An N-heterocyclic carbene-based nickel catalyst for the Kumada–Tamao–Corriu coupling of aryl bromides and tertiary alkyl Grignard reagents

Article abstract of DOI:10.1016/j.tetlet.2016.06.042

In this study, nickel-catalyzed coupling reactions between arylhalides and tert-alkyl Grignard reagents were developed. Our original bicyclic NHC ligands reduced the formation of isomerized products, and we found that NMP as a co-solvent suppressed the reduction process. Under the optimal conditions we developed, the catalyst loading was lowered to 0.5?mol?%, and catalyst loading using ortho-substituted aryl bromides was also applicable at the level of 2.0?mol?%.

Full text of DOI:10.1016/j.tetlet.2016.06.042

Accepted Manuscript
An N-heterocyclic carbene-based nickel catalyst for the Kumada-Tamao-Corriu
coupling of aryl bromides and tertiary alkyl Grignard reagents
Shin Ando, Mai Mawatari, Hirofumi Matsunaga, Tadao Ishizuka
PII:
S0040-4039(16)30711-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.042
TETL 47769
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
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10 May 2016
7 June 2016
10 June 2016
Please cite this article as: Ando, S., Mawatari, M., Matsunaga, H., Ishizuka, T., An N-heterocyclic carbene-based
nickel catalyst for the Kumada-Tamao-Corriu coupling of aryl bromides and tertiary alkyl Grignard reagents,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.042
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An N-heterocyclic carbene-based Nickel
catalyst for the Kumada-Tamao-Corriu
coupling of aryl bromides and tertiary alkyl
Grignard reagents
Leave this area blank for abstract info.
Shin Ando, Mai Mawatari, Hirofumi Matsunaga, and Tadao Ishizuka

1
Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v ie r . c o m
An N-heterocyclic carbene-based nickel catalyst for the Kumada-Tamao-Corriu
coupling of aryl bromides and tertiary alkyl Grignard reagents
Shin Ando,* Mai Mawatari, Hirofumi Matsunaga, and Tadao Ishizuka*
Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi Chuo-ku, Kumamoto 862-0973, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this study, nickel-catalyzed coupling reactions between arylhalides and tert-alkyl Grignard
reagents were developed. Our original bicyclic NHC ligands reduced the formation of
isomerized products, and we found that NMP as a co-solvent suppressed the reduction process.
Under the optimal conditions we developed, the catalyst loading was lowered to 0.5mol%, and
catalyst loading using ortho-substituted aryl bromides was also applicable at the level of 2.0
mol%.
Available online
Keywords:
Nickel
2009 Elsevier Ltd. All rights reserved.
Grignard reagents
Coupling reaction
NHC ligand
Tertiary nucleophile
Transition metal-catalyzed coupling reaction for the formation
of a C–C bond is now a powerful tool for a wide range of
synthetic investigations such as the syntheses of complex natural
products and drug discovery. In addition to numerous excellent
methodologies for the creation of a C(sp2)–C(sp2) bond, C(sp3)-
containing coupling reactions have also been developed, but the
reaction systems using secondary or tertiary nucleophiles often
suffer from a competing b-hydride elimination leading to a
reduction and/or a subsequent isomerization.1 The use of all-
carbon quaternary nucleophiles is particularly challenging
because of a low level of nucleophilicity and a high level of steric
repulsion.2
Over the past decade, the catalysts Co,3 Cu,4 and Ni5 have
been useful in the coupling of tertiary Grignard reagents with
sufficient control of the isomerization of the tertiary alkyl groups.
Among these elegant processes, N-heterocyclic carbene (NHC)-
Ni catalysts, which have been independently developed by
Glorius5a and Biscoe,5b, c have shown a broad substrate scope
during the Kumada-Tamao-Corriu (KTC) coupling of aryl
halides or pseudohalides and tertiary Grignard reagents (Scheme
1). Glorius and co-workers used their original NHC ligand,
which has a carboxylic acid on its side chain and an over-
stoichiometric amount of LiOtBu as an additive, to accomplish
tert-butylation. Biscoe and co-workers reported that the H2O in
hydrated NiCl2 salts affected the reaction, and they confirmed
that NiCl2•1.5H2O, which was prepared by heating under high
coupled products in high yields and selectivities against the
isomerized or reduced products.
During the course of work with our original bicyclic NHC
ligands, we found that the aromatic ring on the bicyclic
framework could shield the bound metal, which resulted into an
acceleration of the reductive elimination during copper-catalyzed
allylic arylations (Scheme 2).6 We hypothesized that this
acceleration effect of our NHC ligand would be preferable in
suppressing the b-hydride elimination and/or the subsequent
isomerization of tert-alkyl groups during the coupling reaction
mentioned above. Here, we present the development of an NHC-
nickel-catalyzed KTC coupling reaction of aryl bromides and
tertiary Grignard reagents, for which our original NHC ligand
enabled us to reduce the catalyst loading to 0.5 mol%.
Additionally, we discovered that NMP as a co-solvent effectively
suppressed the reduction process.
v—ac—uum—, was the most effective Ni source, generating the
* Corresponding author. Tel.: +81-96-371-4579; fax: +81-96-371-4579; e-mail: ando@gpo.kumamoto-u.ac.jp (S.A.)
* Corresponding author. Tel.: +81-96-371-4573; fax: +81-96-371-4573; e-mail: tstone@gpo.kumamoto-u.ac.jp (T.I.)

