Stereoselective synthesis of novel highly substituted isochromanone and isoquinolinone ContainingExocyclic tetrasubstituted alkenes

Article abstract of DOI:10.1021/jo802729s

An efficient synthetic route toward the synthesis of highly substituted arylethylidene-isoquinolinones/isochromanones is reported. The tandem carbopalladation/Suzuki-Miyaura coupling sequence stereoselectively provided various functionalized polycyclic co

Full text of DOI:10.1021/jo802729s

Stereoselective Synthesis of Novel Highly
Substituted Isochromanone and
Isoquinolinone-Containing Exocyclic
Tetrasubstituted Alkenes
Martin Arthuis, Rene´e Pontikis,* and Jean-Claude Florent*
Institut Curie, Centre de Recherche, 26 rue d’Ulm, Paris
F-75248 cedex 05, France, and CNRS, UMR 176,
26 rue d′Ulm, Paris F-75248 cedex 05, France
renee.pontikis@curie.fr; jean-claude.florent@curie.fr
ReceiVed December 12, 2008
FIGURE 1. CA4, oxindole 1, and the designed heterocyclic derivatives.
4-Arylideneisochromanones are usually prepared by Knoev-
enagel condensation of isochromanone with aldehydes.6 How-
ever, in most cases this methodology provides a mixture of (E)-
and (Z)-isomers, in modest yields. Although a few syntheses
of arylidenisoquinolinones have been reported, they require
troublesome processes.7 Furthermore, such heterocyclic deriva-
tives bearing a tetrasubstituted exo double bond were scarcely
reported.
SCHEME 1. Retrosynthetic Approach and Postulated
Vinyl-Palladium Intermediate
An efficient synthetic route toward the synthesis of highly
substituted arylethylidene-isoquinolinones/isochromanones
is reported. The tandem carbopalladation/Suzuki-Miyaura
coupling sequence stereoselectively provided various func-
tionalized polycyclic compounds in moderate to excellent
yields.
The trimethoxyphenyl unit has been established as an essential
structural feature found in a variety of molecules that bind at
the cochicine site of tubulin and consequently display antitumor
properties.1 Combretastatin A4 (CA4), a natural cis-stilbene
(3,4,5-trimethoxy-3′-hydroxy-4′-methoxystilbene) discovered by
Pettit et al., is one of the most potent tubulin polymerization
inhibitors.2
In an ongoing project to identify novel tubulin polymerization
inhibitors,3 we have reported the synthesis of 3′-(3,4,5-tri-
methoxyphenylalkylidene)oxindoles (see Figure 1, oxindole 1)
which may be considered as constrained CA4 analogues.4 In
this study, our attention was focused on the synthesis of six-
membered heterocyclic frameworks bearing three methoxy and
a substituted ethylidene group:5 isoquinolinones A and isoch-
romanones B.
Palladium-catalyzed reactions have proved to be a powerful
method for the preparation of a wide variety of heterocyclic
compounds in a one-step procedure.8 Particular attention has
been paid to the Heck-Suzuki-Miyaura tandem reaction, which
was used for the construction of various fused carbocycles9-11
or heterocyclic cores (indoline,12 isoindolinone,13indolinone,4,14
and dibenzoxapine15) bearing an exocyclic tri- or tetrasubstituted
double bond. This sequence involved alkyne-tethered aryl
(6) Lorand, T.; Forgo, P.; Fo¨ldesi, A.; Osz, E.; Prokai, L. Eur. J. Org. Chem.
2002, 2996.
(7) (a) Black, G. G.; Sainsbury, M.; Majeed, A. J. Tetrahedron 1984, 40,
4383. (b) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291.
(8) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644.
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Eur. J. Org. Chem. 2008, 1418.
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2008, 49, 3713.
(12) Burns, B.; Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.;
Worakun, T. Tetrahedron Lett. 1989, 30, 1135.
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3741. (b) Yanada, R.; Obika, S.; Inokuma, T.; Yanada, K.; Yamashita, M.; Ohta,
S.; Takemoto, Y. J. Org. Chem. 2005, 70, 6972.
* Address correspondence to this author at Institut Curie.
(1) (a) Nguyen, T. L.; McGrath, C.; Hermone, A. R.; Burnett, J. C.;
Zaharevitz, D. W.; Day, B. W.; Wipf, P.; Hamel, E.; Gussio, R. J. Med. Chem.
2005, 48, 6107. (b) Cushman, M.; Nagarathnam, D.; Gopal, D.; He, H. M.; Lin,
C. M.; Hamel, E. J. Med. Chem. 1992, 35, 2293.
(2) Pettit, G. R.; Singh, S. B.; Hamel, E.; Lin, C. M.; Alberts, D. S.; Garcia-
Kendal, D. Experientia 1989, 45, 209.
(3) Kaffy, J.; Pontikis, R.; Florent, J. C.; Monneret, C. Org. Biomol. Chem.
2005, 3, 2657.
(4) Arthuis, M.; Pontikis, R.; Florent, J. C. Tetrahedron Lett. 2007, 48, 6397.
(5) We previously observed that the compound with a methyl-substituted
alkene showed greater chemical stability.4
2234 J. Org. Chem. 2009, 74, 2234–2237
10.1021/jo802729s CCC: $40.75 2009 American Chemical Society
Published on Web 02/05/2009

