Tandem Heck-Suzuki-Miyaura reaction: Application to the synthesis of constrained analogues of combretastatin A-4

Article abstract of DOI:10.1016/j.tetlet.2007.06.129

A series of compounds related to combretastatin A-4 has been synthesized by a tandem Heck-carbocyclization/Suzuki coupling process. From various alkynamides and 3,4,5-trimethoxyphenyl boronic acid or the corresponding styryl derivative, (E)-3-arylmethylen

Full text of DOI:10.1016/j.tetlet.2007.06.129

Tetrahedron Letters 48 (2007) 6397–6400
Tandem Heck–Suzuki–Miyaura reaction: Application to
the synthesis of constrained analogues of combretastatin A-4
*
´
Martin Arthuis, Renee Pontikis and Jean-Claude Florent
Institut Curie, Centre de Recherche, 26 rue d’Ulm, Paris F-75248, France
CNRS, UMR 176, 26 rue d’Ulm, Paris F-75248, France
Received 4 May 2007; revised 19 June 2007; accepted 20 June 2007
Available online 27 June 2007
Abstract—A series of compounds related to combretastatin A-4 has been synthesized by a tandem Heck-carbocyclization/Suzuki
coupling process. From various alkynamides and 3,4,5-trimethoxyphenyl boronic acid or the corresponding styryl derivative,
(E)-3-arylmethyleneoxindoles (type I) and (EE)-3-alkylideneoxindoles (type II) were efficiently obtained in a stereoselective manner.
Factors influencing yield and stereoselectivity are detailed.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Combretastatin A-4 (CA4) is a naturally occurring stil-
bene isolated from Combretum caffrum. This compound,
a
CH3O
which strongly inhibits the polymerization of tubulin by
CH3O
CH3O
CH3O
CH3O
c
binding to the colchicine site, has been shown to selec-
tively target the vascular system of tumours. For these
tumour blood vessels, it ensues a rapid and irreversible
vascular shutdown leading to extensive ischemic necro-
sis of the tumour cells.1 A key structural factor for
potent biological activity is the presence of the cis-dou-
ble bond, or of a suitable linker, forcing the two aro-
matic rings to be within an appropriate distance.2
Recently, we reported the stereospecific synthesis of
vinylogous CA4 analogues, the two geometric isomers
1 and 2, and derivative 3 with a phenyl group as the
B-ring.3 Diene 3 was found to be a more potent inhibitor
of tubulin polymerization than CA4, although display-
ing a poor cytotoxicity. Therefore, compound 3 appears
to be an interesting lead compound for the search of
specific and potent antivascular agents (Fig. 1).
A
B
CH3O
OH
R1
OCH3
R2
1 R1 = OH, R2 = OCH3 (aZ, cE)
2 R1 = OH, R2 = OCH3 (aE, cZ)
3 R1 = R2 = H (aZ, cE)
CA4
Figure 1. Structure of CA4, its vinylogous analogues and their
considered constrained derivatives.
ceivable stereoselectively, by a tandem Heck–Suzuki
coupling process starting from alkyne tethered halo-
genoarenes of type B and boronic acids.4–10 This reaction
sequence involves an intramolecular carbopalladation
of alkynes B in a syn fashion (5-exo-dig cyclization)
followed by cross-coupling of the (E)-vinylpalladium
In view of reducing the conformational flexibility associ-
ated with the two phenyl rings of CA4 and diene 3, struc-
tures incorporating another ring between the cis-double
bond and one of the aromatic substituent were consid-
ered. Access (Scheme 1) to such conformationally
restricted derivatives of type A with carbo or heterocy-
cles fused with one of the aromatic rings could be con-
R2
R2
R2
R3
XL2PdII
Z
Y
Pd0
X
Z
Y
R3-B(OH)2
Z
Y
R1
R1
R1
Keywords: Combretastatin A4; Oxindole; Domino reaction; Palladium
catalysis.
B
A
C
*
Scheme 1. Palladium catalyzed formation of type A-compounds.
