Iron-catalyzed carbonylation-arylation of N-arylacrylamides for synthesis of oxindole derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.09.048

An efficient method for oxindole synthesis is established by iron-catalyzed carbonylation-arylation of N-arylacrylamides with aldehydes. 3-Functionalized oxindoles are synthesized smoothly using FeCl₃ as catalyst and TBHP as oxidant. The obtain

Full text of DOI:10.1016/j.tetlet.2013.09.048

Accepted Manuscript
Iron-Catalyzed Carbonylation-Arylation of N-Arylacrylamides for Synthesis of
Oxindole Derivatives
Fan Jia, Kaisheng Liu, Hui Xi, Shenglin Lu, Zhiping Li
PII:
S0040-4039(13)01602-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.09.048
TETL 43548
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 July 2013
30 August 2013
13 September 2013
Please cite this article as: Jia, F., Liu, K., Xi, H., Lu, S., Li, Z., Iron-Catalyzed Carbonylation-Arylation of N-
Arylacrylamides for Synthesis of Oxindole Derivatives, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/
j.tetlet.2013.09.048
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Iron-Catalyzed Carbonylation-Arylation of
N-Arylacrylamides for Synthesis of Oxindole
Derivatives
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Fan Jia, Kaisheng Liu, Hui Xi, Shenglin Lu, and Zhiping Li

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Iron-Catalyzed Carbonylation-Arylation of N-Arylacrylamides for Synthesis of
Oxindole Derivatives
Fan Jiaa, Kaisheng Liua, Hui Xia, Shenglin Lua, and Zhiping Lia,b
a Department of Chemistry, Renmin University of China, Beijing 100872, China
b State Key Laboratory of Heavy Oil Processing, China University of Petroleum, Beijing 102249, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient method for oxindole synthesis is established by iron-catalyzed carbonylation-
arylation of N-arylacrylamides with aldehydes. 3-Functionalized oxindoles are synthesized
smoothly using FeCl3 as catalyst and TBHP as oxidant. The obtained oxindoles can be used for
further transformations to give diverse indole alkaloids structure motifs.
Available online
2013 Elsevier Ltd. All rights reserved.
Keywords:
Iron catalysis
Carbonylation
Arylation
Oxindoles
Olefin carbonylation is one of the most important methods for
synthesis of organic carbonyl compounds (Scheme 1).1
Hydroformylation and Reppe carbonylation of alkenes are the
most powerful and well investigated processes of the introduction
a carbonyl group into carbon skeletons using carbon monoxide
(CO) as a carbonyl source (Type I).2 However, the methods
without the use of CO are more attractive alternative in fine
chemical synthesis due to the disadvantages of the storage and
transport of the toxic CO gas.3 As one of excellent examples,
hydroacylation of alkenes with aldehydes has been developed as
a direct and efficient approach for carbonyl synthesis (Type II).4
Inspired by these reactions, we envisioned that introducing
another functional group such as alcohol, amine, and carbon unit
to the type II reaction will offer a valuable method for the
buildup of molecular complexity in a single procedure (Type
III).5
peroxides could be used for synthesis of multisubstituted
epoxides and α,β-epoxy-γ-butyrolactones,7 which are shown to
be one of useful reagents in synthetic chemistry. To continue our
efforts on oxidative carbonylation of olefins, we hypothesized
that the introduction of a intramolecular radical accepter such as
phenyl ring might achieve a carbonylation-arylation reaction.8
Herein, we disclosed an iron-catalyzed carbonylation-arylation of
N-arylacrylamides (Scheme 2, II).9 The transformation presents
an efficient method for synthesis oxindole skeleton, which is one
of important scaffords in natural products and a useful synthon in
organic synthesis.10
Scheme 2. Oxidative carbonylation of olefins with aldehydes.
The reaction of N-methyl-N-phenylmethacrylamide 2a with
benzaldehyde 3a was chosen as a model reaction to establish the
reaction conditions (Table 1). The desired transformation was
affected by both the reaction temperature and the choice of
solvents (entries 1-11). A 90% yield of 4a was obtained when
chlorobenzene was used as solvent under 120 oC (entry 8).
Scheme 1. Types of olefin carbonylation.
Recently, we have developed a novel and efficient method of
iron-catalyzed carbonylation-peroxidation of alkenes with
aldehydes and hydroperoxide (Scheme 2, I).6 The generated
———
 Corresponding author. Tel.: +86-10-6251-4226; fax: +86-10-6251-6444; e-mail: zhipingli@ruc.edu.cn

