Synthesis of Alkyl Indium Reagents by Using Unactivated Alkyl Chlorides and Their Applications in Palladium-Catalyzed Cross-Coupling Reactions with Aryl Halides

Article abstract of DOI:10.1021/acs.orglett.8b00441

An efficient method for the preparation of alkyl indium reagents by using unactivated and cheap alkyl chlorides as substrates in the presence of indium and LiI was developed. The thus-formed alkyl indium species effectively underwent palladium-catalyzed cross-coupling reactions with aryl halides with wide functional group tolerance.

Full text of DOI:10.1021/acs.orglett.8b00441

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Alkyl Indium Reagents by Using Unactivated Alkyl
Chlorides and Their Applications in Palladium-Catalyzed Cross-
Coupling Reactions with Aryl Halides
Bing-Zhi Chen,† Man-Ling Zhi,† Chuang-Xin Wang,† Xue-Qiang Chu,† Zhi-Liang Shen,*,†
and Teck-Peng Loh*,†,‡
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for
Advanced Materials, Nanjing Tech University, Nanjing 211816, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: An efficient method for the preparation of alkyl
indium reagents by using unactivated and cheap alkyl chlorides
as substrates in the presence of indium and LiI was developed.
The thus-formed alkyl indium species effectively underwent
palladium-catalyzed cross-coupling reactions with aryl halides
with wide functional group tolerance.
indium and LiI. The thus-obtained alkyl indium species
rganometallic reagents play a central role in organic
1
Osynthesis. In recent decades, apart from the extensive effectively underwent palladium-catalyzed cross-coupling re-
utilization of conventional organometallic reagents1 (such as
actions with aryl halides with wide functional group tolerance.
To begin with, 1-chloro-3-phenylpropane (1a) was employed
as a model substrate in the presence of a variety of additives to
study the feasibility of indium insertion (THF, 60 °C, 24 h) as
well as a subsequent palladium-catalyzed cross-coupling
reaction with 4-iodoacetophenone (2a) in the presence of
PdCl2(PPh3)2 (5 mol %) and LiCl (2 equiv) in DMF at 100 °C.
As shown in Table 1, when LiCl5 or CuCl10a was employed as
additive, almost no insertion reaction of indium powder (2
equiv) was observed (entries 1 and 2). Attempts to improve the
reaction efficiency by using either LiBr or CuBr also failed
(entries 3 and 4). Gratifyingly, when LiI was introduced as
reaction additive, both the insertion and the subsequent cross-
coupling reaction proceeded efficiently to give the desired
product 3a in 95% yield (entry 5). However, when LiI was
replaced by other metallic iodides (e.g., NaI, CuI, ZnI2, AgI,
InI3), the reaction was found to proceed sluggishly (<5% yield;
entries 6−10). It is evident that both Li+ and I− play vital roles
in promoting the reactions,13 and I− might activate the alkyl
chloride by converting it to more reactive alkyl iodide via
Felkinstein-type reaction pathway. To test this hypothesis, we
also performed the reaction of (2-chloroethyl)benzene (1b)
with LiI under the optimized reaction conditions (THF, 60 °C,
24 h) in the absence of indium. As expected, it was found that
70% conversion of alkyl chloride 1b to the corresponding alkyl
iodide was achieved based on NMR analysis of reaction mixture
after 24 h. Moreover, we also performed the insertion reaction
of indium with (2-chloroethyl)benzene (1b) in the presence of
organolithium, organomagnesium, and organozinc) in synthetic
organic chemistry, organoindium reagents have emerged as
powerful and appealing reagents for various organic trans-
formations as a result of their ready accessibility, mild reactivity,
good chemoselectivity, and excellent compatibility with a broad
range of important functional groups.2 Since the first
introduction of an organoindium reagent in organic synthesis
by Nomura and co-workers in 1992,3 the synthetic versatility of
organoindium reagents has been further demonstrated by
Sarandeses, Perez Sestelo, Lee, Minenan, Lei, and others in
transition metal-catalyzed cross-coupling reactions of triorga-
noindium reagents (R3In; prepared by transmetalation of
RMgCl or RLi with InCl3) with organohalides.4 The findings
thereafter have shown that organoindium reagents also can be
conveniently prepared either by direct insertion of indium(0)
into organohalides in the presence of an additive (e.g., LiCl,
CuX) or by other miscellaneous methods (e.g., carboindation),
as demonstrated by Knochel,5 Lee,6 Minehan,7 Yoshikai,8
Baba,9 our group,10 and others,11 arousing further interest and
applications of organoindium reagents in organic synthesis.