Corresponding author. E-mail: martin.arthuis@curie.fr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.129

6398
M. Arthuis et al. / Tetrahedron Letters 48 (2007) 6397–6400
R2
base. In order to set out the desired oxindole products
O
R2
3
O
CH3O
CH3O
(types I and II) with a free NH function, a removable
protecting group of the alkynamide was required and
the SEM group was chosen. The N-SEM derivative 4f
was obtained using the same alkylation process.
3
R1
CH3O
CH3O
N
R1
N
CH3O
CH3O
R3
Type I
Type II
Anilide 4c bearing a methoxy group was prepared by
coupling iodoanisidine 7b (R3 = OMe)15 with but-2-
ynoic acid under the usual conditions (36% yield).
CH3O
CH3O
B(OH)2
CH3O
CH3O
B(OH)2
All the tandem reactions studied were conducted in dry
THF at 60 ꢁC in the presence of 5 mol% Pd(OAc)2,
10 mol% PPh3, 1.1 equiv of the aryl- or vinylboronic
acids 5 or 6 (Table 1). Two bases were investigated,
CsF (3 equiv)9 or aqueous NaOH (1.5 equiv).7 We ini-
tially attempted the reaction of N-free alkynamide 4a
with arylboronic acid 5 in the presence of CsF (entry
1). Propynamide 4a was completely consumed within
2 h but failed to undergo the cascade reaction.
5
6
CH3O
CH3O
+
R2
O
I
N
R1
R3
4
Scheme 2. Synthetic strategy for oxindole derivatives I and II.
Then, we considered coupling reactions with N-alkyl-
amides. With the N-methyl substrate 4d (entry 2) a com-
plete transformation occurred within 3 h, and the
desired 3-arylidene product Id was formed as a single
stereoisomer albeit in low yield (20%). Reaction with
the N-benzyl alkynamide 4e provided alkene Ie in in-
creased yield (50%) and with the same high stereoselec-
tivity (entry 3). Presumably, the efficiency of the cascade
reaction was dependent on conformational aspects of
the starting alkynamides. When the amido group was
alkylated with a bulkier substituent, for example, Bn
versus Me, favourable steric interactions provided a
higher population of the correct rotamer that could then
undergo the carbopalladation step.13,14
intermediates C with boronic acids, proceeding with a
retention of the olefinic configuration.11
Stereoselective syntheses of carbo- or heterocyclic rings
bearing a substituted exocyclic olefin group have been
reported via this palladium catalyzed domino approach:
indanes,5,6 indoles,4 indolinones8,9 or isoindolinones.7
For our purpose, we first planned to synthesize deri-
vatives with a lactam cycle fused to the B-ring, the
(E)-3-arylmethyleneoxindoles (type I) and the (EE)-3-
alkylideneoxindoles (type II), that are considered as
conformationally restricted analogues of CA4 and
dienes 1–3, respectively (Scheme 2).12 This convergent
approach involved coupling of the suitable cyclization
precursors, the alkynamides of type 4, with the commer-
cially available trimethoxyphenyl boronic acid 5 or the
corresponding styryl derivative 6.3
Being a viable substrate for the tandem reaction, benz-
ylamide 4e was also treated with the vinyl boronic acid
6 (entry 4). The corresponding 3-alkylideneoxindole
IIe was obtained in acceptable yield (50%) and good
selectivity (EE/EZ = 97:3). With both boronic acids,
the cascade reactions proceeded with the same stereo-
selectivity when aqueous NaOH was used as a base
(entries 5 and 6). Nevertheless, alkene Ie was obtained
in a slightly diminished yield (30%) and with a longer
reaction time.
To investigate the feasibility of this tandem process,
several alkynamides 4 were prepared from the 2-iodo-
aniline 7a (Scheme 3).13 Thus, coupling with propynoic
8a or but-2-ynoic acid 8b using DCC afforded the cor-
responding anilides 4a and 4b in, respectively, 58%
and 52% yield.14 The N-alkylamides 4d (R1 = CH3)
and 4e (R1 = Bn) were prepared in good yields by reac-
tion of 2-iodopropynamide 4a with, respectively, methyl
iodide or benzyl bromide using sodium hydride as the
With the N-SEM alkynamide 4f, a significant enhance-
ment of the reaction rate was observed (entries 7 and
8). When NaOH was used as a base, cycloadduct IIf
was obtained in 90% yield but as a mixture of the two
stereoisomers (EE/EZ = 6:4), whereas, in the presence
of CsF, this diene was produced in 68% yield as a single
isomer (EE).
