Nickel-catalyzed aromatic C-H alkylation with secondary or tertiary alkyl-bromine bonds for the construction of indolones

Article abstract of DOI:10.1021/ol403021p

A nickel-catalyzed aromatic C-H alkylation with tertiary or secondary alkyl-Br bonds for the construction of indolones was demonstrated. Various functional groups were well tolerated. Moreover, the challenging secondary alkyl bromides were well introduced in this transformation. Radical trapping and photocatalysis conditions exhibited that it is most likely to be a radical process for this aromatic C-H alkylation.

Full text of DOI:10.1021/ol403021p

ORGANIC
LETTERS
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Vol. XX, No. XX
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Nickel-Catalyzed Aromatic CÀH
Alkylation with Secondary or Tertiary
AlkylÀBromine Bonds for the
Construction of Indolones
Chao Liu,† Dong Liu,† Wei Zhang,† Liangliang Zhou,† and Aiwen Lei*,†,‡
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072,
Hubei, P. R. China, and National Research Center for Carbohydrate Synthesis,
Jiangxi Normal University, Nanchang 330022, Jiangxi, P. R. China
aiwenlei@whu.edu.cn
Received October 21, 2013
ABSTRACT
A nickel-catalyzed aromatic CÀH alkylation with tertiary or secondary alkylÀBr bonds for the construction of indolones was demonstrated.
Various functional groups were well tolerated. Moreover, the challenging secondary alkyl bromides were well introduced in this transformation.
Radical trapping and photocatalysis conditions exhibited that it is most likely to be a radical process for this aromatic CÀH alkylation.
Transition-metal-catalyzed CÀH functionalization has
become a hot topic in recent years.1 Many efforts have
been devoted to replace CÀM by using CÀH as nucleo-
philes in the area of transition-metal-catalyzed cross-
couplings between nucleophiles and electrophiles. Until
now, the mainly applied electrophiles have been aryl halides
and aryl pseudo halides.2 Another group of electrophiles,
alkyl halides, have been utilized less to cross-couple with aro-
matic CÀH bonds in which primary alkyl halides were
mainly applied.3 Only isolated examples have been demon-
strated in the cross coupling of secondary or tertiary alkyl
halides with aromatic CÀH bonds.4 This may be mainly
due to the sluggish oxidative addition of secondary or
tertiary alkyl halides and also the facile β-hydride elimina-
tion of the related alkylÀmetal species generated via a
general oxidative addition pathway.
Compared with alkylÀmetal species, the alkyl radicals
do not tend to undergo β-hydride elimination. Moreover,
it is also possible for aromatic CÀH activation via a radical
addition process. Consequently, the aromatic CÀH alkyl-
ation via a radical process has a high likelihood of success
for both secondary and tertiary alkyl halides, which has
always been challenging.
† Wuhan University.
‡ Jiangxi Normal University.
(1) (a) Yu, J.-Q.; Ackermann, L.; Shi, Z. CÀH Activation; Springer:
Heidelberg, 2010; (b) Lyons, T.; Sanford, M. Chem. Rev. 2010, 110, 1147.
(c) Giri, R.; Shi, B.-F.; Engle, K.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev.
2009, 38, 3242.
Scheme 1. Interaction between R-Carbonyl Alkyl Bromide and
Nickel Species
(2) (a) Alberico, D.; Scott, M.; Lautens, M. Chem. Rev. 2007, 107,
174. (b) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
112, 5879. (c) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
(3) (a) Ackermann, L. Chem. Commun. 2010, 46, 4866. (b) Messaoudi,
S.; Brion, J.-D.; Alami, M. Eur. J. Org. Chem. 2010, 6495.
(4) (a) Rudolph, A.; Rackelmann, N.; Lautens, M. Angew. Chem.,
Int. Ed. 2007, 46, 1485. (b) Hofmann, N.; Ackermann, L. J. Am. Chem.
Soc. 2013, 135, 5877. (c) Xiao, B.; Liu, Z.-J.; Liu, L.; Fu, Y. J. Am. Chem.
Soc. 2013, 135, 616. (d) Ren, P.; Salihu, I.; Scopelliti, R.; Hu, X. Org.
ꢀ
Lett. 2012, 14, 1748. (e) Ackermann, L.; Novak, P.; Vicente, R.;
Hofmann, N. Angew. Chem., Int. Ed. 2009, 48, 6045.
r
10.1021/ol403021p
XXXX American Chemical Society

