Cobalt(II)-catalyzed preparation of alkylindium reagents and applications in cross-coupling with aryl halides

Article abstract of DOI:10.1016/j.catcom.2019.105824

The direct insertion of indium powder into alkyl iodides was found to be efficiently catalyzed by a catalytic amount of cobalt(II) bromide (10 mol%). Upon subjection of the thus-formed alkylindium compounds to palladium-catalyzed cross-coupling reactions with a wide range of aryl halides, a series of cross-coupled products could be obtained in moderate to good yields with the tolerance to many important functional groups.

Full text of DOI:10.1016/j.catcom.2019.105824

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Cobalt(II)-catalyzed preparation of alkylindium reagents and
applications in cross-coupling with aryl halides
Peng Wang, Xuan-Di Song, Bing-Zhi Chen, Weidong Rao, Zhi-
Liang Shen
PII:
S1566-7367(19)30286-9
DOI:
https://doi.org/10.1016/j.catcom.2019.105824
CATCOM 105824
Reference:
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
26 July 2019
27 August 2019
11 September 2019
Please cite this article as: P. Wang, X.-D. Song, B.-Z. Chen, et al., Cobalt(II)-catalyzed
preparation of alkylindium reagents and applications in cross-coupling with aryl halides,
Catalysis Communications (2018), https://doi.org/10.1016/j.catcom.2019.105824
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Cobalt(II)-catalyzed preparation of alkylindium reagents and
applications in cross-coupling with aryl halides
a,
c
c
b
c,
Peng Wang *, Xuan-Di Song , Bing-Zhi Chen , Weidong Rao , Zhi-Liang Shen *
a
College of Chemical Engineering and Technology, Tianshui Normal University, Tianshui
41001, China
7
b
Jiangsu Key Laboratory of Biomass-based Green Fuels and Chemicals, College of Chemical
Engineering, Nanjing Forestry University, Nanjing 210037, China
c
School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816,
China
*
Corresponding authors.
E-mail addresses: w.p.david@139.com (P. Wang), ias_zlshen@njtech.edu.cn (Z.-L. Shen).
Abstract: The direct insertion of indium powder into alkyl iodides was found to be efficiently
catalyzed by a catalytic amount of cobalt(II) bromide (10 mol%). Upon subjection of the
thus-formed alkylindium compounds to palladium-catalyzed cross-coupling reactions with a wide
range of aryl halides, a series of cross-coupled products could be obtained in moderate to good
yields with the tolerance to many important functional groups.
Keywords: cobalt catalysis, indium, alkylindium reagent, palladium, cross-coupling reaction,
functional group tolerance
1. Introduction
In the past several decades, organoindium compounds [1-2] have attracted considerable attentions
of synthetic organic chemists due to their unique properties as compared to conventional
organometallics [3]. Thus far, organoindium compounds have been demonstrated to be attractive
alternatives to more reactive organometallic reagents, such as organolithiums, organomagnesiums,
and organozincs, mainly as a consequence of the relatively mild reactivity and water-tolerant
nature of organoindium reagents [1-3]. In general, organoindium compounds could be accessed
via two types of methods [4-28]: 1) transmetallation of organolithium or organomagnesium