2
Tetrahedron Letters
Interestingly, FeCl2 and Fe(OAc)2 also showed the comparable
Table 2. Scope of the substrate 2a
activity (entries 12 and 13). Although a 68% yield of 4a was
obtained in the absence of a catalyst (entry 14), other metal salts
severely inhibited the desired transformation (entries 16-19).
These results indicated that the use of iron catalyst is beneficial
to the efficiency of the reaction.11
Table 1. Optimization of the reaction conditionsa
4a
entry
cat.
solvent
T (oC)
(%)b
1
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl2
Fe(OAc)2
-
MeCN
MeCN
DCE
50
N.D c
2
85
35
34
62
56
67
86
90
23
25
8
3
85
4
DCE
100
100
120
120
120
120
120
120
120
120
120
120
120
120
120
120
5
DME
PhMe
PhBr
PhCl
DMF
DMSO
EtNO2
PhCl
6
7
8
9
10
11
12
13
14
15
16
17
18
19
83
86
68
87 d
23
13
14
35
PhCl
PhCl
-
PhCl
CuCl
CuCl2
CoCl2
Mn(OAc)2
PhCl
PhCl
PhCl
a Conditions: 2 (0.2 mmol), 3a (1.0 mmol), PhCl (1.0 mL), 120 oC, 1 h, under
N2.
PhCl
b NMR yields.
c Z/E = 1:1.
a Conditions: 2a (0.2 mmol), 3a (1.0 mmol), cat. (5 mol %), solvent (1.0 mL),
d Two diastereomers (1.3:1).
1 h, under N2.
b
Reported yields were based on 2a and determined by 1H NMR using an
The scope of aldehydes 3 was also investigated by the use of
2a as a model substrate (Table 3). Electron-donating substituted
benzaldehydes 3b and 3c afforded the desired products 4n and 4o
in good yields (entries 1 and 2). Although aldehyde with halide
3d reacted efficiently with 2a (entry 3), 4-formylbenzonitrile 3e
retarded the efficiency of the transformation (entry 4).
Thiophene-2-carbaldehyde 3f also gave the corresponding
internal standard.
c Not detected by 1H NMR.
d 5 h.
The scope of N-arylmethacrylamides 2 was investigated under
the optimized reaction conditions (Table 2). Substrates 2a-2c
bearing alkyl, aryl protecting groups on the nitrogen were
excellent for this transformation (entries 1-3). α-Substituted
olefins bearing different functional groups led to the expected
products in moderate to excellent yields (entries 4 and 5). To our
delight, internal olefins were compatible with the reaction
conditions (entries 6-8). Halide (Br) and CN were also tolerated
and furnished the desired product 4j, 4k in good yields (entries
10 and 11). Ortho-Substituted substrate 2l gave the
corresponding product 4l in a slight low yield (entry 12), while
the substrate 2m bearing meta substitute exhibited good
reactivity (entry 13). However, the latter showed poor
regioselectivity (1.3:1).
oxindole
in
good
yield
(entry
5).
Gratifyingly,
cyclopropanecarbaldehyde 3g afforded the desired product in an
excellent yield (entry 6). When aliphatic aldehyde, such as
valeraldehyde 3h, was applied under the standard conditions, the
desired product 4t was obtained together with the
decarbonylation product 5 (eq 1). Moreover, pivaldehyde 3i only
gave the decarbonylation product 6 in a good yield (eq 2). These
results indicated that the decarbonylation of aldehydes competed
with the desired carbonylation-arylation reactions.12

