Iron trichloride-promoted cyclization of o-alkynylaryl lsocyanates: synthesis of 3-(chloromethylene)oxindoles

Article abstract of DOI:10.1021/ol9014877

Iron trichloride promotes the cationic cyclizatlon of o-(arylethynyl)aryl isocyanates leading to 3-(arylchloromethylene)oxindoles which can be stereoselectively converted to (Z)-3-(aminomethylene)oxindoles under straightforward conditions. When the alkyne

Full text of DOI:10.1021/ol9014877

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4262-4265
Iron Trichloride-Promoted Cyclization of
o-Alkynylaryl Isocyanates: Synthesis of
3-(Chloromethylene)oxindoles
Guillaume Cantagrel, Benoˆıt de Carne´-Carnavalet, Christophe Meyer,* and
Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France
christophe.meyer@espci.fr; janine.cossy@espci.fr
Received June 30, 2009
ABSTRACT
Iron trichloride promotes the cationic cyclization of o-(arylethynyl)aryl isocyanates leading to 3-(arylchloromethylene)oxindoles which can be
stereoselectively converted to (Z)-3-(aminomethylene)oxindoles under straightforward conditions. When the alkyne is substituted by an alkyl
group, activation of the allylic C-H bond also occurs producing 1,2-(dichloroalkylidene)oxindoles.
Oxindoles constitute an important class of heterocycles. In
particular, substituted 3-methyleneoxindoles have elicited
considerable synthetic interest due to their occurrence in
many biologically active substances.1 As a consequence,
numerous strategies have been developed for the synthesis
of 3-methyleneoxindoles possessing a trisubstituted or tetra-
substituted alkene with alkyl or aryl groups at the exocyclic
olefinic carbon. The most representative routes feature the
nucleophilic addition of oxindoles to carbonyl compounds,1,2
Heck reactions,3 radical cyclizations,4 transition-metal-
catalyzed domino processes with R,ꢀ-acetylenic amides
derived from 2-haloanilines5-7 or anilines (proceeding with
arene ortho C-H bond activation),8 carbonylation of 2-alkynyl-
anilines,9 carbopalladation-Stille coupling reactions with
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Chem. 1999, 42, 5120–5130. (c) Sun, L.; Liang, C.; Shirazian, S.; Zhou,
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2006, 14, 6492–6501. (e) Andreani, A.; Burnelli, S.; Granaiola, M.; Leoni,
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J. Org. Chem. 2005, 70, 3741–3744. (c) Yanada, R.; Obika, S.; Inokuma,
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10.1021/ol9014877 CCC: $40.75
Published on Web 09/09/2009
 2009 American Chemical Society