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compounds with indium(III) halides in anhydrous ethereal solvent [4-7]; 2) direct insertion of
indium powder into organohalides [8-26]. Between the two methods, the second one via direct
indium insertion seems to be superior because the reactions are not only operationally simple
under relatively loose reaction conditions, but also exhibit broad functional group tolerance. In
contrast, the first method via transmetallation should be conducted under strictly anhydrous
conditions with limited functional group compatibility [4-7]. In previous reports, a variety of
organoindium compounds, such as allylindium [8-10], propargylindium [11-13], indium enolate
[
14], benzylindium [15], arylindium [16-17], alkenylindium [18-19], and alkylindium [20-26],
have been prepared by direct indium insertion and applied in organic synthesis. As for the
synthesis of alkylindium reagents, it has been reported that the indium insertion into alkyl halides
could be facilitated by using stoichiometric amounts of CuX [20-22] or LiX [23, 29-32] as
3 2 2 3
reaction additive, or a catalytic amount of InCl [24], I [25], or Cs CO [26] as reaction catalyst.
It should be noted that the application of organoindium reagents in organic synthesis are mainly
hindered by the limited methods for their preparations. In continuation of our task in developing
alternative methods for the synthesis of organoindium reagents, herein we describe an efficient method
for the preparation of alkylindium reagents by means of the direct insertion of indium powder into
alkyl iodides in the presence of a catalytic amount of cobalt(II) bromide [17, and 33-35] (10 mol%)
in THF. Upon subjection of the thus-formed alkylindium compounds to palladium-catalyzed
cross-coupling reactions with a wide range of aryl halides, a series of cross-coupled products
could be obtained in moderate to good yields with the tolerance to many important functional
groups (Scheme 1).
Scheme 1. Cobalt(II)-catalyzed preparation of alkylindium reagents and applications in
cross-couplings with aryl halides

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2
. Results and discussion
First, the catalytic activity of an array of metallic salts in the insertion reaction of indium with
2-iodoethyl)benzene (1a was examined in an attempt to synthesizing the corresponding
(
)
alkylindium reagent; after removal of the remaining indium power in the insertion step (the
presence of indium powder might hamper the subsequent cross-coupling reaction), the formed
alkylindium reagent was directly subjected to Pd(PPh
’-iodoacetopheoneone (2a). The results are summarized in Table 1. It was observed that these
catalysts, including Mn(II or III), Fe(II or III), Co(II or III), and Ni(II), were able to catalyze the
reaction with different performances. Of the catalysts screened, CoBr exhibitedthe best catalytic
activity, leading to the cross-coupled product 3a in 89% NMR yield (83% isolated yield; entry 8).
It should be mentioned that reasonable yields could also be achieved by using MnCl , Co(acac)
3 4
) -catalyzed cross-coupling reactions with
4
2
2
3
,
and NiCl
2
as reaction catalysts (entries 1, 9 and 10). Thus, CoBr
2
(10 mol%) was selected as the
optimum catalyst for the indium insertion reaction.
Table 1
a
Optimization of reaction conditions .
b
Entry
Catalyst
MnCl
Mn(acac)
FeF
Yield (%)
1
2
3
4
5
6
7
8
9
2
80
60
61
51
45
68
54
3
3
FeCl
FeBr
FeCl
3
3
2
Fe(OAc)
CoBr
Co(acac)
2
c
2
89 (83)
3
2
81
84
61
1
0
1
NiCl
2
1
Ni(acac)
a
o
The insertion step was performed at 60 C for 12 h by
using (2-iodoethyl)benzene (1a, 1 mmol), indium (1.5
mmol), catalyst (0.1 mmol) in THF (2 mL); the
o
cross-coupling step was conducted at 100 C for 24 hrs
by using 4-iodoacetopheoneone (2a, 0.7 mmol), LiCl (2

