Nickel-Catalyzed Tandem Reaction of Functionalized Arylacetonitriles with Arylboronic Acids in 2-MeTHF: Eco-Friendly Synthesis of Aminoisoquinolines and Isoquinolones

Article abstract of DOI:10.1002/asia.201901442

The first example of the nickel-catalyzed tandem addition/cyclization of 2-(cyanomethyl)benzonitriles with arylboronic acids in 2-MeTHF has been developed, which provides the facile synthesis of aminoisoquinolines with good functional group tolerance under mild conditions. This chemistry has also been successfully applied to the synthesis of isoquinolones by the tandem reaction of methyl 2-(cyanomethyl)benzoates with arylboronic acids. The use of the bio-based and green solvent 2-MeTHF as the reaction medium makes the synthesis process environmentally benign. The synthetic utility of this chemistry is also indicated by the synthesis of biologically active molecules.

Full text of DOI:10.1002/asia.201901442

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Nickel-catalyzed tandem reaction of functionalized
arylacetonitriles with arylboronic acids in 2-MeTHF: eco-friendly
synthesis of aminoisoquinolines and isoquinolones
Authors: Qianqian Zhen, Lepeng Chen, Linjun Qi, Kun Hu, Yinlin Shao,
Renhao Li, and Jiuxi Chen
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10.1002/asia.201901442
Chemistry - An Asian Journal
FULL PAPER
Nickel-catalyzed
tandem
reaction
of
functionalized
arylacetonitriles with arylboronic acids in 2-MeTHF: eco-friendly
synthesis of aminoisoquinolines and isoquinolones
Qianqian Zhen,[a] Lepeng Chen,[a] Linjun Qi,[a] Kun Hu,[a] Yinlin Shao,[a] Renhao Li[b] and Jiuxi Chen*[a]
Dedication ((optional))
the synthesis of isoquinolines[4a] and isoquinolones[4b] via
Abstract: The first example of the nickel-catalyzed tandem
addition/cyclization of 2-(cyanomethyl)benzonitriles with arylboronic
acids in 2-MeTHF has been developed, which provides the facile
synthesis of aminoisoquinolines with good functional group tolerance
under mild conditions. This chemistry has also been successfully
applied to the synthesis of isoquinolones by the tandem reaction of
methyl 2-(cyanomethyl)benzoates with arylboronic acids. The use of
the bio-based and green solvent 2-MeTHF as the reaction medium
makes the synthesis process environmentally benign. The synthetic
utility of this chemistry is also indicated by the synthesis of
biologically active molecule.
catalytic carbopalladation of nitriles, respectively. Nickel, as a
first-row transition-metal in the same group as that of palladium,
has attracted significant attention due to its low cost and
abundance, meeting the requirements for sustainable chemical
synthesis.[6] Despite the remarkable success of nickel-catalyzed
transformations using alkyne with C≡C bond as the substrate,[7]
nickel-catalyzed nitrile insertion reactions have not been
extensively documented.[8] The development of nickel-catalyzed
addition of organoboron reagents to nitriles has remained a
great challenge due to the lack of reactivity of the inert C≡N
bonds and the competing side reaction.[9]
Scheme 1. Transformation of organonitriles.
Introduction
The development of new transformations in which the inherently
inert nature of the cyano group reacts as a dormant functional
group holds great promise for expediting organic synthesis. In
the past decade, transition-metal-catalyzed addition of
organoborons or other surrogates to nitriles is one of the most
powerful strategies for the synthesis of ketones and derivatives
(Scheme 1a), especially for palladium[1] and rhodium.[2] In recent
years, we developed palladium-catalyzed tandem reactions
involving the addition of organoborons to nitriles as the initial
step for the synthesis of benzofurans and indoles.[3] To improve
the atom economy and reduce the amount of waste generated in
these types of transformations, recent research focused on the
