Six-component reactions for the stereoselective synthesis of 3-arylidene-2-oxindoles via sequential one-pot Ugi/Heck Carbocyclization/ Sonogashira/Nucleophilic addition

Article abstract of DOI:10.1021/jo902713x

An efficient palladium-catalyzed protocol for the synthesis of 3-arylidene-2-oxindoles has been developed. In this approach, a sequential one-pot six-component reaction via Ugi/Heck carbocyclization/Sonogashira/ nucleophilic addition was used for the synthesis of the desired skeleton.

Full text of DOI:10.1021/jo902713x

pubs.acs.org/joc
Six-Component Reactions for the Stereoselective Synthesis of
3-Arylidene-2-oxindoles via Sequential One-Pot Ugi/Heck
Carbocyclization/Sonogashira/Nucleophilic Addition
Morteza Bararjanian,† Saeed Balalaie,*,† Frank Rominger,‡ Barahman Movassagh,† and
Hamid Reza Bijanzadeh§
†Peptide Chemistry Research Group, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran,
Iran, ‡Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270,
69120 Heidelberg, Germany, and §Department of Chemistry, Tarbiat Modares University,
P.O. Box 14115-175, Tehran, Iran
balalaie@kntu.ac.ir
Received December 24, 2009
An efficient palladium-catalyzed protocol for the synthesis of 3-arylidene-2-oxindoles has been
developed. In this approach, a sequential one-pot six-component reaction via Ugi/Heck carbocycli-
zation/Sonogashira/nucleophilic addition was used for the synthesis of the desired skeleton.
Introduction
different tandem reactions in an attempt at constructing
biologically active heterocyclic compounds.3
Designing novel multicomponent reactions (MCRs) lead-
ing to the formation of multiple bonds with a high bond-
forming efficiency (BFE) as well as synthesizing macromo-
lecules in one operation is among the most challenging
objectives in modern organic synthesis.1 Transition metals
have been used for catalyzing transformations in tandem
processes, and significant progress has been made in this
regard,2 including the efficient use of palladium catalysts in
The 2-oxindole unit represents an important structural
motif found in natural products and biologically relevant
compounds.4 Molecules containing this motif benefit from a
broad range of therapeutic activity, including oncology,
inflammation, and CNS immunology.5 3-Arylidene-2-
oxindole derivatives also have a range of medicinal and
biological activities, such as antiangiogenic and anticancer
activities.6 Many 3-arylidene-2-oxindole analogues have
been extensively evaluated for kinase inhibitory activities,
€
ꢀ
(1) (a) Domling, A. In Multicomponent Reaction; Zhu, J., Bienayme, H.,
Eds.; John Wiley-VCH: Weinheim, 2005; pp 76-95. (b) Tietze, L. F. Chem. Rev.
1996, 96, 115. (c) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reaction in
Organic Synthesis: John Wiely-VCH, 2006, Weinheim, pp 542-565. (d) Tietze,
L. F; Hauner, F. In Stimulating Concepts in Chemistry, Eds. Shibasaki, M. L;
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2806 J. Org. Chem. 2010, 75, 2806–2812
Published on Web 04/13/2010
DOI: 10.1021/jo902713x
r
2010 American Chemical Society

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JOCArticle
SCHEME 1. Retrosynthetic Pathway for the Synthesis of 3-
Arylidene-2-oxindoles
FIGURE 1. Representative 3-arylidene-2-oxindoles.
e.g., SU49847 and GW491619.8 Recently, hesperadin has
been identified as an Aurora B inhibitor that is tetrasubsti-
tuted in the exocyclic olefin9 (Figure 1).
Much effort has been made in investigating the synthesis
of derivatives of these compounds to deduce structure-
-activity relationships and discovering new analogues with
improved properties, as well as finding novel methods for the
synthesis of this skeleton.10
chlorides,17and (vii) Pd- or Rh-catalyzed cyclization of 2-
alkynylaryl isocyanates in the presence of an external nu-
cleophile.18 Some of the aforementioned methods have
restrictions due to the lack of generality, poor functional
group tolerance, lengthy synthetic sequences, and also com-
plex starting materials.
Because of the significant biological activities of these
derivatives, stereoselective syntheses of 3-arylidene-2-oxi-
ndoles remain an interesting subject in organic synthesis.
