Nickel-catalyzed intramolecular nucleophilic addition of aryl or vinyl chlorides to α-ketoamides through C-Cl bond activation

Article abstract of DOI:10.1002/chem.201100256

Nickeleophilic addition! The first example of a nickel-catalyzed direct intramolecular nucleophilic addition of aryl or vinyl chlorides to α-ketoamides through C-Cl bond activation is reported, which takes place under mild reaction conditions (see scheme).

Full text of DOI:10.1002/chem.201100256

DOI: 10.1002/chem.201100256
Nickel-Catalyzed Intramolecular Nucleophilic Addition of Aryl or Vinyl
À
Chlorides to a-Ketoamides Through C Cl Bond Activation
Jin-Xiu Hu,[a] Hao Wu,[a] Chuan-Ying Li,[b] Wei-Jian Sheng,[a] Yi-Xia Jia,*[a] and
Jian-Rong Gao*[a]
Organopalladium and organonickel intermediates derived
from aryl or vinyl halides through oxidative addition to Pd0
and Ni0 complexes predominantly act as electrophiles in
carbon–carbon bond-forming reactions.[1] In contrast, their
nucleophilic reactivity has received much less attention;
however, the development of the direct catalytic nucleophil-
ic reaction of aryl or vinyl halides with electrophilic partners
is very attractive because it omits the preparation of active
nucleophilic organometallic reagents.[2] Recently, there have
been a few literature examples reported for this direct nu-
cleophilic addition to carbon–heteroatom bonds under rela-
tively forcing reaction conditions; however, most of the sub-
strates were more reactive aryl bromides and iodides.[3] De-
spite their wide diversity, availability, and low cost, aryl
chlorides have rarely been studied in this area probably due
to their low reactivity,[4,5] which has often been ascribed to
their higher bond energy and makes activation by a homo-
the organo-transition-metal intermediates may improve
their nucleophilicity.[5] Herein, we present the primary re-
sults of a nickel-catalyzed intramolecular addition of aryl or
vinyl chlorides[8] to ketoamides, through C Cl bond activa-
À
tion under mild conditions (Scheme 1).
Scheme 1. Nickel-catalyzed intramolecular addition of aryl or vinyl chlor-
ides to ketoamides. PCy3 =tricyclohexylphosphine.
To find a potential metal catalyst, we initially studied the
intramolecular reaction of the chloro substrate 1a in the
presence of a stoichiometric amount of metal/tricyclohexyl-
phosphine (PCy3) complex (Scheme 2) Fortunately, [Ni-
genous transition-metal catalyst more difficult (bond dissoci-
À1
À
ation energies (kcalmol ) for Ph X: Cl (95); Br (80); I
(65)).[6] In the last decade, owing to the introduction of elec-
tron-rich bulky phosphine or carbene ligands, great advance
has been made for the utilization of aryl chlorides as elec-
trophilic partners in the cross-coupling reaction. These
bulky ligands are thought to facilitate the oxidative addition
À
of the C Cl bond of the aryl chloride to the metal catalyst,
Scheme 2. [NiACHTUNTRGNEUNG(cod)2]/PCy3 promoted intramolecular reaction of 1a
À
which is the initial crucial step required to activate the C Cl
bond in this type of transformation.[7] Enlightened by these
results, we envisioned that the nucleophilic addition reaction
of aryl chlorides might be realized by introducing the appro-
priate above-mentioned ligand, because it facilitates the
same initial oxidative addition reaction and its ligation to
ACHTUNGRTEN(NGNU cod)2] (cod=1,5-cyclooctadiene) was found to promote the
reaction of 1a at 708C in 4 h to give 2a, isolated in 89%
yield (Scheme 2), whereas no conversions were observed
when [PdACTHNUTRGENNG(U dba)2] (dba=dibenzylideneacetone) and CuI were
used to promote the reaction. We then focused on the devel-
opment of the catalytic version with a nickel catalyst. To our
delight, although Et3B and zinc dust were inefficient
(Table 1, entries 11 and 12), Me2Zn accelerated the catalytic
[a] J.-X. Hu, H. Wu, W.-J. Sheng, Prof. Dr. Y.-X. Jia, Prof. Dr. J.-R. Gao
The State Key Laboratory Breeding Base of Green
Chemistry–Synthesis Technology, Zhejiang University of Technology
Chaowang Road 18, Hangzhou, 310014 (P.R. China)
Fax : (+86)571-88320544
reaction (when used in combination with [NiACHTUNGTRENNUNG(cod)2]
(5 mol%) and PCy3 (10 mol%)) to give oxindole 2a in 89%
yield (as calculated from 1H NMR data, Table 1, entry 1).
Et2Zn was found to be less efficient than Me2Zn (Table 1,
entry 9 vs. entry 10). Among the monodentate ligands
tested, PCy3 was found to be the most efficient (Table 1, en-
tries 1–3), but the yields were markedly lower when using
the bidentate ligand diphenylphosphine ethane (dppe) or
without using any ligand (Table 1, entries 4 and 5). A screen
of the reaction solvent revealed that dimethoxyethane
(DME) was the best, which enabled 2a to be isolated in
E-mail: yxjia@zjut.edu.cn
gdgjr@zjut.edu.cn
[b] Prof. Dr. C.-Y. Li
Department of Chemistry, Zhejiang Sci-Tech University
5 Second Avenue, Xiasha Higher Education Zone
Hangzhou, 310018 (P.R. China)
Supporting information (including full experimental and spectroscop-
ic data) for this article is available on the WWW under http://
dx.doi.org/10.1002/chem.201100256.
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Chem. Eur. J. 2011, 17, 5234 – 5237