Recently, we have demonstrated a Heck-type alkenyla-
tion of R-carbonyl alkyl halides in the presence of a nickel
catalyst.5 The R-carbonyl alkyl radical was believed to be
generated via the SET reduction of R-carbonyl alkyl
bromides in the presence of a low valent nickel species
(Scheme 1). We envisioned that this R-carbonyl alkyl
radical might effect intramolecular radical addition to
the aromatic rings (when R is an aromatic group, Scheme 1)
to realize aromatic CÀH alkylation.6 Herein, we demon-
strated a nickel-catalyzed aromatic CÀH alkylation with
secondary or tertiary alkylÀBr bonds for the construction
of indolones (eq 1).7
Table 1. Nickel-Catalyzed Aromatic CÀH Alkylation with
Tertiary AlkylÀBr Bondsa
With the above idea in mind, the following reactions
were first tested (Scheme 2). When anarylR-bromoester 1a
was applied as substrate under the conditions of 5 mol %
of Ni(PPh3)4/6 mol % of dppp, 2 equiv of K3PO4, in
toluene at 100 °C for 24 h, no product 2a was detected.
When 1b, in which the O-atom was replaced by an NH
group, was tested, no product 2b was detected either. To
our delight, when 1c (Z = NMe) was applied, the corre-
sponding CÀH alkylation product 2c was obtained in an
86% isolated yield. Theseresults indicated that the Z group
has a significant influence on the reactivity of the aromatic
rings for the CÀH alkylation process.8
Scheme 2. Reactions of Aryl R-Bromoester and Amides
a Reactions were carried out with
(0.025 mmol), dppp (0.030 mmol), and K3PO4 (1.0 mmol) in toluene
1 (0.5 mmol), Ni(PPh3)4
(2 mL) at 100 °C for 24 h. Yields shown were of isolated products.
Then, other aryl R-bromoamides were further tested
for this aromatic CÀH alkylation process with tertiary
alkylÀBr bonds following the same reaction conditions
(Table 1). Various substituents on the aromatic rings were
well tolerated. Electron-donating groups such as p-NMe2-
and p-OMe-containing substrates afforded the corre-
sponding products 2d and 2e in good to excellent yields,
respectively. Electron-withdrawing groups p-Acyl (2f),
p-CN (2g), and p-NO2 (2h) were also well tolerated. The
aromatic CÀCl bond was remained untouched, and the
corresponding cyclization product 3i was obtained in an
isolated yield of 84%. When a N-benzyl-containing sub-
strate was applied, the selective CÀH alkylation on the
N-Ph ring to form the corresponding indolone 2j was
observed, and no CÀH alkylation on the N-benzyl ring
was detected. Furthermore, the R2 group was changed to
be a phenyl group (2k) or an electron-deficient acyl group (2l).
(5) Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A.
Angew. Chem., Int. Ed. 2012, 51, 3638.
(6) Selected examples on Ni-catalyzed CÀH alkylation, see: (a)
Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308. (b) Yao,
T.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51,
775. (c) Hu, X. Chimia 2012, 66, 154. (d) Vechorkin, O.; Proust, V.; Hu,
X. Angew. Chem., Int. Ed. 2010, 49, 3061.
(7) Three previous reports on CÀH alkylation with tertiary alkylÀBr
bonds have been demonstrated. For the reactions using excess nickel
powder or light irradiation, see: (a) Nishio, T.; Asai, H.; Miyazaki, T.
Helv. Chim. Acta 2000, 83, 1475. (b) Nishio, T.; Iseki, K.; Araki, N.;
Miyazaki, T. Helv. Chim. Acta 2005, 88, 35. For the reaction with 1,3-
dicabonyl tertiary alkylÀBr bonds, see (c) Xuhui, J.; Yan, L.; Pingjing,
J.; Weifei, L.; Wei, Y. Org. Biomol. Chem. 2012, 10, 498.
(8) (a) Peng, H.; Yuan, Z.; Wang, H.-y.; Guo, Y.-l.; Liu, G. Chem.
Sci. 2013, 4, 3172. (b) Mu, X.; Wu, T.; Wang, H.-y.; Guo, Y.-l.; Liu, G.
J. Am. Chem. Soc. 2012, 134, 878. (c) Li, Y.-M.; Sun, M.; Wang, H.-L.;
Tian, Q.-P.; Yang, S.-D. Angew. Chem., Int. Ed. 2013, 52, 3972.
B
Org. Lett., Vol. XX, No. XX, XXXX