2
Tetrahedron
selective formation of a tert-butylated product rather than the
reduced product.
Table 1. The comparison between DHASIBn and commercial
NHCs using KTC coupling of tert-BuMgCla
Entry
Ligand
none b
L1
Conversion (%)
Ar-tBu:Ar-isoBu:Ar-H
67:0:33
1
2
3
4
5
6
7
9
42
56
64
74
60
32
43:17:40
Scheme 1. NHC-Ni-catalyzed KTC coupling between aryl
halides and tert-alkyl Grignard reagents.
SIPr
27:23:50
SIMes
IPr
11:70:19
10:66:24
IMes
IMe
7:78:15
38:9:53
a
1.5 eq. of t-BuMgCl was used for this screening. The
reaction was carried out for 1.5 h at r.t. (see Supporting
Information for detail). The conversion and products ratios were
1
b
calculated using H NMR. The reaction was carried out for 24
h.
Scheme 2. Regio-selective allylic arylations using our
Table 2. The effects of a co-solventa
original NHC ligand.
We started our study by comparing NHC ligands in order to
probe the properties required for a coupling reaction between aryl
bromide and tert-BuMgCl (Table 1). Ni(acac)2 was used as a
nickel source for our reaction system based on our screening
experiment (see Table S1 in the Supporting Information for
details), and an NHC-Ni complex was prepared in situ using n-
BuLi as a base at 0 °C. The substrates for the screening included
tert-BuMgCl and 4-bromoanisole, which were added sequentially
to the solution, and the reactions were performed at ambient
temperature for 1.5 h. The conversion of aryl bromide was
negligible in the absence of an NHC ligand even after 24 h (Entry
1). Theoretically, a Grignard reagent could also serve as a base to
deprotonate an NHC precursor; however, it is important to note
that the reaction without n-BuLi resulted in an 11% conversion.
This indicated that the role of n-BuLi would be the deprotonation
of an NHC precursor as well as the reduction of Ni(II) to an
active form.7 Although the conversion of the substrate was
moderate, our original NHC ligand, DHASIBn (Entry 2),
suppressed the formation of the isobutylated product more
effectively than commercially available N-aryl NHCs (entries 3
to 6). This characteristic should be highly preferable for this
reaction because isobutylated compounds are difficult to separate
from desired tertiary butylated products in most cases.
Intriguingly, a 2:1 ratio of NHC ligand : Ni(acac)2, as well as the
addition of another ligand such as COD, resulted in no
conversion.8 N,N’-dimethyl imidazol-2-ylidene was also
available for this transformation, but its conversion was
somewhat lower than other NHCs (Entry 7). These results
encouraged us to optimize the reaction conditions for the
Entry
L
Co-solv.
NMP
Conv. (%)
Ar-tBu:Ar-isoBu:Ar-H
75:4:21
1
L1
L2
L3
L4
L5
L6
L7
L5
L5
L5
52
52
40
62
59
57
56
38
57
15
2
NMP
73:6:21
3
NMP
78:5:17
4
NMP
79:6:15
5
NMP
80:5:15
6
NMP
75:5:20
7
NMP
77:3:20
8
DMPU
DMI
61:8:31
9
84:4:12
10
DMAc
73:0:27