3
disubstituted indoline derivatives are potentially useful in
synthetic chemistry.17
Table 3. Scope of the substrate 3a
a Conditions: 2a (0.2 mmol), 3 (1.0 mmol), PhCl (1.0 mL), 120 oC, 1 h, under
N2.
b NMR yields.
Figure 1. ORTEP drawing of 9
On the basis of the above results and literature reports,18
a
tentative reaction mechanism for iron-catalyzed carbonylation-
arylation of N-arylacrylamides is proposed (Scheme 3). Firstly,
acyl radical A is generated by hydrogen abstraction of aldehydes.
Radical addition of A to carbon-carbon double bond forms the
intermediate B, which is trapped by a benzenoid π-system to give
C.19 The resulting cyclohexadienyl radical C is aromatized into
the final oxindole 4 by the further oxidation.20
To demonstrate the utility of the present method in synthetic
chemistry, the further transformations of the obtained oxindoles
were then investigated. The treatment of compound 4a with
lithium aluminium hydride (LAH) in THF under 0 oC led to
tetrahydro-2H-furo[2,3-b]indole 7 (d.r. = 2.5:1) in 90% yield (eq
3). The skeleton was found in indole alkaloid physovenine and
related natural products.13
Scheme 3. A proposed mechanism.
In conclusion, we demonstrated an example of iron-catalyzed
carbonylation-arylation of N-arylacrylamides by the application
of aldehyde as a carbonyl source. This transformation represents
an efficient method for synthesis of functional oxindoles from
simple arylacrylamides and aldehydes. The achieved oxindoles
could be transformed into some useful synthetic intermediates.
The further studies on the understanding mechanism and
application are under progress in our laboratory.
Furthermore, the treatment of 4a with NH2OH·HCl in EtOH
under basic conditions gave the desired ketoximes 8 (8a/8b =
1.5:1) in 98% yield (eq 4).14 To our delight, the reduction of 8a
efficiently gave tetrahydro-[1,2]oxazino[6,5-b]indole 9 by the use
of LAH as
dimethylindolin-3-yl)-1-phenylethanone
a
reducing reagent (eq 5), while 2-(1,3-
oxime 10 was
quantitatively obtained by the application of DIBALH as a
reducing reagent (eq 6). The ORTEP drawing of 9 was showed in
Figure 1.15 It should be noted that the pyrrolobenzoxazine motif
could be found in geneserine and related alkaloids16 and 3,3-
Acknowledgment. Financial support by the National Science
Foundation of China (21072223, 21272267), State Key

4
Tetrahedron Letters
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Laboratory of Heavy Oil Processing (2012-1-06), the
3984. (b) Groth, U.; Köttgen, P.; Langenbach, P.; Lindenmaier,
A.; Schütz, T.; Wiegand, M. Synlett 2008, 1301-1304.
Fundamental Research Funds for the Central Universities, and
the Research Funds of Renmin University of China (10XNL017).
18. (a) Dunford, H. B. Coord. Chem. Rev. 2002, 233-234, 311-318.
(b) Stavropoulos, P.; Celenligil-Cetin, R.; Tapper, A. E. Acc.
Chem. Res. 2001, 34, 745-752. (c) Gozzo, F. J. Mol. Catal. A:
Chem. 2001, 171, 1-22. (d) MacFaul, P. A.; Wayner, D. D, M.;
Ingold, K. U. Acc. Chem. Res. 1998, 31, 159-162. (e) Barton, D.
H. R. Tetrahedron 1998, 54, 5805-5817. (f) Kim, J.; Harrison, R.
G.; Kim, C.; Que, L., Jr. J. Am. Chem. Soc. 1996, 118, 4373-4379.
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Lett. 1999, 40, 2533-2536.
Supporting information available: Experimental procedures,
spectrum data, and NMR spectra of the compounds. This
material is available free of charge via the Internet at
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