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mmol), Pd(PPh
3
)
4
(0.05 mmol), and DMA (2 mL).
b
1
The yield was determined by H NMR spectroscopy by
using 1,4-dimethoxybenzene as an internal standard.
c
Isolated yield.
It should be mentioned that the present reaction involves two steps: 1) the initial formation of an
organoindium reagent; and 2) the subsequent palladium-catalyzed cross-coupling reaction of
organoindium reagent with aryl halide. It was found that the presence of indium(0) powder might
inhibit the ensuing cross-coupling reaction and thus the remaining indium powder in the insertion
step should be removed prior to performing the ensuing cross-coupling reaction, thought the exact
cause is currently uncertain. For example, we also performed the indium insertion and
cross-coupling reaction in one-pot by stirring the mixture of (2-iodoethyl)benzene (1a, 1 mmol),
indium (1.5 mmol), CoBr
Pd(PPh
2
(0.1 mmol), 4-iodoacetopheoneone (2a, 0.7 mmol), LiCl (2 mmol),
o
3
)
4
(0.05 mmol), DMA (2 mL) and THF (2 mL) in a seal tube at 100 C for 24 h. However,
no cross-coupled product 3a was obtained. Such kind of phenomenon was also observed in many
palladium-catalyzed-catalyzed cross-coupling reactions involving organometallic reagents of
organoaluminium or organozinc reagent, where the remaining metal should be removed from the
formed organometallic reagents prior to the ensuing palladium-catalyzed cross-coupling reaction
[
29-30].
To demonstrate the efficiency and scope of the current method, we applied this catalytic system
to a wide range of alkyl iodides 1 and coupling partner of aryl halides 2. As shown in Table 2, the
alkylindium compound formed from the cobalt(II)-catalyzed indium insertion into alkyl iodide 1a
efficiently cross-coupled with a wide variety of aromatic halides, affording the coupling products
3a-l in 43-95% yields. The presence of nitro group at the different positions of phenyl ring (2c-e)
did not diminish the efficiency of the reaction (entries 3-5). Apart from aryl iodides, comparatively
less reactive aryl bromides (2g and 2i) made good substrates as well, giving rise to the expected
products 3g and 3i in moderate yields (entries 7 and 9). In addition, heteroaryl iodides could be
used as coupling partners with equal ease, as illustrated by the reactions using 2k-l as substrates
that gave the desired products 3k-l in 44-72% yields (entries 11-12). Moreover, substrates bearing
functional groups of acetyl (2a), cyano (2b), nitro (2c-e), ethoxycarbonyl (2f-g), and formyl (2h-i

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and 2k) could be directly employed in the reaction without being altered, which could be utilized
for further manipulation. However, when less reactive aryl iodide bearing electron-donating Me or
OMe group (1-iodo-4-methylbenzene or 1-iodo-4-methoxybenzene) was employed as electrophile
for cross-coupling reaction under the established reaction conditions, the reaction proceeded very
poorly (<20% NMR yield).
Table 2
Substrate scope study by using various aryl
a
halides .
b
Entry Substrate
Product Yield (%)
1
2
3
2a (R = Ac)
2b (R = CN)
2c (R = NO2)
3a
3b
3c
83
81
73
4
5
2d
2e
3d
3e
85
71
6
7
2f (X = I)
3f
69
45
2g (X = Br)
3g
8
9
2h (X = I)
2i (X = Br)
3h
3i
66
43
1
0
2j
3j
95
44
11
2k
3k

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12
2l
3l
72
a
See the Supporting Information for detailed
reaction conditions.
b
Yield of isolated product based on aryl halides
2
as limiting reagent.
Following the successful results with different coupling partners of aryl halides 2, the substrate
scope of the present reaction was further explored by utilizing a number of structurally diverse
alkyl iodides as starting materials. As illustrated in Table 3, alkyl iodides 1b-m were capable of
effectively undergoing indium insertion in the presence of a catalytic amount of cobalt(II) catalyst.
Upon subjection of the thus-generated alkylindium species to palladium-catalyzed cross-coupling
reactions with 4’-iodoacetophenone (2a), the corresponding products could be generated in
modest to high yields. In addition to primary alkyl iodides, secondary alkyl iodides of cyclohexyl
iodide (1l) and cyclopentyl iodide (1m) were also demonstrated to be appropriate starting
materials for the reaction, producing the desired products 4l-m in reasonable yields (entries 11-12).
In an analogous manner, the reactions exhibited good tolerance to a range of functional groups,
2
including CO Et (1e), BzO (1f), OTBS (1g), CH=CH (1h), OH (1i), CONRR’ (1j), and CN (1k),
which could potentially be kept for further derivatization at a later stage if necessary. However,
when (2-bromoehtyl)benzene was employed as a substrate for indium insertion as well as the
ensuing cross-coupling with aryl iodide 2a under optimized reaction conditions, the reaction
proceeded sluggishly (<5% NMR yield), most likely because of the relatively low reactivity of
alkyl bromide as compared to alkyl iodide.
Table 3
Substrate scope study by using various alkyl
a
iodides .
b
Entry
Substrate
Product Yield (%)