The corresponding products 2k and 2l were obtained in
moderate to good yields. An ortho-substituted aromatic
ring has one reactive site, and the corresponding CÀH
alkylation product 3m was obtained in 72% yield. When
meta-substituent-containing substrates were utilized, two
different reactive sites (R, β) were available for the cycliza-
tion. Two isomers were obtained in a total yield of 95%
(2n) and 65% (2o), respectively. The ratio of the two
isomers is 2:1 (R/β). Similarly, when β-naphthyl amide
was applied, both isomers of the cyclization on the R and
β positions were obtained, in which the R-position alkylation
isomer was dominant (2p). The total yield was 98%. When
1,4-diaminobenzene-derived diamide was subjected to this
transformation, the corresponding dicyclization product
2q was obtained in a good yield.
Table 2. Nickel-Catalyzed Aromatic CÀH Alkylation with
Secondary AlkylÀBr Bondsa
Compared to the tertiary alkyl radical, the secondary
alkyl radical is less stable, which makes this aromatic CÀH
alkylation with secondary alkylÀBr bonds more challeng-
ing. To the best of our knowledge, only one compound
was successfully reported to achieve the aromatic CÀH
alkylation with a secondary alkylÀX bond for the con-
struction of the corresponding indolones.9 Thus, sub-
strates with secondary alkylÀBr were further tested in
this aromatic CÀH alkylation process. To our delight, the
cyclization proceeded well to generate the corresponding
indolones (Table 2, 2rÀx). Electron-neutral (2r), electron-
rich (2s, 2t), and electron-deficient (2u) aromatic rings
could all be alkylated to generate the cyclization products.
Furthermore, aromatic carbon halide bonds were well
tolerated (2v, 2w, 2x). In particular, the tolerance of the
CÀBr (2w) and CÀI (2x) bonds allows further transforma-
tionto introducetheindoloneunitintocomplex molecules.
As stated above, this transformation is most likely to
proceed via a radical process. To establish this possibility
further, a radical scavenger TEMPO (2,2,6,6-tetramethyl-
piperidine 1-oxyl) was added in the reaction of 1c under the
standard conditions (eq 2). As a result, only a trace amount
of the desired product was observed, indicating that it is
likely to be a radical process.
a Reactions were carried out with
(0.025 mmol), dppp (0.030 mmol), and K3PO4 (1.0 mmol) in toluene
(2 mL) at 100 °C for 24 h. Yields shown were of isolated products.
1 (0.5 mmol), Ni(PPh3)4
for the cyclization of substrate 1e (eq 3). The correspond-
ing CÀH alkylation product 2e was obtained in 88% yield.
This promising result further indicates the radical process
of this nickel-catalyzed CÀH alkylation.
Scheme 3. Proposed Mechanism
Furthermore, it is well-known that visible light-promote
organic transformation usually proceeds via a radical
process.10 We have previously shown that the iridium
complex Ir(bpy)3 could activate R-carbonyl alkyl bromide
via a radical process in the presence of visible light.11 To
establish the SET process for this transformation further,
the reaction conditions of the photocatalysis were applied
(9) Only ref 7a provided one secondaryl alkyl chloride with good
yield. Secondary alkyl bromides have also been tested in both ref 7b and
7c, while the desired indolone synthesis was not successfully achieved.
(10) (a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev.
2011, 40, 102. (b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C.
Chem. Rev. 2013, 113, 5322.
(11) Liu, Q.; Yi, H.; Liu, J.; Yang, Y.; Zhang, X.; Zeng, Z.; Lei, A.
Chem.;Eur. J. 2013, 19, 5120.
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C

Moreover, it has been suggested that Ni0 reacts with alkyl
halides via a single-electron-transfer process to generate
a NiI species, which could further react with alkyl halide
to generate alkyl radical and a NiII species.5,12 Here, a
mechanism involving NiI/NiII catalytic cycle was believed
to proceed (Scheme 3). First, the active NiI species C1 was
generated by the reaction of alkyl halide 1 with Ni(PPh3)4.
The catalytic cycle starts from the further reaction of C1
with alkyl halide 1 via a SET process. The radical species 2-
I and a NiII species C2 are generated. Then, the intramo-
lecular radical addition of the carbon radical to the aro-
matic ring affords intermediate 2-II, which is further
oxidized by the NiII species C2 to afford the final product
2. Meanwhile, C2 was reduced to regenerate the active NiI
species C1.
bonds for the construction of indolones. Various func-
tional groups were well tolerated. In particular, the chal-
lenging secondary alkyl bromides were well introduced in
this transformation. Radical trapping and photocatalysis
conditions showed that this aromatic CÀH alkylation is
most likely a radical process.
Acknowledgment. This work was supported by the
973 Program (2012CB725302), the National Natural
Science Foundation of China (21025206, 21272180, and
21302148), the China Postdoctoral Science Founda-
tion funded project (2012M521458), and the Program for
Changjiang Scholars and Innovative Research Team in
University (IRT1030).
In summary, we have demonstrated a nickel catalyzed
aromatic CÀH alkylation with tertiary or secondary alkylÀBr
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) (a) Heimbach, P. Angew. Chem., Int. Ed. Engl. 1964, 3, 648. (b)
Porri, L.; Gallazzi, M. C.; Vitulli, G. Chem. Commun. 1967, 228. (c)
Otsuka, S.; Nakamura, A.; Yoshida, T.; Naruto, M.; Ataka, K. J. Am.
Chem. Soc. 1973, 95, 3180.
The authors declare no competing financial interest.
D
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