Until now, the previously reported methods for the preparation
of organoindium reagents via the direct insertion of indium into
organohalides are largely limited to the use of relatively more
reactive benzyl halides or aryl/alkyl iodides and bromides. In
comparison, the synthesis of alkyl indium reagents commencing
from cheap, stable, and unactivated alkyl chlorides remains
unexplored. In continuation of our efforts to develop indium
chemistry in our group,10,12 herein, we report an efficient
method for the preparation of alkyl indium reagents by using
unactivated alkyl chlorides as substrates in the presence of
Received: February 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00441
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Table 2. Substrate Scope Study by Using Various Aryl
a
Halides
b
entry
additive
yield (%)
1
2
3
4
5
6
7
8
9
10
LiCl
CuCl
LiBr
CuBr
LiI
<5
<5
<5
<5
95
<5
<5
<5
<5
<5
NaI
CuI
ZnI2
AgI
InI3
a
The insertion step was performed at 60 °C for 24 h by using 1-
chloro-3-phenylpropane (1a, 1 mmol), indium (2 mmol), additive (2
mmol) in THF (2 mL); the cross-coupling reaction was performed at
100 °C for 24 h by using 4-iodoacetophenone (2a, 0.7 mmol),
PdCl2(PPh3)2 (5 mol %), and LiCl (2 mmol) in DMF (2 mL).
b
Isolated yield.
LiI under the optimized reaction conditions. On the basis of the
NMR analysis of the reaction mixture after 24 h, the formation
of two different types of alkyl indium reagents (presumably as a
mixture of R2InX and RInX2 or in the form of an aggregated
indium sesquihalide R3In2X3) with >80% conversion was
observed, which is also in accordance with previously
documented observations.8a,10a After LiI was established as an
efficient reaction additive, subsequently we explored the
substrate scope of the reaction by using different alkyl chlorides
as substrates and aryl halides as coupling partners.
As shown in Table 2, the alkyl indium reagents prepared by
indium insertion in the presence of LiI effectively underwent
PdCl2(PPh3)2-catalyzed cross-coupling reactions with a variety
of aryl halides to produce the cross-coupling products 3b−l in
moderate to good yields. In addition to aryl iodides, aryl
bromide and chloride (2g and 2i) were also proven to be
suitable coupling partners for the reactions. Moreover,
heteroaryl iodides containing furyl and pyridinyl substituents
worked equally well under the optimized reaction conditions
(2k and 2l). Furthermore, a wide array of important functional
groups (e.g., nitro, cyano, carbonyl, and formyl group) survived
the present reaction conditions and were kept intact during the
course of the reaction.
The substrate scope of the present protocol was further
surveyed by utilizing a wide range of structurally varied alkyl
chlorides as starting materials. As shown in Table 3, various
alkyl chlorides were demonstrated to be appropriate substrates
for the reaction, leading to the anticipated cross-coupling
products in yields ranging between 52% and 94%. Most
importantly, alkyl chlorides bearing cyano, carbonyl, hydroxyl,
TBS, CC, and other functionalities well tolerated the mild
reaction conditions and, thus, could be kept for late-stage
functional group manipulation.
To further demonstrate the effectiveness and mildness of the
present method, an organoindium reagent synthesized by the
insertion of indium into 4-chlorobutanenitrile (1d) was
subjected to cross-coupling with (2-iodophenyl)methanol
a
See the Supporting Information for detailed reaction conditions.
Yield of isolated product based on aryl halides 2 as limiting reagent.
b
B
DOI: 10.1021/acs.orglett.8b00441
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction conditions, product 6 was delivered in an acceptable
yield (52%; Scheme 2).
Table 3. Substrate Scope Study by Using Various Alkyl
Chlorides
a
Scheme 2. Substrate Scope Study by Using 1,6-
Dichlorohexane (1l) as Substrate
In summary, we have developed an efficient method for the
synthesis of an alkyl indium reagent by indium insertion into
unactivated alkyl chlorides. LiI was demonstrated to be an
additive of choice for promoting the insertion reaction among
all the additives screened. The thus-formed alkyl indium
reagents participated in palladium-catalyzed cross-coupling
reactions with various aryl halides to afford the desired
products in moderate to good yields. The mild reaction
conditions also allowed the presence of a spectrum of
important functionalities, such as nitro, cyano, formyl, and
hydroxyl groups, either in the alkyl chloride substrates or in the
aryl halide coupling partners. Further applications of the
method in organic synthesis are currently underway in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00441.
Experimental procedures, characterization data, and
NMR spectra of products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
a
See the Supporting Information for detailed reaction conditions.
b
Yield of isolated product based on aryl iodide 2a as limiting reagent.
*E-mail: ias_zlshen@njtech.edu.cn.
c
d
Indium (1 equiv) was used. 0.8 equiv 2a was used as limiting
*E-mail: teckpeng@ntu.edu.sg.
ORCID
reagent.
Teck-Peng Loh: 0000-0002-2936-337X
Notes
(2m) containing a labile hydroxyl group. As expected, the
reaction proceeded with good compatibility with hydroxyl
group to afford the corresponding product 5 in a moderate
yield of 49% (Scheme 1).