3
11b
12c
13d
L5
ICy NMP
L5 NMP
NMP
100
100
100
78:4:18
83:5:12
79:6:15
Scheme 3. Substrate scope of a DHASICy-Ni-catalyzed
KTC coupling between arybromides and t-BuMgCl.a a The
yields of t-Bu-Ar after purification via column
chromatography are shown. Inseparable i-Bu-Ar was obtained
as a mixture. A ratio of t-Bu-Ar/i-Bu-Ar calculated via NMR,
a
0.2 mL of a co-solvent was added to 4.0 mL of THF. The
b
and is shown in the parentheses. The reaction was carried
reaction was carried out for 1.5 h at r.t. (see Supporting
Information for detail). The conversion and product ratios were
out on an 8.0 mmol scale, and the products were purified
using a Kugelrohr apparatus. c The yield of the crude mixture
is shown as calculated via NMR, and the reduced product was
obtained in a 33% yield.
calculated using H NMR. b 2.5 eq. of t-BuMgCl was used. c 2.5
1
mol% of ICy, Ni(acac)2, and 2.5 eq. of t-BuMgCl were used
along with 1.0 mL of THF. 0.80 mmol of 4-bromoanisole, 0.5
mol% of L5, Ni(acac)2, and 2.5 eq. of t-BuMgCl, NMP (0.4
mL)/THF (2.0 mL) were used.
d
With the optimal reaction conditions in hand, we tested the
substrate scope of this reaction system. As a result, a wide range
of EWGs and EDGs on the para- and meta- positions of bromine
were well tolerated and gave the coupled product in moderate to
good yields with high selectivity (Scheme 3). It should be
emphasized that Friedel-Crafts alkylation, which is the most
powerful method for tert-butylation, is applicable only to the
alkylation of electron-rich arenes and heteroarenes. The reaction
on a larger scale and for distillation using a Kugelrohr apparatus
resulted in a higher yield, suggesting that the volatility of the
product might lower the yields in some cases.
After extensive studies, we found that when an aprotic polar
solvent, particularly NMP, was used as a co-solvent, it effectively
accelerated the tert-butylation (Table 2). Although the influences
for the yield of the copper- and iron-catalyzed coupling reactions
were clearly described in the report by Cahiez and co-workers,9
the effects for the b-hydride elimination during the reaction using
a tertiary alkyl nucleophile had never been described, as far as we
could ascertain.9-10 Among the aprotic polar solvents we tested,
NMP was the most effective (Entries 5, 8–10).11 The N-
substituents of DHASI and the counter anion of the NHC
precursors showed no significant effect (Entries 1 to 7). Increases
in the amount of Grignard reagent resulted in higher conversions.
Finally, we found that the 2.5 equivalent of tert-Bu-MgCl in the
presence of the DHASICy-Ni (L5-Ni) complex and NMP
produced the coupled product in a complete conversion with high
selectivity (t-Bu-Ar:i-Bu-Ar = >19:1, Entry 11). We also
optimized the amounts of NMP (see Supporting Information for
detail). Under the conditions we established, gratifyingly, the
catalyst loading was reduced to 0.5 mol%, which is in an order of
magnitude smaller than the previous methods (Entry 13; ICy
ligand, which was used on the report by Biscoe,5b was also
compatible under these conditions, but 2.5 mol% loading was
required (Entry 12)).
Among the substrates we tested, para-dimethylamino
bromobenzene showed only 18% conversion, and substrates with
an ortho-substituent resulted in an uncompleted conversion and
poor selectivity (the results from 2-bromoanisole are shown in
Scheme 3 for example). To convert these tough substrates, we
optimized the conditions again, and increases in the loads of the
catalyst and NMP proved useful. The reaction using 2.0 mol% of
a NHC-Ni complex and a higher amount of NMP (0.6 mL in 1.0
mL of THF) gave us the tert-butylated product in the same levels
of yield and selectivity as the substrates shown in Scheme 3. By
using the re-optimized conditions, the substrates with an EWG or
an EDG at the ortho-position were coupled with tert-Bu-MgCl in
an efficient manner (Scheme 4).12 Unfortunately, the coupling
with 2-bromo-m-xylene was unsuccessful probably because of
larger levels of steric repulsion.
Scheme 4. Substrate scope of DHASICy-Ni catalyzed KTC
coupling between ortho-substituted arybromides and t-
BuMgCl.a a The yields of t-Bu-Ar after purification via
column chromatography are shown. The inseparable i-Bu-Ar
was obtained as a mixture. The ratio for t-Bu-Ar/i-Bu-Ar was
calculated via NMR and is shown in parentheses.
We also tested more sterically demanding Grignard reagents.
tert-Amyl-MgCl reacted smoothly and returned the coupled

