomerase II
with Chemotherapeutic Agents. In DNA Topoisomerase in Cancer;
Potmesil, M., Kohn, K. W., Eds.; Oxford University Press: New
York, 1991; pp 119–214.
O
MeO MeO2C CO2Me
RO2C CO2R
4
5 (a: R = Me, b: R = Et)
11. (a) Giambastiani, G.; Pacini, B.; Porcelloni, M.; Poli, G. J. Org.
Chem. 1998, 63, 804–807; (b) Madec, D.; Prestat, G.; Martini, E.;
Fristrup, P.; Poli, G.; Norrby, P.-O. Org. Lett. 2005, 7, 995–998.
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Poli, G. J. Organomet. Chem. 2003, 687, 291–300; (b) Prestat, G.; Poli,
G. Chemtracts—Org. Chem. 2004, 17, 97–103.
O
O
MeO
MeO
MeO
ref. 16
OH
6 steps
13. Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456–9459.
14. Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002, 1823–1826.
15. For syntheses of podophyllotoxin, see: (a) Gensler, W. J.; Gastonis,
C. G. J. Org. Chem. 1966, 31, 4004–4006; (b) Murphy, W. S.;
Wattanasin, S. J. J. Chem. Soc., Chem. Commun. 1980, 262–263; (c)
Rajapaksa, D.; Rodrigo, R. J. Am. Chem. Soc. 1981, 103, 6208–6209;
(d) Van der Eycken, J.; De Clercq, P.; Vandewalle, M. Tetrahedron
Lett. 1985, 26, 3871–3874; (e) Jung, M. E.; Lam, P. Y. S.; Mansuri,
M. M.; Speltz, L. M. J. Org. Chem. 1985, 50, 1087–1105; (f) Van der
Eycken, J.; De Clercq, P.; Vandewalle, M. Tetrahedron 1986, 42,
4297–4308; (g) Jung, M. E.; Lowen, G. T. Tetrahedron Lett. 1986, 27,
5319–5322; (h) Macdonald, D. I.; Durst, T. J. Org. Chem. 1986, 51,
4749–4750; (i) Vyas, D. M.; Skonezny, P. M.; Jenks, T. A.; Doyle, T.
W. Tetrahedron Lett. 1986, 27, 3099–3102; (j) Kaneko, T.; Wong, H.
Tetrahedron Lett. 1987, 28, 517–520; (k) Jones, D. W.; Thompson, A.
M. J. Chem. Soc., Chem. Commun. 1987, 1797–1798; (l) Andrews, R.
C.; Teague, S. J.; Meyers, A. I. J. Am. Chem. Soc. 1988, 110, 7854–
7858; (m) Macdonald, D. I.; Durst, T. J. Org. Chem. 1988, 53, 3663–
3669; (n) Jones, D. W.; Thompson, A. M. J. Chem. Soc., Chem.
Commun. 1989, 1370–1371; (o) Peterson, J. R.; Hoang, D. D.; Rogers,
R. D. Synthesis 1991, 275–277; (p) Kraus, G. A.; Wu, Y. J. Org.
Chem. 1992, 57, 2922–2925; (q) Bush, E. J.; Jones, D. W. J. Chem.
Soc., Chem. Commun. 1993, 1200–1201; (r) Hadimani, S. B.; Tanpure,
R. P.; Bhat, S. V. Tetrahedron Lett. 1996, 37, 4791–4794; (s) Medarde,
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Clairac, R.; San Feliciano, A. Tetrahedron Lett. 1996, 37, 2663–2666;
(t) Bush, E. J.; Jones, D. W. J. Chem. Soc., Perkin Trans. 1 1996, 151–
155; (u) Berkowitz, D. B.; Choi, S.; Maeng, J.-H. J. Org. Chem. 2000,
65, 847–860; (v) Reynolds, A. J.; Scott, A. J.; Turner, C. I.; Sherburn,
M. S. J. Am. Chem. Soc. 2003, 125, 12108–12109; (w) Casey, M.;
Keaveney, C. M. Chem. Commun. 2004, 184–185; (x) Wu, Y.; Zhang,
O
O
(
)-podophyllotoxin
Scheme 5. Reagents and conditions: (a) (i) NMO (2 equiv), OsCl3
(5 mol %) THF/H2O (9/1), rt, 16 h; (ii) NaIO4 (3 equiv), acetone/H2O
(6/4), rt, 16 h, 75%.
overall yield (pseudo-domino version), or five steps and
56% overall yield (sequential version), starting from benz-
hydrol 1a, dimethyl malonate, and allyl acetate. This new
route may be regarded as a valid alternative to the previ-
ously reported synthesis of 5b.16
In summary, the above described sequence represents a
successful nine-step formal synthesis of podophyllotoxin.