Pd catalysts are of considerable importance because they are
used in the synthesis of many biologically active 3-arylidene-
2-oxindoles. N-Substituted-2-alkynamides were generally
used as starting materials for the synthesis of 2-oxindole
derivatives.10a,b,12,14a-c,15,19
There are several approaches for the synthesis of 3-aryli-
dene-2-oxindoles, such as (i) nucleophilic addition of oxi-
ndoles to carbonyl compounds,11 (ii) Heck reaction,12 (iii)
radical cyclization,13 (iv) transition-metal-catalyzed domino
processes with R,β-acetylenic amides derived from 2-haloa-
nilines14 or anilines (proceeding with arene ortho C-H bond
activation),15 (v) carbonylation of 2-alkynylanilines,16 (vi)
carbopalladation Stille coupling reaction with carbamoyl
In our retrosynthetic analysis, the formation of the exo-
cyclic double bond in 3-arylidene-2-oxindoles was investi-
gated by ring-closure procedure of N-substituted-2-alkyna-
mides (I) resulting from the four-component reaction of
aldehydes, 2-haloanilines, propiolic acids, and isocyanides,
using Pd-catalyst (Scheme 1).
In continuation of our research for the construction of new
heterocyclic skeletons via one-pot reactions, we became
interested in the synthesis of 3-arylidene-2-oxindols. Herein,
we wish to report a novel type of Ugi/Heck carbocyclization/
Sonogashira/nucleophilic addition reaction sequences for
the synthesis of 3-arylidene-2-oxindoles 7a-j via one-pot
six-component reactions in the presence of palladium cata-
lyst in high yields and bond-forming efficiency. The reactions
were carried out in one pot in three steps in MeOH
(Scheme 2).
(7) (a) Mohammadi, M.; McMahon, G.; Sun, L.; Tang, C.; Hirth, P.;
Yeh, B. K.; Hubbard, S.; Schlessinger, R. J. Science 1997, 276, 955. (b) Sun,
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Results/Discussions
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lation/Sonogashira cross coupling approach for the reaction of
N-(2-iodophenyl) alkynamides with terminal alkynes, which
led to oxindoles possessing exocyclic conjugated enynes that
could enter the subsequent cascade of reactions to yield rigid
spirocycles.14a In our strategy, a novel six-component reaction
of benzaldehyde (1), 2-iodoaniline (2), phenylpropiolic acid (3),
isocyanides (4), phenylacetylene (5), and secondary amines (6)
was used for the synthesis of 3-arylidene-2-oxindoles 7a-j in
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SCHEME 2
MeOH in the presence of palladium catalyst in one-pot reaction
conditions. The reactions could be carried out in the presence of
5% PdCl2(PPh3)2, 10% CuI, and DIEA as the base in MeOH.
The results have been summarized in Table 1.
of compounds 7a-j were obtained as the sole product
because of the phenyl group participation.
To gain more insight into the reaction mechanism, the Ugi
adduct was allowed to react with phenylacetylene in the
presence of palladium catalyst and cuprous iodide in cataly-
tic amounts. The reaction of benzaldehyde, 2-iodoaniline,
phenylpropiolic acid, and tert-butyl isocyanide in MeOH
was selected as a model reaction (Scheme 4). After the
formation of the desired N-substituted-2-alkynamide (Ib),
phenyl acetylene (1.5 equiv) was also added to the mixture.
Control experiments indicate that this sequential reaction
could proceed in three steps, namely, (i) Ugi 4-MCR between
benzaldehyde, 2-iodoaniline, phenylpropiolic acid, and iso-
cyanides that is the presumed first step of this tandem process
leading to N-substituted-2-alkynamides I (a, b), (ii) Heck
carbocyclization/Sonogashira cross-coupling of N-(2-iodo-
phenyl) alkynamides with phenylacetylene as a domino
insertion, coupling sequence, and finally (iii) the forma-
tion of the intermediates 8 (E isomer) and 9 (Z isomer) and
nucleophilic addition of secondary amines to activated
triple bond in dihydroindolones 8 and 9 to form the 3-
arylidene-2-oxindoles 7a-j.The proposed mechanism is
shown in Scheme 3. The following steps show the role of
palladium catalyst in the formation of 3-arylidene-2-oxi-
ndoles (Scheme 3).
The second step of the proposed mechanism is a known
domino Heck/Sonogashira reaction process, and the reac-
tion procedure could be categorized, respectively, as follows:
(1) Occurence of oxidative addition of haloarene to Pd(0)
(intermediate A). (2) Insertion reaction to alkyne moiety and
formation of intermediate B (carbopalladation). (3) Trans-
metalation with copper and the addition of copper phenyla-
cetylide to intermediate B and formation of intermediate C.
(4) Final reductive elimination leads the formation of the
mixture of E and Z isomers of dihydroindolones 8 and 9.
