Palladium-catalyzed carbonylative α-arylation of 2-oxindoles with (Hetero)aryl bromides: Efficient and complementary approach to 3-acyl-2-oxindoles

Article abstract of DOI:10.1002/anie.201404217

An efficient Pd-catalyzed carbonylative α-arylation of 2-oxindoles with aryl and heteroaryl bromides for the one-step synthesis of 3-acyl-2-oxindoles has been developed. This reaction proceeds efficiently under mild conditions and is complementary to the

Full text of DOI:10.1002/anie.201404217

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DOI: 10.1002/anie.201404217
Palladium Catalysis
Palladium-Catalyzed Carbonylative a-Arylation of 2-Oxindoles with
(Hetero)aryl Bromides: Efficient and Complementary Approach to
3-Acyl-2-oxindoles**
Zhong Lian, Stig D. Friis, and Troels Skrydstrup*
Abstract: An efficient Pd-catalyzed carbonylative a-arylation
of 2-oxindoles with aryl and heteroaryl bromides for the one-
step synthesis of 3-acyl-2-oxindoles has been developed. This
reaction proceeds efficiently under mild conditions and is
complementary to the more common oxindole forming
reactions. The transformation only requires a mild base and
provides good to excellent yields even with heteroaromatic
substrates. Employing
a near stoichiometric amount of
13COgen, the methodology was easily extended to [13C] acyl
labeling. The general applicability of the reaction conditions
was demonstrated in the synthesis of a structure related to the
pharmaceutically active 3-acyl-2-oxindoles, tenidap.
I
ndoles and oxindoles are highly privileged structures, found
in countless natural products and drug candidates.[1] Accord-
ingly, the derivatization of these structural motifs is of
continuing interest to both the medicinal industry and the
academic society.[2] The formation of 3-acyl-2-oxindoles is no
exception as these compounds are featured in a number of
natural products and biologically active molecules, e.g., GSK3
kinase inhibitors,[3] influenza endonuclease inhibitors,[4] and
Tendidap,[5] a potent inhibitor of cyclooxygenase.
Scheme 1. Synthetic routes to 3-acyl-2-oxindoles. PMB: p-methoxy-
benzyl.
Despite their versatile significance, only a limited number
of synthetic routes to 3-acyl-2-oxindoles have been reported
in the literature. The reactions can be grouped into two
approaches on the basis of the bond formed (Scheme 1). In
the oxindole forming approach (Scheme 1, disconnection A,
dotted box), a number of transition-metal-catalyzed trans-
formations have been described. These include the gold-
catalyzed SEAr cyclization of N-arylynamides with subse-
quent oxidation of the gold carbene,[6] a copper-catalyzed a-
arylation of 2-iodoanilines carrying a 1,3-dicarbonyl on the
iodine was published.[9] Common to all these transformations
is the use of relatively complex starting materials, which all
originate from substituted anilines.
The alternative approach to 3-acyl-2-oxindoles is through
À
a C C bond forming reaction directly with the oxindole
(Scheme 1, disconnection B, dashed box). So far, this
approach has found limited application and only a narrow
range of compounds have been synthesized in low to
moderate yields.[10] This may be attributed to the relatively
harsh reactions conditions employed, because acid halides or
a strong base are required. Furthermore, the need for
a stoichiometric amount of coupling reagent makes this
approach less appealing.
aniline,[7] and a rhodium- or silver-catalyzed C H carbene
À
insertion starting from a-diazoketoamides.[8] Recently,
another SEAr-type transformation mediated by hypervalent
[*] Z. Lian, S. D. Friis, Prof. Dr. T. Skrydstrup
Center for Insoluble Protein Structures (inSPIN), Interdisciplinary
Nanoscience Center (iNANO), and Department of Chemistry
Aarhus University
Despite considerable efforts to develop three-component
carbonylative coupling reactions of (hetero)aryl (pseudo)ha-
lides, carbon monoxide, and nucleophiles,[11,12] the first
carbonylative a-arylation was only reported recently.[13,14]
However, these transformations generally require a strong
base or an adjacent electron withdrawing group to ensure
efficient enolization to furnish synthetically useful yields.[15]
Furthermore, the utilization of more complex, enolizable
compounds, which upon carbonylative a-arylation generate
products that are directly applicable in medicinal chemistry,
has not yet been demonstrated.
Gustav Wieds Vej 14, 8000 Aarhus C (Denmark)
E-mail: ts@chem.au.dk
[**] We appreciate the financial support from the Danish National
Research Foundation, (grant no. DNRF59), the Villum Foundation,
the Danish Council for Independent Research: Technology and
Production Sciences, the Lundbeck Foundation, the Carlsberg
Foundation, the Chinese Scholarship Council (grant to Z.L.), and
Aarhus University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404217.