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1
2
3
4
1b
4b
4c
4d
4e
71
1c
1d
1e
85
86
49
5
1f
4f
66
6
7
8
1g
1h
1i
4g
4h
4i
62
75
69
c
9
1
1j
4j
86
63
0
1k
4k
1
1
1l
4l
60
79
12
1m
4m
a
See the Supporting Information for detailed
reaction conditions.
b
Yield of isolated product based on aryl iodide
2
a as limiting reagent.
c
Using DMA as solvent instead of THF in the
insertion step.
It should be mentioned that, when compared to the method developed by Yoshikai where
cobalt(II) was also used to catalyze the insertion of pre-activated indium metal into aryl bromide
in the co-existence of a nitrogen-containing ligand (bathophenanthroline) and stoichiometric

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amounts of LiCl additive [17], the present indium insertion into alkyl iodide could also work well
2
even in the presence of only a catalytic amount of CoBr , without the necessity of using any extra
ligand, stoichiometric amounts of LiCl, and pre-activation of indium metal.
By analogy with the method developed by Yoshikai by using cobalt(II) as catalyst for indium
insertion into aryl bromide [17] and the previous method developed by our group where
indium(III) chloride was employed for catalyzing indium insertion into alkyl iodide [24], we
speculated that the formed organoindium species in the present insertion reaction is most likely to
2 2
be the mixture of a monoalkyl indium dihalide (RInX ) and a dialkyl indium halide (R InX). In
addition, we speculated that the present indium insertion reaction should also share a similar
reaction mechanism as what Yoshikai and co-worker proposed in their work on the preparation of
arylindium reagent [17], where CoBr
catalytic cycle.
2
served as reaction catalyst and it could be re-generated in
3. Conclusion
In a nutshell, a catalytic amount of cobalt(II) bromide (10 mol%) was found to effectively
catalyze the direct insertion of indium powder into alkyl iodides. Upon subjection of the
thus-formed alkylindium compounds to Pd-catalyzed cross-coupling reactions with a wide range
of aryl halides, a series of cross-coupled products could be obtained in moderate to good yields. In
addition, an array of important functional groups (e.g., cyano, nitro, formyl, and hydroxyl group)
were well tolerated in the reactions as a result of the mildness of both the reaction conditions and
the formed organoindium reagents. In comparison with previous methods for the synthesis of
2
alkylindium compounds [20-26], the present method using a catalytic amount of CoBr as reaction
catalyst could also work equally well with comparable efficiency, providing an attractive
alternative and/or complement to existing methods for accessing organoindium reagents.
Acknowledgments
We gratefully acknowledge the financial support from Nanjing Tech University (Start-up Grant
No. 39837118), Tianshui Normal University, and Nanjing Forestry University.

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Conflicts of interest
The authors declare no conflict of interest.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
https://doi.org/10.1016/j.catcom.xxxxxxxxxxxx.
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Graphical abstract
Cobalt(II)-catalyzed preparation of alkylindium reagents and applications in cross-couplings
with aryl halides
Peng Wang,* Xuan-Di Song, Bing-Zhi Chen, Weidong Rao, Zhi-Liang Shen*
The direct insertion of indium powder into alkyl iodides was found to be efficiently catalyzed by a
catalytic amount of cobalt(II) bromide (10 mol%). Upon subjection of the thus-formed
alkylindium compounds to palladium-catalyzed cross-coupling reactions with a wide range of aryl
halides, a series of cross-coupled products could be obtained in moderate to good yields with the
tolerance to many important functional groups.

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Highlights
1
2
3
. Cobalt(II) efficiently catalyzed the insertion of indium into alkyl iodides
. The formed alkylindium could effectively cross-couple with aryl halides
. Both the insertion and cross-coupling exhibited good functional group tolerance