The key pseudo-domino step was accomplished through
the succession of an intermolecular palladium-catalyzed
allylic alkylation and an intramolecular Mizoroki–Heck
coupling. Extension of the present strategy to the prepara-
tion of other aryltetralin lignan lactones is currently
underway.
Acknowledgments
CNRS, CNR, and UPMC are acknowledged for finan-
cial support. The sponsorship of COST Action D40 ‘Inno-

F. Mingoia et al. / Tetrahedron Letters 49 (2008) 760–763
763
H.; Zhao, Y.; Zhao, J.; Chen, J.; Li, L. Org. Lett. 2007, 9, 1199–
1202.
16. (a) Kende, A. S.; Liebeskind, L. S.; Mills, J. E.; Rutledge, P. S.;
Curran, D. P. J. Am. Chem. Soc. 1977, 99, 7082–7083; (b) Kende, A.
S.; Logan King, M.; Curran, D. P. J. Org. Chem. 1981, 46, 2828–2830.
17. See Ref. 15e.
was purified by flash chromatography (cyclohexane/ethyl acetate 8/2)
to afford cyclic diester 4 (93%). 1H NMR (CDCl3, 400 MHz): 2.95–
3.22 (2d, J = 15.1 Hz, AB system, 2H), 3.58 (s, 3H), 3.66 (s, 3H), 3.73
(s, 6H), 3.79 (s, 3H), 4.82 (s, 1H), 5.02 (d, J = 1.5 Hz, 1H), 5.46 (d,
J = 1.5 Hz, 1H), 5.89 (d, J = 1.2 Hz, 1H), 5.92 (d, J = 1.2 Hz, 1H),
6.22 (s, 2H), 6.46 (s, 1H), 7.08 (s, 1H). 13C NMR (CDCl3, 100 MHz):
33.0, 49.6, 52.4, 52.9, 56.0, 59.3, 60.8, 101.1, 102.9, 107.0, 109.4,
110.1, 126.8, 131.3, 136.0, 137.2, 138.1, 147.1, 148.3, 152.8, 169.7,
170.6.
18. Experimental procedure for the benzhydrylation reaction: To a solution
of benzhydryl acetate 1b (520 mg, 1.18 mmol, 1 equiv) in toluene
(10 mL) were added, under argon atmosphere, at 0 °C dimethyl-
malonate (270 lL, 2.37 mmol, 1 equiv) and TiCl4 (155 lL, 1.42 mmol,
1.2 equiv). The resulting solution was allowed to warm up slowly to
room temperature and stirred overnight before a solution of saturated
aqueous NaHCO3 and CH2Cl2 were added. The separated aqueous
layer was extracted with CH2Cl2 and the collected organic layer dried
over MgSO4. Solvents were removed under reduced pressure and the
crude material purified by flash column chromatography (cyclo-
hexane/ethyl acetate 8/2) to afford 2 in 86% yield as an oil. 1H NMR
(CDCl3, 400 MHz): 3.61 (s, 3H), 3.63 (s, 3H), 3.79 (s, 3H), 3.83 (s,
6H), 4.24 (d, J = 12.4 Hz, 1H), 5.25 (d, J = 12.4 Hz, 1H), 5.93 (d,
J = 1.3 Hz, 1H), 5.96 (d, J = 1.3 Hz, 1H), 6.53 (s, 2H), 6.80 (s, 1H),
7.00 (s, 1H). 13C NMR (CDCl3, 100 MHz): 48.6, 52.9, 56.2, 57.1, 60.8,
101.9, 104.7, 107.3, 113.3, 115.1, 133.3, 135.7, 137.0, 147.2, 147.7,
153.2, 167.5.
19. Experimental procedure for the allylic alkylation: To a solution of
Pd(OAc)2 (10 mol %) in dry DMF (500 lL) under nitrogen atmo-
sphere was added dppe (20 mol %). In a separate flask, to a solution
of diester 2 (50 mg, 0.1 mmol) in dry DMF (1 mL) at 0 °C under
nitrogen atmosphere was added NaH (60% in oil, 0.117 mmol,
1.2 equiv). The resulting mixture was stirred at 0 °C for 15 min and,
after warming to room temperature, added to the reaction vessel
containing the catalytic system. Allyl acetate (27 lL, 0.244 mmol,
2.5 equiv) was then added and the resulting mixture was stirred at
room temperature for 2 h. A saturated aqueous NH4Cl solution was
added and the aqueous phase was extracted three times with Et2O.