COMMUNICATION
Table 1. Optimization of the nickel-catalyzed reaction.[a]
droxyoxindoles (2a–2n) in good to excellent yields, except
oxindole 2l (with an alkyl group (phenylethyl) at the 3-posi-
tion), which was obtained in a lower yield. In addition, high
chemoselectivities were observed and no methylation by-
products from the cross-coupling of aryl chloride with
Me2Zn were detected. It is noteworthy that excellent yields
were attained for the synthesis of oxindoles 2h and 2m, in
which the chlorides remained unreacted and ready for fur-
ther functionalization. As shown in Scheme 4, the biaryl
Entry Ni cat.
Ligand (L) Reductant[b] Solvent Yield [%][c]
1
2
3
4
5
6
7
8
[Ni
[Ni
[Ni
[Ni
[Ni
[Ni
[Ni
[Ni
[Ni
[Ni
[Ni
[Ni
[Ni
N
PCy3
PPh3
Me2Zn
Me2Zn
THF
THF
THF
THF
THF
89
82
72
33
21
PtBu3·HBF4 Me2Zn
dppe
–
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Et2Zn
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
–
Toluene 60
Ether
CH2Cl2
DME
DME
DME
DME
DME
DME
DME
21
0
9
98 (95)[d]
10
11
12
13
14
15
80[d]
0
Et3B
Zn dust
Me2Zn
Me2Zn
Me2Zn
0
93
88
0
ACHTUNGTRENNUNG[NiCl CHTUNGTRENNUNG
–
PCy3
[a] Reaction conditions: 1a (0.2 mmol) in solvent (2 mL) at 408C. cod=
1,5-cyclooctadiene; acac=acetylacetonate; PCy3 =tricyclohexylphos-
phine; dppe=diphenylphosphine ethane; DME=1,2-dimethoxyethane.
[b] Me2Zn (2.0m in toluene); Et2Zn (1.0m in hexane); Et3B, (2.0m in
hexane). [c] Yield calculated from 1H NMR analysis, using 1-methoxy-
2,3-dimethylbenzene as the internal standard. [d] Yield of isolated prod-
uct.
Scheme 4. Suzuki coupling of 2h and 2m with PhB(OH)2.
products were obtained in excellent yields by a Pd-catalyzed
Suzuki-coupling of 2h and 2m with PhB(OH)2. Although
the cross-coupled methylation byproduct was observed
(<10% yield), this process was further extended to the anal-
ogous vinyl chlorides and the intramolecular reaction pro-
95% yield (Table 1, entry 9). Finally, an investigation of the
ceeded well with [NiCl2ACTHUNGTER(UNNG PCy3)2] (5 mol%) as the catalyst in
catalyst precursor disclosed that [Ni
acetonate) was nearly as efficient as [Ni
entry 13), however the preformed catalyst [NiCl
slightly decreased the yield (Table 1, entry 14). Not surpris-
ingly, the reaction could not proceed without a nickel cata-
lyst (Table 1, entry 15).
We next investigated the substrate scope; a series of
chloro substrates were tested under the optimal reaction
conditions established above (Table 1, entry 9). As shown in
Scheme 3, all the reactions afforded the corresponding 3-hy-
G
1,4-dioxane at 508C, to give the corresponding pyrrolidi-
nones 2o–2r in moderate to good yields (Scheme 3).
E
ACHTUNGTRENNUNG
G
The scope of bromo substrates was also probed under the
same reaction conditions. As expected and shown in
Scheme 5, the reactivity of aryl bromides was generally
higher than that of the analogous chlorides, giving the oxin-
doles in excellent yields. For the synthesis of pyrrolidinones,
the reactions could be carried out at room temperature and
good yields were observed except for the product 2u. Nota-
bly, the product 2q was obtained in high yield and the chlo-
ride was retained as in the case of 2h and 2m. The adduct 5
was formed instead of the desired oxindole for the reaction
À
of 4, indicating that the presence of a free N H bond in the
substrate was incompatible with this transformation.
Considering the mechanism, the following pertinent re-
sults are worth noting: 1) The stoichiometric reaction of 1a
and the [NiACTHUNTRGNEUNG(cod)2] complex of PCy3 revealed the nucleophi-
Scheme 3. Substrate scope of the intramolecular addition reaction with
aryl or vinyl chlorides. For 2a–2n, reaction conditions are identical to
Table 1, entry 9. The reaction time was 12h (except 2n, in which the reac-
licity of the aryl–nickel intermediate, derived from the oxi-
dative addition of aryl chloride to Ni0, which is similar to
the Grignard reagent (Scheme 2); 2) The reaction of aryl
bromide 6 with dimethylzinc was examined under the reac-
tion time was 18h). For 2o–2r, [NiCl
2ACHTNUGTREN(NNUG PCy3)2] (5 mol%) was used as the
catalyst in 1,4-dioxane at 508C for 10h. Napthth=naphthalene
Chem. Eur. J. 2011, 17, 5234 – 5237
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Y.-X. Jia, J.-R. Gao et al.