R1
H
R3
N
O
N
O
R3
NH2
I
a
b
I
I
Although the desired E-isomers of the synthesized oxin-
dole products Id,e and IIe,f were obtained in pure form
after silica gel chromatography, they are prone to isom-
erization under the influence of light or in protic med-
ia.16 Nevertheless, it is conceivable that substitution of
the olefinic proton (R2) with a small alkyl group, such
as a methyl group, could stabilize the E-configuration
of the exocyclic double bond, without altering their bio-
logical activity.17,18 Moreover, it is noteworthy that the
R2
4a R2 = R3 = H
4b R2 = Me, R3 = H
4c R2 = Me, R3 = OMe
7a R3 = H
4d R1 = CH3
4e R1 = Bn
4f R1 = SEM
7b R3 = OCH3
Scheme 3. Synthesis of alkynamides 4a–f. Reagents and conditions: (a)
R2-C„CCO2H 8a or 8b, DCC, CH2Cl2, 0 ꢁC to rt 36–58%; (b) from
4a, (i) NaH, THF, 0 ꢁC, (ii) R1X, rt 68–82% (0.1 equiv tetrabutyl-
ammonium bromide was added for 4e).

M. Arthuis et al. / Tetrahedron Letters 48 (2007) 6397–6400
6399
Table 1. Palladium catalyzed tandem reactions of various alkynamides 4 with boronic acids 5 or 6a
R2
R2
O
R2
O
O
I
CH3O
CH3O
CH3O
CH3O
R1
R1
N
5 or 6
N
N
R1
or
Pd 0, base
CH3O
CH3O
R3
R3
(
E-E)-II b,e,f
(E
)-I c,d,e
4
+ (E-Z)-isomers
Entry
Alkyne-amide
R1
H
CH3
Bn
Bn
Bn
R2
R3
Boronic acid
Base
Time
Ratiob E/Z
Global yieldc (%)
Product
1
2
3
4
5
6
7
8
9
4a
4d
4e
4e
4e
4e
4f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5
5
5
6
5
6
6
6
6
6
5
CsF
CsF
CsF
CsF
NaOH
NaOH
NaOH
CsF
CsF
NaOH
CsF
2 h
3 h
1 h
2 h
4 h
2 h
0.5 h
0.5 h
2 h
0.25 h
3 h
—
E
—
20
50
55
30
50
90
68
70
70
80
Ia
Id
E
Ie
97/3
E
IIe
Ie
Bn
96/4
6/4
E
IIe
IIf
IIf
IIb
IIb
Ic
SEM
SEM
H
H
H
4f
4b
4b
4c
CH3
CH3
CH3
H
H
OMe
E
10
11
2/8
E
a All reactions were performed with alkynamide 4 (1 equiv), boronic acid 5 or 6 (1.1 equiv), 5 mol% Pd(OAc)2, 10 mol% PPh3, CsF (3 equiv) or 2 N
aqueous NaOH (1.5 equiv) in refluxing THF.19
b E/Z stereochemistry refers to the newly formed double bond. Ratio was determined by 1H NMR analysis of the crude product.
c Isolated yield after column chromatography.
tandem reaction can be considered with a N-free alkyn-
amide when the terminal end of the triple bond is substi-
tuted.8,9 Indeed, when the reactions were performed
with the N-free butynamide 4b and vinylboronic acid
6, in both reaction conditions, diene IIb was produced,
in 70% yield (entries 9 and 10). As previously observed,
cycloadduct IIb was obtained as a single isomer using
CsF. In the presence of NaOH, a complete transforma-
tion occurred within 15 min, however leading to both
isomers (ratio EE/EZ = 2:8). Surprisingly, the major
product appeared to be the (EZ)-isomer. Results of runs
7–10 confirmed that CsF was a better additive than
NaOH in our tandem process.