Nucleophilic addition of the secondary amines to the elec-
trophilic carbon center in the alkynyl moiety of the inter-
mediate 8 or 9 would produce the zwitterionic intermediates
10 and 11. The intermediate 10 leads to product 12, which has
a strong steric hindrance. As is shown, the intermediate 10
could be converted to the intermediate 11 as a result of steric
hindrance in the structure of 12 compared to 7a-j. Rotation
of the newly formed bond between the indole core and the
allenyl moiety and subsequent tautomerization leads to
stereoselective synthesis of 7a-j. In all cases, the Z isomers
1
The H NMR study of the reaction mixture showed the
formation of two E and Z isomers (8b, 9b) with a E/Z ratio of
41:59. The E isomer was recrystallized and its structure was
also confirmed by X-ray crystallographic data as shown in
Figure 2
The distinguished peaks for the E and Z isomers (8b, 9b)
were observed as two doublets for the proton H-4 of oxindole
ring at δ 8.49 and 6.51 ppm, respectively.
The solvent effect in the domino Heck/Sonogashira reac-
tion (second step in Scheme 3) was examined by replacing
THF with MeOH. Ugi 4-MCR was carried out in MeOH,
and after evaporation of the solvent, without separation of
the Ugi 4-MCR intermediate (Ib), addition of phenylacety-
lene (3 equiv) was performed in the presence of 5% PdCl2-
(PPh3)2, 10% CuI, and 5 equiv of DIEA as the base in THF.
Gratifyingly, the use of MeOH as the solvent resulted in a
dramatic reduction of the reaction time (1 h) compared to
that using THF (24 h). The yield of the reactions was better in
MeOH than in THF. When THF was used as the solvent, 3
equiv of phenylacetylene should be used compared to MeOH
as the solvent (1.5 equiv). The ratio of E/Z isomers (8b/9b) in
THF was (65:35), whereas in MeOH it was (41:59). Mean-
while, 1,4-diphenyl-1,3-butadiyne was formed in THF as a
byproduct.
The ratio of E and Z isomers for compounds 8b and 9b
depends on the polarity of the solvent. In MeOH, the ratio of
polar form (9b, Z) is higher (59%), and in THF, the dominate
isomer is E (8b, 65%). There is a distinguished peak in the 1H
NMR spectra of the products. As a model compound, in the
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TABLE 1. Stereoselective Synthesis of 3-Arylidene-2-oxindoles via Sequential Ugi/Heck Carbocyclization/Sonogashira/Nucleophilic Addition
aIsolated yield. bCyclohexyl.
FIGURE 3. Structure of compound 7i.
FIGURE 2. X-ray structure of compound 8b.
structure of compound 7i (Figure 3), proton H-4 reso-
nates at δ 5.49 ppm as a doublet, compared to H-4 in
compound 8b (δ 8.49 ppm). The shielding effect for this
proton is related to the ring current of the aryl group. In fact,
this proton lies in the diamagnetic region of the ring, which
could be observed for all the products 7a-j. Meanwhile,
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SCHEME 3. Proposed Mechanism for the One-Pot Ugi/Heck Carbocyclization/Sonogashira/Nucleophilic Addition Reaction
Sequences for the Synthesis of 3-Arylidene-2-oxidoles
SCHEME 4
the structure of compound 7i was unambiguously supported
by NOE data. It should be mentioned that the decoupling
of the H-4 proton at δ 5.49 ppm does not cause any changes
in the singlet at δ 7.74 for the olefinic proton (H-c), and
in this way, the geometry of the double bond could be
confirmed.
The role of aryl group in the formation of 3-arylidene-2-
oxindoles 7a-j were investigated by using 2-butynoic acid
instead of phenyl propiolic acid, and after the formation of
the desired N-alkynamide 14 without separation, phenyla-
cetylene was added to the mixture in the presence of palla-
dium catalyst, cuprous iodide, and DIEA as the base
(Scheme 5). 1H NMR study of the crude reaction shows that
the sole product is the E isomer (15). It seems that there is a
strong steric hindrance between the methyl and hydrogen in
compound 16, but there is no such hindrance in compound
15.The distinguished peak at δ 8.36 ppm in 1H NMR
spectrum of compound 15 is related to H-4 proton. The
NOE experiment data could confirm the proposed E stere-
ochemistry of compound 15. The experiment was done by
irradiation on CH3 and H-4 at δ 2.777 and 8.385 ppm,
respectively.
In another attempt, the one-pot six-component reaction of
2-iodoaniline, benzaldehyde, 2-butynoic acid, cyclohexyl
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FIGURE 4. Synthesis of 1,4-disubstituted piperazine contained 3-arylidene-2-oxindole (19).
SCHEME 5
SCHEME 6
isocyanide, phenylacetylene, and morpholine was performed
according to our reaction sequences. The products were 17
(Z) and 18 (E) with the ratio of 63:37 (Scheme 6). The H-4
protons in compounds 17 (isomer Z) and 18 (isomer E) were
observed at δ 7.25 and 7.81 ppm, respectively.