carbamoyl chlorides derived from 2-alkynylanilines,10 and
Pd- or Rh-catalyzed cyclizations of 2-alkynylaryl isocyanates
in the presence of an external nucleophile.11,12
Scheme 1. Routes toward 3-(Aminomethylene)oxindoles
Substituted 3-methyleneoxindoles in which the exocyclic
alkene is substituted by a heteroatom also constitute an
important class of functionalized oxindoles, especially
3-(aminomethylene)oxindoles which have been identified as
protein kinases inhibitors.13 Several strategies have been
developed to synthesize this class of oxindoles of type
A. One of the most straightforward route involves the
reaction of amines with enol ethers derived from 3-acyl-
oxindoles B. The latter compounds are usually prepared by
condensation of oxindoles C with activated acyl derivatives
or orthoesters.13 Another route to 3-acyloxindoles B capital-
izes on the copper-catalyzed intramolecular arylation of
ꢀ-keto amides D.14 Metal-catalyzed reactions that allow
access to 3-methyleneoxindoles bearing alkyl or aryl sub-
stituents on the exocyclic alkene have been successfully
extended to some classes of nitrogen nucleophiles. Thus, in
the presence of phthalimide (PhtNH), a catalytic amount of
Pd(OAc)2, and PhI(OAc)2, R,ꢀ-acetylenic amides E undergo
syn-amino-palladation, followed by arene C-H bond activa-
tion and reductive elimination, leading to 3-(aminomethyl-
ene)oxindoles A.15 Pd-catalyzed cyclizations involving 2-alky-
nylaryl isocyanates F with amides, carbamates, or sulfonamides
as external nucleophiles have also been recently reported.16
Another class of potential precursors to oxindoles of type A
are 3-(chloromethylene)oxindoles G, which have been
Herein, we report a new route toward 3-(chloromethyl-
ene)oxindoles G relying on the iron trichloride-promoted
cationic cyclization of 2-alkynylaryl isocyanates. Addition-
ally, straightforward conditions for their subsequent stereo-
selective transformation into 3-(aminomethylene)oxindoles
have been developed.
In our retrosynthetic analysis, the formation of the exo-
cyclic double bond in 3-(arylchloromethylene)oxindoles of
type G′ was envisaged by addition of a chloride ion to a
developing vinylic carbocation resulting from the nucleo-
philic attack of the alkyne onto an imidoyl cation I. The
latter species would be generated by activation of isocyanates
F with a Lewis acidic metal salt (MCln) (Scheme 2).
prepared by chlorination of 3-acyloxindoles B.13,17
A
complementary route from 2-alkynylanilines, involving a
chloropalladation-carbonylation sequence (cat. PdCl2,
excess CuCl2, CO atmosphere), has also been described
(Scheme 1).18
Scheme 2. Synthesis of 3-(Arylchloromethylene)oxindoles
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our knowledge, alkynes have not been used as π-nucleophiles
to intercept the resulting imidoyl cation.20 Although several
Lewis acidic metal chlorides could be considered, FeCl3 was
selected for its ease of handling and environmentally benign
character.21 Additionally, cationic cyclizations involving
oxycarbenium ions22 or enoates23 as electrophilic species and
alkynes, as π-nucleophiles, have been efficiently promoted
by FeCl3.
Table 1. Synthesis of 3-(Arylchloromethylene)oxindoles
Thus, several 2-alkynylaryl isocyanates 1a-k were syn-
thesized and treated with FeCl3 [(1.5 equiv), CH2Cl2, rt,
1-12 h]. A smooth reaction took place, and the correspond-
ing 3-(arylchloromethylene)oxindoles 2a-k were isolated in
good to excellent yields (54-99%) as mixtures of geometric
isomers (Table 1).24 The E/Z ratio seems to result from
kinetic control and was not altered by extended reaction times
or resubjection of the mixture of geometric isomers to FeCl3.
Although an anti-addition process across the alkyne was
anticipated, isomerization of the developing vinylic cation,
stabilized by the aromatic group, presumably occurred. The
reaction tolerates esters, methyl ethers, benzodioxole, and
nitro groups. A high regioselectivity was observed in all
cases. Despite the presence of a p-nitrophenyl substituent
on the alkyne in isocyanate 1k, the regioselectivity was still
in favor of a 5-exo-dig cationic cyclization process leading
to 2k, whose structure was unambiguously confirmed by a
chemical correlation.25
The lack of stereoselectivity observed in the cationic
cylizations of isocyanates 1a-k leading to 3-(arylchloro-
methylene)oxindoles 2a-k was in fact of little importance
for the subsequent substitution of the chlorine atom with an
amine by a 1,4-addition-elimination process.
We found that this transformation could be accomplished
under straightforward conditions and in very high yields
using microwave irradiation.26,27 The scope of the reaction
under these conditions (EtOH, 150 °C) is broad since
ammonia, primary and secondary aliphatic amines (acyclic
or cyclic), as well as p-anisidine all reacted well with
substrate 2a (R′ ) H, Ar ) Ph), providing the corresponding
3-(aminoarylmethylene)oxindoles 3-8 (83-99%).28 The
(20) Recently, TfOH-promoted tandem Friedel-Crafts alkenylation-
cyclization of 2-alkynylphenyl isothiocyanates has been disclosed; see:
Otani, T.; Kunimatsu, S.; Takahashi, T.; Nihei, H.; Saito, T. Tetrahedron
Lett. 2009, 50, 3853–3856.
(21) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104,
6217–6254.
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V. S. Org. Lett. 2003, 5, 1979–1982. (b) Miranda, P. O.; D´ıaz, D. D.; Padro´n,
J. I.; Ram´ırez, M. A.; Mart´ın, V. S. J. Org. Chem. 2005, 70, 57–62. (c) Xu,
T.; Yu, Z.; Wang, L. Org. Lett. 2009, 11, 2113–2116.
(23) (a) Yamazaki, S.; Yamada, K.; Yamabe, S.; Yamamoto, K. J. Org.
Chem. 2007, 67, 2889–2901. (b) Snider, B. B.; Roush, D. M. J. Org. Chem.
1979, 44, 4229–4232.
1
(24) The E/Z ratio was determined by H NMR. The chemical shift of
the aromatic proton H4 serves as a reliable diagnostic for the configurational
assignment; see the Supporting Information.
(25) See the Supporting Information.
(26) A few examples of such reactions have been previously reported,
with 3-(chloromethylene)oxindoles bearing an acyl group on the nitrogen,
by heating with an amine.13c,17b Enol ethers derived from 3-acyloxindoles
have been more extensively used as substrates.13
reaction was next generalized to other 3-(arylchloromethyl-
ene)oxindoles bearing substituents on the aromatic rings with
different amines. The reactions proceeded equally well to
afford compounds 9-17 (77-99%) (Scheme 3). In all cases,
(27) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284
.
(28) Treatment of 1a under similar conditions [piperidine (2 equiv),
EtOH, microwave, 150 °C, 0.3 h] only led to the corresponding ethyl
carbamate (55%) and urea (45%) resulting from addition of ethanol and
piperidine, respectively, to the isocyanate.
4264
Org. Lett., Vol. 11, No. 19, 2009