SCHEME 2. Synthesis of Acetylenic Precursors 3a-e
halides and boronic acids. The key step of the domino reaction
is the intramolecular syn-carbometalation of the triple bond by
an arylpalladium halide complex, followed by cross-coupling
of the (E)-vinyl-palladium intermediate with a boronic species
to provide the polycyclic product in a stereocontrolled fashion.13
Herein, we wish to report the first synthesis of isoquinolinone
A and isochromanone B via this carbopalladation/cross-coupling
sequence. The convergent approach involved preparation of
cyclization precursors 3a-e, which could derive from benzyl
alcohol 4a and benzylamine derivatives 4b (Scheme 1).
Initially, we planned to synthesize the alkyne precursors 3a-e
from the common 2,3,4-trimethoxy-6-iodobenzaldehyde 516
(Scheme 2). Reduction of 5 by sodium borohydride afforded
the benzyl alcohol 4a, which was subsequently esterified with
butynoic acid by a carbodiimide-mediated reaction, to give the
acetylenic precursor 3a in 73% overall yield. Reductive ami-
nation of aldehyde 5 with ammonium acetate, in the presence
of sodium cyanoborohydride, failed to give the benzylamine
4b. Thus, the sequence was reconsidered, by using a two-step
procedure starting from trimethoxybenzonitrile 6. Regioselective
iodination of nitrile 6 was achieved by a directed ortho-
metalation process.17 Treatment with lithium tetramethylpip-
eridine (LiTMP), followed by quenching with iodine, gave 2,3,4-
trimethoxy-6-iodobenzonitrile 7 in 72% yield. Treatment of
3b with cyclopropylbromide. Instead, reductive amination of
iodoaldehyde 5 with cyclopropylamine and sodium triacetoxy-
borohydride22 gave the secondary amine 4e (87% yield), which
was directly coupled with butynoic acid following standard
conditions to provide amide 3e in 90% yield.
With alkyne precursors in hand, we then turned our attention
to the preparation of trimethoxyisoquinolinones and examined
the ability of acetylenic derivatives 3b-e to be efficient
substrates of the projected tandem carbopalladation/coupling
sequence, using 4-methoxyphenylboronic acid 8a as a trapping
agent (Table 1). With secondary amide 3b, the reaction occurred
in the presence of CsF (3.3 equiv), Pd(OAc)2 (5 mol %), and
PPh3 (10 mol %) in refluxing THF4 within 6 h and regio- and
stereoselectively provided the (E)-cyclized isoquinolinone 9 but
in only 29% yield (entry 1). Two other catalyst systems were
tested but they both failed to improve the reaction rate or yield
(Pd2dba3/PPh3 or PEPPSI-iPr:23 12.5% and 26% yields, respec-
tively). We thought that this low efficiency could be ascribed
to the high conformational freedom of the starting secondary
amide 3b. As expected, efficiency of the reaction was dramati-
cally enhanced by the use of tertiary amides (compare entries
1 to 2-4). The N-cyclopropylamide 3e led to isoquinolin-3-
one 10 in 84% yield within 10 h, whereas with the benzyl amide
3c, the reaction was accelerated (1 h, 84% yield, entry 3).
Finally, N-methylbutynamide 3d gave the best result (3.5 h,
92%, entry 4) and was next chosen to scope the reaction with
various boronic acids.
18
iodonitrile 7 with AlH3 failed to provide the amine 4b
(deiodination and reduction occurred concomitantly). To cir-
cumvent this problem, borane dimethylsulfide in refluxing
THF19 was used to give the desired amine 4b, although in
moderate yield.
Amine 4b was next coupled with butynoic acid (DCC,
DMAP) to provide the secondary amide 3b in 83% yield as a
mixture of rotamers. To potentially get a higher proportion of
the cis conformer, required for the following carbopalladation
step,20 N-alkylation of the amide nitrogen with different-sized
substituents was investigated. Treatment of 3b with benzyl
bromide or methyl iodide, using NaH as a base, gave the amido
derivatives 3c and 3d both in 82% yield. Introduction of a
cyclopropyl group21 was unsuccessful by direct alkylation of
Electron rich 4-N-dimethylphenylboronic acid 8b proved to
be more reactive than the electron poor 4-trifluoromethylphe-
nylboronic acid 8c (62 vs 48%, entry 5 vs 6). The 3-OTBDMS-
4-methoxyphenylboronic acid24 8d was also effective in this
series, providing the desilylated compound 15,25 albeit in a
moderate yield (30%, entry 7). 2-Benzofuranboronic acid also
(21) Zhu and co-workers reported during this work an elegant copper-
mediated direct N-cyclopropylation of amides by cyclopropylboronic acid: Be´nard,
S.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 6441, and references cited
therein.
(22) Murugesan, N.; Gu, Z.; Spergel, S.; Young, M.; Chen, P.; Mathur, A.;
Leith, L.; Hermsmeier, M.; Liu, E. C. K.; Zhang, R.; Bird, E.; Waldron, T.;
Marino, A.; Koplowitz, B.; Humphreys, W. G.; Chong, S.; Morrison, R. A.;
Webb, M. L.; Moreland, S.; Trippodo, N.; Barrish, J. C. J. Med. Chem. 2003,
46, 125.
(15) Yu, H.; Richey, R. N.; Carson, M. W.; Coghlan, M. J. Org. Lett. 2006,
8, 1685.
(16) Cherkaoui, M. Z.; Scherowsky, G. New J. Chem. 1997, 21, 1203.
(17) Fraser, R. R.; Savard, S. Can. J. Chem. 1986, 64, 621.
(18) Crich, D.; Krishnamurthy, V. Tetrahedron 2006, 62, 6830.
(19) Brown, H. C.; Choi, Y. M.; Narasimhan, S. Synthesis 1981, 605.
(20) (a) Saito, A.; Toriumi, Y.; Tomika, N.; Itai, A. J. Org. Chem. 1995, 60,
4715. (b) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006, 8, 4927.
(23) O′Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass, G. A.;
Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem.-Eur. J. 2006, 12, 4743.
(24) Banwell, M. G.; Hamel, E.; Hockless, D. C. R.; Verdier-Pinard, P.;
Willis, A. C.; Wong, D. J. Bioorg. Med. Chem. 2006, 14, 4627.
(25) Deprotection of silyl ether by CsF was previously reported; see: Cirillo,
P. F.; Panek, J. S. J. Org. Chem. 1990, 55, 6071.
J. Org. Chem. Vol. 74, No. 5, 2009 2235