The collected organic phases were washed three times with brine,
dried over MgSO4, and the solvent was removed in vacuo. The crude
product was purified by flash chromatography (cyclohexane/ethyl
acetate 8/2) to afford 3 (92%). 1H NMR (CDCl3, 400 MHz): 2.72–2.90
(2dd, J = 14.2, 7.1 Hz, AB system, 2H), 3.55 (s, 3H), 3.63 (s, 3H), 3.79
(s, 3H), 3.80 (s, 6H), 4.95 (d, J = 16.9 Hz, 1H), 5.00 (d, J = 10.1 Hz,
1H), 5.31 (s, 1H), 5.53–5.63 (m, 1H), 5.96 (d, J = 1.0 Hz, 1H), 5.98 (d,
J = 1.0 Hz, 1H), 6.64 (s, 2H), 7.00 (s, 1H), 7.42 (s, 1H). 13C NMR
(CDCl3, 100 MHz): 40.5, 52.1, 52.3, 52.9, 56.0, 60.7, 63.4, 101.8,
107.3, 109.4, 113.0, 116.7, 119.1, 132.4, 132.6, 134.7, 136.7, 146.9,
147.3, 152.4, 170.7, 171.2.
21. Although the yield of this step (65%) is somewhat lower to the
calculated global yield of the two separated steps (86%), the success of
the pseudo-domino sequence represents an interesting goal from the
conceptual (as it validates the feasibility of the principle) as well as
practical viewpoint (as it saves a work-up procedure and a purifica-
tion step).
22. Experimental procedure for the allylic alkylation/Mizoroki–Heck
coupling pseudo-domino process: To
a solution of Pd(OAc)2
(10 mol %) in dry DMF (500 lL) under nitrogen atmosphere was
added dppe (20 mol %). After 5 min stirring allyl acetate (27 lL,
0.244 mmol, 2.5 equiv), then tetra-n-butyl ammonium acetate (60 mg,
0.20 mmol, 2 equiv) were added. In a separate flask, to a solution of
diester 2 (50 mg, 0.1 mmol) in dry DMF (1.5 mL) at 0 °C under
nitrogen atmosphere was added NaH (60% in oil, 0.117 mmol,
1.2 equiv). The resulting mixture was stirred at 0 °C for 15 min and,
after warming to room temperature, added to the reaction vessel
containing the catalytic system. After stirring at 100 °C for 2 h, a
saturated aqueous NH4Cl solution was added and the aqueous phase
was extracted three times with Et2O. The collected organic phases
were washed three times with brine, dried over MgSO4, and the
solvent was removed in vacuo. The crude product was purified by
flash chromatography (cyclohexane/ethyl acetate 8/2) to afford cyclic
diester 4 in 65% yield.
23. Experimental procedure for the oxidative cleavage: To a solution of
4
(87 mg, 0.185 mmol, 1 equiv) in THF/H2O (4.5 mL/0.5 mL),
4-methylmorpholine-N-oxide (51 mg, 0.37 mmol, 2 equiv) and
Å
OsCl3 Â H2O (2.75 mg, 5 mol %) were added in this order. The
resulting dark suspension was allowed to stir at room temperature
overnight. An excess of 50 wt.% aqueous NaHSO3 solution (20 mL)
was added and the solution was stirred for further 15 min. The
separated aqueous layer was extracted with AcOEt (3 Â 10 mL) and
solvents were removed under reduced pressure. The resulting crude
product was then dissolved in acetone/H2O (12 mL/8 mL) and NaIO4
(119 mg, 0.56 mmol, 3 equiv) was added in one portion. After stirring
for 3 h at room temperature, acetone was removed under reduced
pressure, brine was added (10 mL) and the resulting aqueous layer
extracted with AcOEt (3 Â 10 mL). The organic layer was then dried
over MgSO4, and the solvent removed under reduced pressure. The
crude material was purified by flash chromatography (cyclohexane/
ethyl acetate 6/4) to afford keto diester 5 in 75% yield. 1H NMR
(CDCl3, 400 MHz): 3.18–3.30 (2d, J = 18.2 Hz, AB system, 2H), 3.65
(s, 6H), 3.72 (s, 6H), 3.79 (s, 3H), 5.05 (s, 1H), 6.02 (s, 2H), 6.19 (s,
2H), 6.63 (s, 1H), 7.47 (s, 1H). 13C NMR (CDCl3, 100 MHz): 38.3,
49.8, 52.9, 53.4, 56.1, 60.0, 60.8, 102.0, 105.5, 106.6, 108.8, 126.3,
132.7, 137.7, 140.3, 147.9, 153.2, 153.4, 168.3, 169.9, 192.8.
20. Experimental procedure for the Mizoroki–Heck coupling reaction: To a
solution of Pd(OAc)2 (10 mol %) in dry DMF (2 mL) under nitrogen
atmosphere were added dppe (20 mol %), tetra-n-butyl ammonium
acetate (181 mg, 0.60 mmol, 2 equiv) and a DMF solution (2 mL) of 3
(166 mg, 0.30 mmol). The resulting mixture was stirred at 100 °C for
2 h. Then, a saturated aqueous NH4Cl solution was added and the
aqueous phase was extracted three times with Et2O. The collected
organic phases were washed three times with brine, dried over
MgSO4, and the solvent was removed in vacuo. The crude product