In summary, for the first time
we have developed an efficient
process for the direct nucleo-
philic addition of aryl and vinyl
chlorides to ketoamides for the
construction of 3-hydroxyoxin-
doles and pyrrolidinones under
mild reaction conditions. This
method was then successfully
extended to the analogous bro-
mides. Further application of
this method to other electro-
philic substrates, the develop-
Scheme 5. Substrate scope of the intramolecular addition reaction with aryl or vinyl bromides. The reaction
conditions for oxindole synthesis are identical to entry 9 of Table 1. For pyrrolidinone synthesis, [NiCl2ACTHNUTRGEN(UNG PCy3)2]
(5 mol%) was used as the catalyst in 1,4-dioxane at 258C for 6 h.
tion conditions; only a 6% yield of 7 obtained from the
cross-coupling of 6 with Me2Zn was isolated in 4 h (25% in
14 h) incorporating a trace amount of dehalogenated prod-
uct, which was consistent with the observation by Subburaj
and Montgomery.[9] This excludes the involvement of the nu-
cleophilic aryl–zinc species in the addition step thus imply-
ing the role of Me2Zn as reducing agent and base in the re-
action (Scheme 6); 3) Low but important enantiomeric
Scheme 6. Conversion of 6 under the established reaction conditions.
Scheme 8. Proposed mechanism for the nucleophilic addition reaction.
excess (ee) values were detected when the chiral phosphor-
ACHTUNGTRENNUNGamidite ligand (8, (R,S,S)-MonoPhos-PE) was introduced
into the reaction of 1a or 3a (Scheme 7), which further sup-
ment of an asymmetric version, and the detailed mechanistic
study are in progress in our laboratory.
Experimental Section
Synthesis of 2a: [NiACHTNUGTRNEG(UN cod)2] (2.8 mg, 0.01 mmol) and PCy3 (5.7 mg,
0.02 mmol) was added to a dried Schlenk tube under N2, and then freshly
distilled DME (2 mL) was introduced by a syringe. The resulting mixture
was stirred at room temperature for 1 h before addition of the substrate
1a (56 mg, 0.2 mmol) under N2, followed by treatment with a solution of
Me2Zn in toluene (0.2 mL, 2m). The reaction mixture was then stirred at
408C for 12 h (reaction monitored by TLC). After cooling to room tem-
perature, the mixture was quenched with sat. NH4Cl (5 mL). Extraction
with diethyl ether (2ꢁ10 mL), drying of the combined organic phases
over MgSO4, and final evaporation of the ether afforded a crude product
that was then purified by flash chromatography to give oxindole 2a
(46.5 mg, 95%).
Scheme 7. Asymmetric reaction.
ported the theory that the aryl–nickel intermediate was
most likely involved in the nucleophilic addition step and
hence asymmetric induction was observed. On the basis of
the above observations, we proposed the reaction pathway
shown in Scheme 8. The nucleophilic addition occurs after
the generation of the nucleophilic aryl–nickel intermediate
A through oxidative addition to give the adduct B, followed
by metathesis with Me2Zn, to afford the product precursor
D and the NiII species C, which is reduced to Ni0 in the pres-
ence of Me2Zn to fulfill the catalytic cycle (Scheme 8).
Acknowledgements
Support of this work by the National Natural Science Foundation of
China (21002089) is gratefully acknowledged.
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Chem. Eur. J. 2011, 17, 5234 – 5237

Nickel-Catalyzed Intramolecular Nucleophilic Addition
COMMUNICATION
[4] An electrochemical Nozaki–Hiyama–Kishi coupling of an active aryl
chloride with an aldehyde has been reported: a) M. Durandetti, J.
Perichon, J.-Y. Nedelec, Tetrahedron Lett. 1999, 40, 9009–9013; b) M.
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[5] Pd/PtBu3-catalysed intramolecular nucleophilic addition of arylha-
lides to ketoamides in the presence of nBuOH and base has been re-
ported with high yields when arylbromides were used. Arylchlorides
reacted sluggishly and afforded the oxindole products in low yields,
see: Y.-X. Jia, D. Katayev, E. P. Kꢂndig, Chem. Commun. 2010, 46,
130–132.
Keywords: aryl chloride
ketoamide · nickel · nucleophilic addition
·
homogenous catalysis
·
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Received: January 23, 2011
Published online: April 1, 2011
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www.chemeurj.org
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