TABLE 1. Tandem Reactionsa
a All reactions were carried out with boronic acid (1.1 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), and CsF (3.3 equiv), THF reflux (0.03 M) until
complete conversion. b Isolated yield.
SCHEME 3. Synthesis of Conjugate Dienic Derivativesa
participated well in this reaction to give the corresponding
isoquinolinone 16 (73%, entry 8).
Afterward, we explored the tandem reaction with ester 3a
(entries 9-12). The cyclization/alkylation reaction with boronic
acid 8a occurred smoothly, exclusively providing the (E)-
isochromanone 17 in good yield26 (entry 9). Similar efficiency
was obtained with arylboronic acid 8b (70%, entry 10), whereas
coupling with boronic acid 8c bearing the 4-trifluoromethyl
group needed a longer reaction time and furnished compound
19 with a lower yield (entry 17, 34%). Reaction with 8d gave
the phenol derivative 20 in moderate yield (entry 12, 50%).
Finally, a tandem reaction was attempted with a vinyl
boronic acid (Scheme 3). We were pleased to observe that
a Reagent and conditions: Pd(OAc)2 (5 mol %), PPh3 (10 mol %), CsF
(3.3 equiv), THF refux (0.03 M), 0.3 h for 21, 4 h for 22. b Direct Suzuki
coupling byproduct was also recovered in 29% yield.
the tandem reaction between ester 3a and trans-styrylboronic
acid 8f stereoselectively provided (E,E)-isochromanone 21
in 55% yield within only 20 min. It is noteworthy that direct
Suzuki coupling occurred concomitantly in 29% yield,
22 in 73% yield. NOESY experiments supported the E
configuration of the newly formed double bond of both
compounds (Figure 2 and Supporting Information).
For isoquinolinone 9 and isochromanone 17, a cross peak
between H-5 of the heterocyclic moieties and H-2′/H-6′ of the
probably due to the high reactivity of the boronic acid.
Butynamide 3d reacted more slowly (4 h for complete
4-methoxyphenyl, unambiguously confirmed the E configuration
conversion) but exclusively gave the (E,E)-dienic derivative
of the tetrasubstituted double bond (Figure 2 and Supporting
Information). Furthermore, chemical shift of the olefinic methyl
group (2.55 and 2.56 ppm for 9 and 17) could be used as a
(26) For precursor 3a, ester function favors a Z configuration, providing the
triple bond next to the PdI in the carbopalladation step.
2236 J. Org. Chem. Vol. 74, No. 5, 2009