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With the apparent need for a practical and general
method to prepare 3-acyl-2-oxindoles in mind, we set out to
identify conditions for the carbonylative a-arylation of 2-
oxindoles with aryl bromides. The optimization of this
transformation was initiated with N-methyl-2-oxindole (1a)
and 4-bromoanisole (2a), using a XantPhos-based catalytic
system, which has frequently been used in carbonylation
chemistry (Table 1).[11a,c,16] The combination of MgCl2 and
catalyst stability and no product was observed (entries 8–
11).[18] Employing more sterically encumbered bases
(entries 12 and 13) or using the stronger base DBU
(entry 14) only reduced the yield. Triethylamine, in combina-
tion with MgCl2, was therefore the selected base system,
because the omission of MgCl2 halted the reaction (entry 15).
Finally, a slight increase of the amount of aryl bromide raised
the yield of 3a to 84% (entry 16).
Having identified the optimal reaction conditions for this
carbonylative a-arylation of 2-oxindoles with aryl bromides
and a near stoichiometric amount of carbon monoxide, we set
out to probe the scope of the (hetero)aryl bromides employed
(Scheme 2). The product 3a, resulting from the coupling of
Table 1: Optimization of the carbonylative a-arylation of 2-oxindoles.[a]
Entry
Pd catalyst
Ligand
Base
Yield[b] [%]
1
2
3
4
5
6
7
Pd(dba)2
[Pd(cinnamyl)Cl]2
PdCl2
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
DPEPhos
PPh3
(tBu)3P·HBF4
CataCXium A
XPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Cy2NMe
DIPEA
DBU
Et3N
Et3N
20
57
54
23
44
64
20
0
0
0
0
34
25
33
0
Pd(PPh3)2Cl2
Pd(cod)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
8[c]
9[c]
10[c]
11[c]
12
13
14
15[d]
16[e]
84
[a] CO generated from COgen. [b] 1H NMR yield with internal standard.
[c] Ligand (10 mol%). [d] MgCl2 was omitted. [e] 2a (0.30 mmol). cod:
cyclooctadiene; dba: dibenzylideneacetone; XantPhos: 4,5-bis(diphe-
nylphosphino)-9,9-dimethylxanthene; DPEPhos: bis[(2-diphenylphos-
phino)phenyl] ether; CataCXium A: di(1-adamantyl)-n-butylphosphine;
XPhos: 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl; DIPEA:
N,N-diisopropylethylamine; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.
triethylamine as base is known to improve the ratio of C-
acylation versus O-acylation of the formed enol and thereby
furnish the desired compound in higher yield.[15b,c] When the
reaction was performed in dioxane at 808C in the presence of
1.5 equivalents of carbon monoxide, which is generated
ex situ from 9-methylfluorene-9-carbonyl chloride (COgen),
the desired product 3a was produced in 20% NMR yield
(entry 1).[11f,17] The use of Pd(dba)2 proved detrimental,
because the yields were significantly increased when other
Pd sources were tested (entries 2–6). Only Pd(PPh3)2Cl2 did
not perform notably better, suggesting that excess phosphine
ligand retards the reaction (entry 4). Employing the inex-
pensive and easy to handle palladium(II) acetate proved to be
optimal for this reaction (entry 6).
Scheme 2. Carbonylative a-arylation of N-methyl-2-oxindole with vari-
ous (hetero)aryl bromides, 1a (0.50 mmol, 0.25m). CO was generated
from COgen. [a] Also examined at 1008C. [b] 2 was exchanged for 4-
biphenyl triflate (0.75 mmol). [c] 2 was exchanged for BnCl
(0.75 mmol).
the electron-rich 4-bromoanisole, was isolated in 82% yield.
With a methyl group in either the para- or the meta-position
(3b and 3c) also provided the isolated products in good yields,
whereas the increased steric bulk associated with an ortho-
substituent was detrimental to the reaction (ortho analogues
of 3a, 3b, and 3g). Besides the coupling of the simple
bromobenzene, which afforded the product 3d in good yield,
the presence of a terminal olefin was also tolerated, with no
We next determined the preferred ligand for this reaction.
The more flexible DPEPhos did provide conversion to the
desired product (entry 7), albeit in a low yield, whereas the
use of monodentate ligands proved detrimental for the
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observation of Heck-type side reactions. This was exemplified
by the isolation of compound 3e in 92% yield. The coupling
of 4-bromobiphenyl gave product 3 f in a satisfactory yield of
85%. Remarkably, using identical reaction conditions, the
corresponding triflate was coupled with a similar yield,
thereby expanding the scope of this transformation.