compounds IIe and IIf. Therefore, due to the aniso-
tropic effect of the carbonyl group, proton H-c for the
(EE)-isomer of derivative IIe appeared at a lower field
than the corresponding signal for the (EZ)-isomer,
whereas proton H-b appeared at a lower field for the
(EZ)-isomer. Stereochemistry was unambiguously sup-
ported by NOESY experiments (Fig. 2). For both com-
pounds bearing a methyl group on the exocyclic olefin
(Ic and IIb), the configuration was also confirmed by
chemical shifts (H-20/H-60 protons and H-b, respec-
tively) and NOESY experiments.22 For derivatives
IIb,e,f a large coupling constant between H-a and H-b
(14.5–16.0 Hz) confirmed the (E)-geometry of the intro-
duced double bond.
Finally, the reaction was attempted, in the presence of
CsF, with arylboronic acid 5 and anilide 4c bearing a
5-methoxy group (entry 11). Reaction outcome was
not affected, and the desired constrained CA4 analogue
Ic was obtained in good yield (80%) as a single isomer.
As expected, methyl derivatives Ic and IIb proved to
be of great stability.
In summary, the tandem Heck–Suzuki–Miyaura ap-
proach has proven to be a practical means for preparing
3-arylmethylene (type I) and 3-arylallylidene (type II)
oxindoles. In both series, high stereocontrol was ob-
tained by using CsF as an additive. We have shown that
the trimethoxyphenyl boronic acid 5 and the corre-
sponding vinyl derivative 6 are suitable coupling part-
ners for this tandem reaction. It is noteworthy that the
substitution (e.g. by a methyl group) of the newly
formed double-bond stabilizes these oxindole deriva-
tives. Compounds Ic,d,e and IIb,e,f, which are consi-
dered as new CA4 analogues are currently under
The configuration (E) or (Z) of the newly formed double
bond within this series of oxindole derivatives could be
assigned based on the chemical shifts of particular pro-
tons:9,20,21 H-vinylic and H-20/H-60 protons for deriva-
tives Id and Ie, olefinic protons H-b and H-c for
4
O
O
a
c
6'
a
c
CH O
3
CH O
3
CH O
3
b
b
R
Bn
N
N
2'
N
Bn
CH O
3
CH O
3
CH O
3
O
4
4
CH O
CH O
CH O
3
3
3
Id (R=Me), Ie (R=Bn)
Figure 2. Configuration determination using NOESY experiments.
IIe EE
IIe EZ

6400
M. Arthuis et al. / Tetrahedron Letters 48 (2007) 6397–6400
isomerize to the (Z)-isomeric forms, which does not inhibit
tubulin polymerization. See: (a) Andreani, A.; Burnelli, S.;
Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.;
Rambaldi, M.; Varoli, L.; Kunkel, M. W. J. Med. Chem.
2006, 49, 6922–6924; (b) Pandit, B.; Sun, Y.; Chen, P.;
Sackett, D. L.; Hu, Z.; Rich, W.; Li, C.; Lewis, A.; Schaefer,
K.; Li, P.-K. Bioorg. Med. Chem. 2006, 14, 6492–6501.
17. Ducki, S.; Forrest, R.; Hadfield, J. A.; Kendall, A.;
Lawrence, N. J.; McGown, A. T.; Rennison, D. Bioorg.
Med. Chem. Lett. 1998, 8, 1051–1056.
biological evaluation. Expansion of this work to the syn-
thesis of derivatives with other heterocyclic cores is in
progress.
Acknowledgements
The authors are pleased to thank C. Meyer and S. Couty
(UMR 7084, CNRS/ESPCI, Paris) for helpful discus-
sions. This work was financially supported by CNRS
18. Hadfield, J. A.; Gaukroger, K.; Hirst, N.; Weston, A. P.;
Lawrence, N. J.; McGown, A. T. Eur. J. Med. Chem.
2005, 40, 529–541.