4
Tetrahedron
20, 1871; (e) Hayashi, T.; Konishi, M.; Kumada, M. J.
Organomet. Chem. 1980, 186, C1.
Iwasaki, T.; Takagawa, H.; Singh, S. P.; Kuniyasu, H.; Kambe, N.
J. Am. Chem. Soc. 2013, 135, 9604.
(a) Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N.
Angew. Chem. Int. Ed. 2007, 46, 2086; (b) Hintermann, L.; Xiao,
L.; Labonne, A. Angew. Chem. Int. Ed. 2008, 47, 8246; (c) Ren,
P.; Stern, L.-A.; Hu, X. Angew. Chem. Int. Ed. 2012, 51, 9110.
(a) Lohre, C.; Droge, T.; Wang, C.; Glorius, F. Chem. Eur. J.
2011, 17, 6052; (b) Joshi-Pangu, A.; Wang, C. Y.; Biscoe, M. R.
J. Am. Chem. Soc. 2011, 133, 8478; (c) Joshi-Pangu, A.; Biscoe,
M. R. Synlett 2012, 1103.
product in a 66% yield with good selectivity (isomerized
product was not observed in NMR). On the other hand, 3-
methylpent-3-yl-MgCl was not tolerated (Scheme 5).
3.
4.
5.
6.
7.
Ando, S.; Matsunaga, H.; Ishizuka, T. Tetrahedron 2013, 69,
1687.
A Ni(0)–Ni(II) cycle and a Ni(I)–Ni(III) cycle have been proposed
for similar reactions, and Biscoe and co-workers discussed about
the catalytic cycle for this reaction (see reference 5c). For
examples of other discussions about catalytic cycles for similar
processes, see; (a) Morrell, D. G.; Kochi, J. K. J. Am. Chem. Soc.
1975, 97, 7262; (b) Saito, S.; Sakai, M.; Miyaura, N. Tetrahedron
Lett. 1996, 37, 2993; (c) McGuinness, D. S.; Cavell, K. J.;
Skelton, B. W.; White, A. H. Organometallics 1999, 18, 1596; (d)
Böhm, V. P. W.; Gstöttmayr, C. W. K.; Weskamp, T.; Herrmann,
W. A. Angew. Chem. Int. Ed. 2001, 40, 3387; (e) Sato, Y.;
Sawaki, R.; Mori, M. Organometallics 2001, 20, 5510; (f)
Anderson, T. J.; Jones, G. D.; Vicic, D. A. J. Am. Chem. Soc.
2004, 126, 11113; (g) Dible, B. R.; Sigman, M. S.; Arif, A. M.
Inorg. Chem. 2005, 44, 3774; (h) Jones, G. D.; Martin, J. L.;
McFarland, C.; Allen, O. R.; Hall, R. E.; Haley, A. D.; Brandon,
R. J.; Konovalova, T.; Desrochers, P. J.; Pulay, P.; Vicic, D. A. J.
Am. Chem. Soc. 2006, 128, 13175; (i) Phapale, V. B.; Guisan-
Ceinos, M.; Bunuel, E.; Cardenas, D. J. Chem. Eur. J. 2009, 15,
12681; (j) Miyazaki, S.; Koga, Y.; Matsumoto, T.; Matsubara, K.
Chem. Commun. 2010, 46, 1932; (k) Tekavec, T. N.; Zuo, G.;
Simon, K.; Louie, J. J. Org. Chem. 2006, 71, 5834.
Scheme 5. NHC-Ni catalyzed KTC coupling using branched
tert-alkyl Grignard reagents.
In conclusion, we report the KTC coupling of aryl bromides
and tert-alkyl Grignard reagents using our original NHC-Ni
catalyst. DHASI-type NHC ligands effectively suppressed the
pathways leading to the isomerized product. We also discovered
that NMP as a co-solvent is useful in suppressing the reduction,
and the optimal conditions we established allowed us to reduce
the catalyst loading to 0.5 mol%. More challenging ortho-