In addition, dichloro-containing alkane 1l was also capable of
undergoing indium insertion to give the desired alkyl indium
species possessing two indium atoms. Upon Pd-catalyzed cross-
coupling with 4-iodobenzonitrile (2e) under the optimum
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from Nanjing
Tech University (Start-up Grant Nos. 39837118, 39837101,
and 39837146), the SICAM Fellowship from Jiangsu National
Synergetic Innovation Center for Advanced Materials, and
Nanyang Technological University.
Scheme 1. Substrate Scope Study by Using Hydroxyl-
Containing Aryl Iodide (2m) as Coupling Partner
REFERENCES
■
(1) Handbook of Functionalized Organometallics; Knochel, P., Ed.;
Wiley-VCH: Weinheim, 2005.
(2) For selected reviews, see: (a) Shen, Z.-L.; Wang, S.-Y.; Chok, Y.-
K.; Xu, Y.-H.; Loh, T.-P. Chem. Rev. 2013, 113, 271. (b) Zhao, K.;
Shen, L.; Shen, Z.-L.; Loh, T.-P. Chem. Soc. Rev. 2017, 46, 586.
(c) Araki, S.; Hirashita, T. In Comprehensive Organometallic Chemistry
III; Crabtree, R. H., Mingos, D. M. P., Eds.; Elsevier, Oxford, 2007;
Vol. 9, Chapter 9.14, pp 649−722. (d) Roy, U. K.; Roy, S. Chem. Rev.
C
DOI: 10.1021/acs.orglett.8b00441
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2010, 110, 2472. (e) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev.
2011, 111, 1417.
(3) Nomura, R.; Miyazaki, S. I.; Matsuda, H. J. Am. Chem. Soc. 1992,
they believed that LiCl might help to dissolve the formed
organometallic reagent on the metal surface so that the metal is
clean enough to allow further insertion reaction to proceed on its
surface; see: Blumke, T. D.; Chen, Y. H.; Peng, Z.; Knochel, P. Nat.
114, 2738.
̈
Chem. 2010, 2, 313−318. We speculated that Li+ (or the in situ
generated LiCl in our ptotocol after the reaction of alkyl chloride with
LiI) should also play the same role.
(4) For selected typical examples, see: (a) Perez, I.; Perez Sestelo, J.;
Sarandeses, L. A. Org. Lett. 1999, 1, 1267. (b) Perez, I.; Perez Sestelo,
J.; Sarandeses, L. A. J. Am. Chem. Soc. 2001, 123, 4155. (c) Takami, K.;
Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K. Org. Lett.
2001, 3, 1997. (d) Lehmann, U.; Awasthi, S.; Minehan, T. Org. Lett.
2003, 5, 2405. (e) Pena, M. A.; Perez, I.; Perez Sestelo, J.; Sarandeses,
L. A. Chem. Commun. 2002, 2246. (f) Lee, W.; Kang, Y.; Lee, P. H. J.
Org. Chem. 2008, 73, 4326. (g) Bouissane, L.; Perez Sestelo, J.;
Sarandeses, L. A. Org. Lett. 2009, 11, 1285. (h) Mosquera, A.; Riveiros,
R.; Perez Sestelo, J.; Sarandeses, L. A. Org. Lett. 2008, 10, 3745.
(i) Lee, P. H.; Lee, S. W.; Lee, K. Org. Lett. 2003, 5, 1103. (j) Zhao, Y.;
Jin, L.; Li, P.; Lei, A. J. Am. Chem. Soc. 2008, 130, 9429. (k) Jin, L.;
Zhao, Y.; Zhu, L.; Zhang, H.; Lei, A. Adv. Synth. Catal. 2009, 351, 630.
(l) Riveiros, R.; Rodriguez, D.; Perez Sestelo, J.; Sarandeses, L. A. Org.
Lett. 2006, 8, 1403. (m) Moral, J. A.; Moon, S.-J.; Rodriguez-Torres,
S.; Minehan, T. G. Org. Lett. 2009, 11, 3734. (n) Caeiro, J.; Perez
Sestelo, J.; Sarandeses, L. A. Chem. - Eur. J. 2008, 14, 741.
(o) Bernhardt, S.; Shen, Z.-L.; Knochel, P. Chem. - Eur. J. 2013, 19,
828. (p) Perez-Caaveiro, C.; Perez Sestelo, J.; Martinez, M. M.;
Sarandeses, L. A. J. Org. Chem. 2014, 79, 9586. (q) Mosquera, A.;
Fernandez, M. I.; Lopez, M. C.; Perez Sestelo, J.; Sarandeses, L. A.