`
and Institut Curie. M.A. thanks the Ministere de l’Ens-
´
eignement Superieur et de la Recherche for a PhD Fel-
19. Representative experimental procedure: synthesis of 1-benz-
yl-3-[3-(30,40,50-trimethoxyphenyl)allylidene]indolin-2-one
IIe (entry 4): To a stirred solution of alkyneamide 4e
(80 mg, 0.221 mmol) in dry THF (12 mL) were added (E)-
2-(30,40,50-trimethoxyphenyl)vinylboronic acid 6 (58 mg,
0.243 mmol) and CsF (100 mg, 0.663 mmol). The resulting
mixture was degassed (argon bubbling, 15 min) then PPh3
(5.8 mg, 0.022 mmol) and Pd(OAc)2 (2.5 mg, 0.011 mmol)
were added. After heating at reflux for 2 h, the reaction
was cooled to rt, quenched with distilled water and
extracted with diethylether (twice). The combined organic
extracts were washed with brine, dried over MgSO4,
filtered and concentrated in vacuo. The resultant crude
product was purified by column chromatography on silica
gel (cyclohexane/EtOAc: 8/2) to give successively (EZ)-IIe
as an orange oil (2 mg) and (EE)-IIe (52 mg) as a pale
orange crystalline solid (global yield: 55%) (EZ)-IIe: 1H
NMR (300 MHz, CDCl3) d 8.54 (dd, J = 15.6, 11.5 Hz,
1H, H-b), 7.46 (d, J = 7.4 Hz, 1H, H-4), 7.33 (d,
J = 11.5 Hz, 1H, H-c), 7.32–7.26 (m, 5H, H-Ph), 7.14
(td, J = 7.6, 1.0 Hz, 1H, H-6), 7.00 (td, J = 7.6, 1.0 Hz,
1H, H-5), 6.97 (d, J = 15.6 Hz, 1H), 6.83 (s, 2H, H-20,60),
6.70 (d, J = 7.6 Hz, 1H, H-7), 4.98 (s, 2H, CH2), 3.91 (s,
6H, OCH3 · 2), 3.88 (s, 3H, OCH3); 13C NMR (75 MHz,
CDCl3) d 167.5 (C), 153.4 (C · 2), 143.3 (CH-a), 141.6 (C),
139.5 (C), 136.4 (CH-c), 136.2 (C), 132.0 (C), 128.7
(CH · 2), 128.6 (CH), 127.5 (CH), 127.2 (CH · 2), 124.0
(CH-b), 123.9 (C), 123.5 (C), 121.9 (CH), 119.2 (CH),
108.9 (CH), 104.9 (CH · 2), 61.0 (CH3), 56.2 (CH3 · 2),
43.3 (CH2); ESI+-MS: m/z = 428 [M+H]+, 450 [M+Na]+,
466 [M+K]+. (EE)-IIe: orange crystals, mp 195 ꢁC; 1H
NMR (300 MHz, CDCl3) d 7.68 (d, J = 7.6 Hz, 1H, H-4),
7.58–7.47 (m, 2H, H-b, H-c), 7.32–7.26 (m, 5H, H-Ph),
7.17 (td, J = 7.6, 1.4 Hz, 1H, H-6); 7.10 (d, J = 14.5, 1H,
H-a), 7.05 (td, J = 7.6, 1.0 Hz, H-5), 6.80 (s, 2H, H-20,60),
6.74 (d, J = 7.6 Hz, 1H, H-7), 4.98 (s, 2H, CH2), 3.94 (s,
6H, OCH3 · 2), 3.90 (s, 3H, OCH3). 13C NMR (75 MHz,
CDCl3) d 168.7 (C), 153.5 (C · 2), 144.4 (CH-a), 142.7 (C),
139.9 (C), 136.1 (CH-c), 136.0 (C), 131.7 (C), 128.8 (CH),
128.7 (CH · 2), 127.5 (CH), 127.2 (CH · 2), 124.8 (C),
123.2 (CH), 122.8 (CH-b), 122.5 (C), 122.0 (CH), 109.2
(CH), 104.9 (CH · 2), 61.0 (CH3), 56.3 (CH3 · 2), 43.7
(CH2). HRMS (DCI-NH3): m/z calcd for C27H26O4N
[M+H]+: 428.1862; found: 428.1852.
lowship Grant.
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´
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indole core.