The tolerance of the reaction for other halides on the aryl
bromide ring was demonstrated by the synthesis of com-
pounds 3g and 3h. Derivative 3h allows for post coupling
modification, e.g., by Suzuki or Buchwald–Hartwig coupling
of the aryl chloride.[19] The coupling of electron-poor aryl
bromides also worked well, as exemplified by the preparation
of the trifluoromethyl-substituted compound 3i, which was
isolated in 85% yield. Despite their electrophilic nature, both
3-acyl-2-oxindole products 3j and 3k, generated from para-
and meta-bromoacetophenone, were isolated in good yields
and no aldol-type side reactions were detected. This was also
the case for the preparation of the benzonitrile containing 3l,
which could be isolated in 78% yield. The presence of a nitro
group is potentially problematic in carbonylation chemistry as
it may be reduced by carbon monoxide under Pd catalysis.[20]
However, in this transformation, no such side reaction was
observed and 3m was isolated in 81% yield.
Benzylic chlorides were demonstrated to be equally good
substrates for this reaction and by using the same reaction
conditions as for the aryl bromides, compound 3n was
isolated in a 67% yield. Heteroaromatic groups were also
tolerated and 5-bromobenzofurane could be coupled in 89%
yield. The reactions with heteroaromatic bromides such as 3-
bromothiophene and 3-bromobenzothiophene under the
optimized conditions gave good yields of the desired products
3p and 3q. The formation of 3-acyl-2-oxindoles starting from
the rather electron-deficient 3- and 4-bromopyridine also
resulted in the smooth formation of 3r and 3s.
Scheme 3. Carbonylative a-arylation of various substituted 2-oxindoles,
1 (0.50 mmol, 0.25m). CO was generated from COgen.
labeling of the acyl carbon in 3-acyl-2-oxindoles was therefore
demonstrated using 13CO generated from [13C]-COgen.[22] In
this way, products [13C]-3e and [13C]-3d were isolated in yields
comparable to those obtained for their unlabeled counter-
parts (Scheme 4).
Next, we turned our attention to the scope of the 2-
oxindoles (Scheme 3). The presence of a methyl substituent in
the 5-position, as in 4b, slightly hampered the reaction and led
to a moderately reduced yield of 71%, compared to 3e,
whereas the 5-methoxy-2-oxindole yielded 76% of 4c. Both
the 5-fluoro- and the 5-chloro-N-methyl-2-oxindole were
coupled to provide the desired products 4d and 4e in
satisfactory yields. The therapeutically important trifluoro-
methoxy group or a nitro group in the 5-position of the
oxindole were tolerated well, which was illustrated by the
isolation of compounds 4 f and 4g.
Scheme 4. Carbonylative a-arylation to access [13C]-acyl 3-acyl-2-oxin-
doles using near stoichiometric amount of 13CO (generated from [13C]-
COgen).
We also tested different N-protecting groups for the
oxindole motif. The reaction with a simple benzyl protecting
group worked nicely and 3-acyl-2-oxindole 4h was isolated in
82% yield. The p-methoxybenzyl (PMB) protected oxindole
gave a slightly lower, but synthetically still useful yield of
70%, whereas the N-allyl protected 2-oxindole was coupled
to give 4j in 68% yield. Efforts toward the coupling of the
unprotected 2-oxindole proved unfruitful even at higher
temperature (results not shown).
The isotopic labeling of organic compounds is an impor-
tant area of research, constituting for example the 14C labeling
of potential drug molecules for metabolic studies.[21] Working
with radioactive carbon-14, however, requires specialized
laboratories. The capability of this transformation for the
The synthetic potential of this reaction was demonstrated
by applying the methodology to the synthesis of a biologically
interesting molecule (Scheme 5). An analogue of tenidap,
a potent cyclooxygenase inhibitor,[5] was easily synthesized
through the carbonylative a-arylation of oxindole 1k with 2-
bromothiophene, affording product 5a in 86% NMR yield.
Subsequent triflation of the enol allowed for purification by
flash column chromatography and the isolation of compound
5b in 51% yield over two steps.
Finally, a proposed mechanistic scenario for this Pd-
catalyzed transformation is illustrated in Figure 1. An oxida-
tive addition of Pd0 into the (hetero)aryl (pseudo)halide
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Keywords: a-arylation · carbonylation · isotope labeling ·
.
oxindoles · palladium
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Received: April 11, 2014
Published online: July 9, 2014
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