charged with amide 3d (106 mg, 0.263 mmol), 4-methoxyphenyl-
boronic acid 8a (44 mg, 0.289 mmol), and CsF (132 mg, 0.867
mmol, flame-dried under high vacuum prior to use) and purged 3
times with argon. Anhydrous THF was added (0.03 M) and the
resulting mixture was degassed (argon bubbling, 15 min) before
Pd(OAc)2 (2.9 mg, 0.013 mmol) and PPh3 (6.9 mg, 0.026 mmol)
were added. After refluxing under argon for 3.5 h, the reaction was
cooled to rt, quenched with water, and extracted twice with diethyl
ether. The combined organic layers were washed with water and
brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 6/4) and recrystallization (dichloromethane/
hexane) to give 12 as a yellow solid (92 mg, 92%): mp 115-116
°C; IR (CHCl3, cm-1) ν 3005, 2938, 2838, 1719, 1639, 1609, 1509,
1463, 1245, 1107; 1H NMR (300 MHz, CDCl3) δ 6.98 (d, J ) 8.7
Hz, 2H), 6.76 (d, J ) 8.7 Hz, 2H), 5.87 (s, 1H), 4.38 (s, 2H), 3.87
(s, 3H), 3.79 (s, 3H) 3.76 (s, 3H), 3.22 (s, 3H), 3.15(s, 3H), 2.53
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.2, 158.6, 151.6, 148.1,
144.6, 139.9, 136.2, 130.3, 129.5 (2C), 126.7, 119.3, 113.7 (2C),
108.7, 61.2, 60.9, 55.4, 55.2, 46.5, 30.9, 23.2; MS (ES+) m/z 406.2
[M + Na]+; HRMS (ES+) m/z calcd for C22H25NO5Na [M + H]+
406.1630, found 406.1636.
FIGURE 2. NOESY correlations of cyclized compounds.
diagnostic signal27 for assignment of stereochemistry of all other
compounds (δ methyl group: 2.50-2.57 ppm).
The structure of compounds 9-22 confirmed the postulated
mechanism of the tandem reaction: intramolecular syn-carbo-
palladation in a 6-exo-dig process followed by cross coupling
with retention of configuration of the (E)-Pd-vinyl intermediate.
In conclusion, the tandem Heck-Suzuki-Miyaura reaction has
proved to be a diversity-oriented strategy for rapid construction of
various highly functionalized new arylalkylidene-isoquinolinones
and isochromanones of biological interest. In all cases, the reaction
proceeded regio- and stereoselectively to provide the cyclized
products as a single isomer in moderate to high yields. Conse-
quently, this domino approach could be extended to the synthesis
of new substituted benzo-fused heterocyclic compounds.
Acknowledgment. This work was financially supported by
Centre National de la Recherche Scientifique, Institut Curie, and
INCa. M.A. thanks the Ministe`re de l′Enseignement Supe´rieur
et de la Recherche for a Ph.D. Fellowship Grant.
Experimental Section
Supporting Information Available: Synthetic procedures,
Representative Procedure: Example of (E)-1,2-Dihydro-6,7,8-
trimethoxy-4-[1-(4-methoxyphenyl)ethylidene]-2-methylisoquin-
olin-3(4H)-one (12). A flask, flame-dried under high vacuum, was
1
characterization data, and copies of the H NMR, 13C NMR,
and NOESY experiments. This material is available free of
charge via the Internet at http://pubs.acs.org.
(27) This diagnostic signal would appear at a lower field for Z isomers due
to the anisotropic effect of the carbonyl group.
JO802729S
J. Org. Chem. Vol. 74, No. 5, 2009 2237