corresponding 3-(chloroalkylidene)oxindole iron alkoxide J.
Homolytic scission of the O-Fe bond30 would generate an
oxy radical K able to promote a remarkably efficient 1,5-
hydrogen abstraction leading to the allylic radical L. Chlorine
atom transfer from FeCl3 would then produce the corre-
sponding oxindoles 18-20 and FeCl2 (Scheme 4).31
Scheme 3. Synthesis of 3-(Aminoarylmethylene)oxindoles
Scheme 4. Reactivity of 2-(n-Alkylethynyl)aryl Isocyanates
b
c
a With 30% aq NH4OH (8 equiv). R1R2NH (2 equiv). R1R2NH (1
equiv), i-Pr2NEt (1 equiv). PMP ) 4-methoxyphenyl.
In conclusion, we have reported that iron trichloride
promotes an efficient cationic cyclization of 2-(arylethy-
nyl)aryl isocyanates to 3-(arylchloromethylene)oxindoles,
which can be subsequently stereoselectively converted to
(Z)-3-(aminoarylmethylene)oxindoles. For 2-(n-alkylethy-
nyl)aryl isocyanates, the FeCl3-promoted cationic cycliza-
tion is followed by C-H bond functionalization leading
to 3-(1,2-dichloroalkylidene)oxindoles. Further applica-
tions of isocyanates in cationic cyclizations are being
investigated.
a single Z-geometric isomer was formed.29 This result was
not surprising when a primary amine was used as a
nucleophile due to the intramolecular hydrogen bond that
can exist between the amino group and the carbonyl group
of the amide. In fact, whatever the amine, the stereochemical
preference is likely to result from thermodynamic control.1f
The reactivity of isocyanates 1l-n, in which the alkyne
is substituted by a n-alkyl group, was also examined in the
FeCl3-promoted cationic cyclization. Interestingly, these
compounds behave differently as more FeCl3 (2.5 equiv) was
required to ensure complete consumption of the starting
material. After optimization of the conditions (CH2Cl2, 0 °C),
3-(1,2-dichloroalkylidene)oxindoles 18-20, in which the
allylic C-H bond of the alkyl chain has been functionalized
in the form of a C-Cl bond, were isolated as single
geometric isomers (50-69%). The formation of oxindoles
18-20 was explained by a stereoselective cationic cycliza-
tion, with attack of the imidoyl cation by the alkyne and
addition of chloride ion in an anti fashion, producing the
Acknowledgment. One of us (G.C.) thanks the MRES
for a grant.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR data for all compounds and
chemical correlation confirming the structure of oxindole 2k.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL9014877
(30) (a) Ito, Y.; Fujii, S.; Saegusa, T. J. Org. Chem. 1976, 41, 2073–
2074. (b) Blanco, L.; Mansouri, A. Tetrahedron Lett. 1988, 29, 3239–3242.
(31) The presence of FeCl2 was confirmed by hydrolysis of the reaction
mixture and addition of phenanthroline (phen) followed by qualitative
detection of the (phen)3Fe(II) complex (λmax ) 511 nm).
(29) The chemical shift of the oxindole proton H4 (5.32-6.30 ppm)
supported the Z configuration of those compounds, and the configuration
of 14 was unambiguously confirmed by NMR (NOE).
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