Chem. - Eur. J. 2014, 20, 14524. (r) Thapa, S.; Gurung, S. K.; Dickie,
D. A.; Giri, R. Angew. Chem., Int. Ed. 2014, 53, 11620. (s) Jung, H.;
Hwang, H.; Park, K.-M.; Kim, J.; Kim, D.-H.; Kang, Y. Organometallics
2010, 29, 2715.
(5) (a) Chen, Y.-H.; Sun, M.; Knochel, P. Angew. Chem., Int. Ed.
2009, 48, 2236. (b) Chen, Y.-H.; Knochel, P. Angew. Chem., Int. Ed.
2008, 47, 7648. (c) Shen, Z.-L.; Knochel, P. Chem. - Eur. J. 2015, 21,
7061.
(6) (a) Lee, K.; Kim, H.; Miura, T.; Kiyota, K.; Kusama, H.; Kim, S.;
Iwasawa, N.; Lee, P. H. J. Am. Chem. Soc. 2003, 125, 9682. (b) Kim, S.;
Kim, C.-E.; Seo, B.; Lee, P. H. Org. Lett. 2014, 16, 5552. (c) Lee, D.;
Ryu, T.; Park, Y.; Lee, P. H. Org. Lett. 2014, 16, 1144. (d) Park, Y.;
Min, J.; Eom, D.; Lee, P. H. Org. Lett. 2015, 17, 3934. (e) Lee, P. H.;
Lee, K.; Kang, Y. J. Am. Chem. Soc. 2006, 128, 1139. (f) Lee, P. H.;
Lee, K. Angew. Chem., Int. Ed. 2005, 44, 3253. (g) Lee, K.; Seomoon,
D.; Lee, P. H. Angew. Chem., Int. Ed. 2002, 41, 3901.
(7) Papoian, V.; Minehan, T. J. Org. Chem. 2008, 73, 7376.
(8) (a) Adak, L.; Yoshikai, N. J. Org. Chem. 2011, 76, 7563. (b) Adak,
L.; Yoshikai, N. Tetrahedron 2012, 68, 5167.
(9) (a) Nishimoto, Y.; Moritoh, R.; Yasuda, M.; Baba, A. Angew.
Chem., Int. Ed. 2009, 48, 4577. (b) Nishimoto, Y.; Yasuda, M.; Baba, A.
Org. Lett. 2010, 12, 3390.
(10) (a) Shen, Z.-L.; Goh, K. K. K.; Yang, Y.-S.; Lai, Y.-C.; Wong, C.
H. A.; Cheong, H.-L.; Loh, T.-P. Angew. Chem., Int. Ed. 2011, 50, 511.
(b) Shen, Z.-L.; Goh, K. K. K.; Wong, C. H. A.; Yang, Y.-S.; Lai, Y.-C.;
Cheong, H.-L.; Loh, T.-P. Chem. Commun. 2011, 47, 4778. (c) Shen,
Z.-L.; Goh, K. K. K.; Cheong, H.-L.; Wong, C. H. A.; Lai, Y.-C.; Yang,
Y.-S.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132, 15852. (d) Shen, Z.-L.;
Lai, Y.-C.; Wong, C. H. A.; Goh, K. K. K.; Yang, Y.-S.; Cheong, H.-L.;
Loh, T.-P. Org. Lett. 2011, 13, 422.
(11) Chupak, L. S.; Wolkowski, J. P.; Chantigny, Y. A. J. Org. Chem.
2009, 74, 1388.
(12) For a review, see: (a) Loh, T.-P.; Chua, G.-L. Chem. Commun.
2006, 2739. For selected typical examples of indium chemistry
developed in our group, see: (b) Zhao, Y.-J.; Loh, T.-P. J. Am. Chem.
Soc. 2008, 130, 10024. (c) Li, B.; Lai, Y.-C.; Zhao, Y. J.; Wong, Y.-H.;
Shen, Z.-L.; Loh, T.-P. Angew. Chem., Int. Ed. 2012, 51, 10619.
(d) Shen, L.; Zhao, K.; Doitomi, K.; Ganguly, R.; Li, Y.-X.; Shen, Z.-L.;
Hirao, H.; Loh, T.-P. J. Am. Chem. Soc. 2017, 139, 13570. (e) Shen, Z.-
L.; Loh, T.-P. Org. Lett. 2007, 9, 5413. (f) Zhao, J.-F.; Loh, T.-P.
Angew. Chem., Int. Ed. 2009, 48, 7232. (g) Zhao, J.-F.; Tsui, H.-Y.; Wu,
P.-J.; Lu, J.; Loh, T.-P. J. Am. Chem. Soc. 2008, 130, 16492.
(13) Knochel and co-workers have performed considerable works in
the LiCl-mediated insertion reactions of metal into organic halides and
D
DOI: 10.1021/acs.orglett.8b00441
Org. Lett. XXXX, XXX, XXX−XXX