substituted aryl bromides were also successfully converted using
increased amounts of catalyst and NMP.
Acknowledgments
This research was financially supported in part by a Grant-in-
Aid for Young Scientists (B) (No.15K18832) from JSPS.
8.
9.
This observation is simlar to the report by Hermann and co-
workers, in which they proposed the NHC-Ni(0) complex is the
catalytically active species. See reference 7d.
(a) Cahiez, G.; Marquais, S. Synlett 1993, 45; (b) Cahiez, G.;
Marquais, S. Tetrahedron Lett. 1996, 37, 1773; (c) Cahiez, G.;
Avedissian, H. Synthesis 1998, 1199; (d) Cahiez, G.; Chaboche,
C.; Jézéquel, M. Tetrahedron 2000, 56, 2733.
Supplementary Material
Supplementary data (experimental details and the
characterization data) associated with this article can be found, in
the online version, at
10. For examples of reactions using NMP as an effective co-solvent,
see; (a) Devasagayaraj, A.; Stüdemann, T.; Knochel, P. Angew.
Chem. Int. Ed. 1996, 34, 2723; (b) Fürstner, A.; Leitner, A.
Angew. Chem. Int. Ed. 2002, 41, 609; (c) Fürstner, A.; Leitner, A.;
Méndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856; (d)
Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527; (e)
Hadei, N.; Kantchev, E. A. B.; O'Brie, C. J.; Organ, M. G. Org.
Lett. 2005, 7, 3805.
References and notes
1.
2.
Reviews; (a) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004,
346, 1525; (b) Frisch, A. C.; Beller, M. Angew. Chem. Int. Ed.
2005, 44, 674; (c) Glorius, F. Angew. Chem. Int. Ed. 2008, 47,
8347; (d) Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009,
48, 2656; (e) Hu, X. Chem. Sci. 2011, 2, 1867.
For earlier examples of the coupling reaction using tert-alkyl
nucleophiles, see (a) Hayashi, T.; Konishi, M.; Yokota, K.-i.;
Kumada, M. Chem. Lett. 1980, 767; (b) Bell, T. W.; Hu, L. Y.;
Patel, S. V. J. Org. Chem. 1987, 52, 3847; (c) Daniel Rehm, J. D.;
Ziemer, B.; Szeimies, G. Eur. J. Org. Chem. 1999, 2079; (d)
Hayashi, T.; Konishi, M.; Kumada, M. Tetrahedron Lett. 1979,
11. These are shown for example. DMI was not effective in the
reaction with lowered catalyst loading.
12. It should be noted that the Ni catalyst developed by Lei and co-
workers, which worked well for the coupling sec-alkyl zinc
nucleophile, gave only isobutylated product in the case of the
coupling of ethyl 2-iodobenzoate and tert-butyl zinc reagent. See;
Luo, X.; Zhang, H.; Duan, H.; Liu, Q.; Zhu, L.; Zhang, T.; Lei, A.
Org. Lett. 2007, 9, 4571.

*Highlights
Our original NHC-Ni complex aptly catalyzes a tert-butylation of aryl bromides.
n-BuLi works as a reductant of Ni(II) salts to generate the active species.
NMP is an effective co-solvent to yield the tert-butylated products.
Hindered substrates are also applicable to the coupling reaction we established.