Making a comparison between the chemical shift for H-4
in compounds 7a-j and also compound 17 confirms the role
of phenyl ring current effect on the chemical shift of H-4.
To expand the applicability of this domino reaction, after
optimization of experimental conditions, piperazine was
used as the secondary amine in our one-pot reaction to
afford compound 19 in 60% yield (Figure 4).
In conclusion, the aforementioned strategy presents a
new and direct route to biologically relevant heterocyclic
scaffolds by new one-pot Ugi/Heck carbocyclization/
Sonogashira/nucleophilic addition reaction sequences. The
high stereoselectivity, the ability of carrying out the reaction
in mild conditions with high yields, and the introduction of
the novel six-component reaction are the major advantages
of this work.
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Experimental Section
4H, 2CH2, CH2NCd), 3.62 (t, 2H, J = 5.3 Hz, CH2OH), 3.89
(m, 1H, CH, HCyclohexyl) 5.46 (d, 1H, J = 7.9 Hz, H4), 6.23 (d,
1H, J = 7.8 Hz, NH), 6.41 (t, 1H, J = 7.6 Hz, HAr), 6.44 (s, 1H,
CH), 6.70 (d, 1H, J = 7.9 Hz, HAr), 6.78 (t, 1H, J = 7.6 Hz,
General Procedure for the Synthesis of 3-Arylidene-2-oxi-
ndoles 7a-j. 2-Iodoaniline (219 mg, 1 mmol) and benzaldehyde
(106 mg, 1 mmol) were mixed together in MeOH (5 mL) and
stirred for 30 min. Then, phenyl propiolic acid (146 mg, 1 mmol)
and after 15 min isocyanide (1 mmol) were added, and the
mixture was stirred for 24 h. CuI (20 mg, 0.1 equiv) PdCl2
(PPh3)2, (35 mg, 0.05 equiv), phenylacetylene (153 mg, 1.5
mmol), and DIEA (650 mg, 5 mmol) were simultaneously added
to the solution of Ugi adduct in MeOH. The mixture was stirred
at room temperature for 1 h. After this time, the secondary
amine (1.5 mmol) was added as the sixth starting material in one
portion, and the resulting solution was heated at 50 °C for 8 h.
After cooling to room temperature, the reaction mixture was
diluted with brine (30 mL) and extracted with ethyl acetate (3 ꢀ
20 mL). The combined organic layers were dried with sodium
sulfate, concentrated to dryness in vacuo, and purified by
column chromatography on silica gel (hexane/ethyl acetate) to
give 7a-j (yields 62-73%) as red solids.
H
Ar), 6.81-7.41 (m, 15H, HAr), 7.76 (s, 1H, dCH); 13C NMR
(125 MHz, CDCl3) δ 24.6, 24.7, 25.5, 32.7, 32.8, 48.6, 48.8, 49.2,
52.8, 53.0, 57.8, 58.0, 59.2, 106.3, 110.2, 113.7, 120.8, 121.3,
124.7, 124.9, 127.1, 127.6, 127.7, 127.9, 128.1, 128.3, 128.4,
129.3, 130.2, 135.2, 136.5, 138.0, 139.9, 157.1, 162.4, 167.4,
168.2; HR-MS (ESI) calcd for C43H47N4O3 [M þ 1]þ
667.36427, found 667.36427; calcd for C43H46N4NaO3 [M þ
Na]þ 689.34732, found 689.34728.
Acknowledgment. S.B and M.B. gratefully acknowledge
Alexander von Humboldt foundation for the research fel-
lowship. We are grateful to Prof. R. Gleiter for helpful
discussions. We also thank Kimia Exir Company for chemi-
cal donation and financial support.
N-Cyclohexyl-2-((3E)-3-((E)-3-(4-(2-hydroxyethyl)piperazin-
1-yl)-1,3-diphenylallylidene)-2-oxoindolin-1-yl)-2-phenylaceta-
mide (7a) (Table 1, entry 1). Isolated yield 62%; mp 239-241 °C;
IR (KBr, cm-1) ν 3427, 3052, 2929, 1670, 1628; 1H NMR (500
MHz, CDCl3) δ 1.10-1.65 (m, 10H, HCyclohexyl), 2.55 (m, 5H,
2CH2 (CH2N), OH), 2.57 (t, 2H, J = 5.3 Hz, CH2N), 3.29 (s,
Supporting Information Available: Experimental proce-
dures, complete analytical data, NOE results, X-ray crystal-
lographic data, and copies of 1H and 13C NMR spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
2812 J. Org. Chem. Vol. 75, No. 9, 2010