development of efficient synthetic methods for the construction
of various N-heterocycles skeletons in a selective manner to
avoid the formation of ketone products from hydrolysis of
ketimine intermediates without further tandem transformation.
Very recently, our group[4] and others[5] have achieved several
tandem transformation of functionalized nitriles with arylboronic
acids for access to N-heterocycles. For example, palladium-
Additionally, 2-methyltetrahydrofuran (2-MeTHF) as the bio-
based and green reaction medium has recently received
increased attention in organic synthesis due to its environmental
acceptability, abundance and low cost, and would thus be highly
advantageous alternatives to other organic solvents from both
economical and ecological perspectives.[10] Herein, we report a
catalyzed
tandem
addition/cyclization
of
2-
(cyanomethyl)benzonitriles (Scheme 1b) and methyl 2-
(cyanomethyl)benzoates (Scheme 1c) with arylboronic acids for
challenging
nickel-catalyzed
tandem
reaction
of
2-
(cyanomethyl)benzonitrile with arylboronic acids for the
preparation of unexpected aminoisoquinolines under mild
reaction conditions (Scheme 1d, left). When methyl 2-
(cyanomethyl)benzoates were used as substrates, tandem
reaction in 2-MeTHF delivered isoquinolones which could be
amenable to further synthetic elaborations (Scheme 1d, right).
[a]
[b]
Zhen, Q., Chen, L., Qi, L., Hu, K., Shao, Y., Chen, J.
College of Chemistry & Materials Engineering, Wenzhou University,
Wenzhou 325035, China.
E-mail: jiuxichen@wzu.edu.cn
Li, R.
School of Pharmaceutical Sciences, Wenzhou Medical University,
Wenzhou 325035, China.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Results and Discussion
Table 2. Ni-catalyzed synthesis of aminoisoquinolines[a]
Our study began with the reaction of 2-(cyanomethyl)benzonitrile
(1a) and phenylboronic acid (2a). As shown in Table 1, no
desired product 3-phenylisoquinolin-1-amine (3a) was observed
using the combination of NiCl2, bpy and ZnCl2 in THF (entry 1).
However, replacement of bpy with phosphine ligands (e.g., dppf,
dppe and dppp), 3a could be obtained 28-41% yields (entries 2-
4). Other nickel catalysts, including Ni(dppf)Cl2, Ni(dppe)Cl2,
Ni(dppp)Cl2, Ni(PPh3)Cl2 and Ni(acac)2 were evaluated (entries
5-9). Delightedly, the yield of 3a was improved to 72% in the
presence of Ni(dppp)Cl2 and ZnCl2 (entry 7). A brief screen of
additives showed that ZnCl2 remained the optimal choice
(entries 7, 10-13). Alternative zinc salts proved to be ineffective
for this transformation (entries 14-16). Finally, among various
solvents that we screened (entries 17-22), 2-MeTHF afforded 3a
in the highest yield (89%, entry 22). In the presence of
Ni(dppe)Cl2 and ZnCl2 in 2-MeTHF, 3a was obtained in 82%
yield (entry 23). The reaction in the absence of nickel catalyst or
additive proved to be inefficient (entries 24-25).
Table 1. Optimization of the reaction conditions[a]
[a] Conditions: 1 (0.4 mmol), 2 (0.8 mmol), Ni(dppp)Cl2 (5 mol%), ZnCI2 (0.6
mmol), 2-MeTHF (2.5 mL), air, 80 oC, 4 h. Isolated yield.
The reaction scope was then investigated under the optimized
reaction conditions (Table 2). This transformation proceeded
efficiently with electron-rich methyl- (3b-3d), ethyl- (3e),
methoxy- (3f-3g), and [1,3]-dioxolo- (3h) substituted arylboronic
acids, providing the corresponding aminoisoquinolines in
[a] Conditions: 1a (0.4 mmol), 2a (0.8 mmol), Ni catalyst (5 mol %), additive
(0.6 mmol), solvent (2.5 mL), 80 oC, 4 h, air. [b] Isolated yield. bpy = 2,2'-
bipyridine, dppf
=
1,1'-bis(diphenylphosphino)ferrocene, dppe
=
1,2-
bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenyphosphino)propane.
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moderate to good yields. It is worth noting that substrate bearing
could be amenable to diverse functionalization. We next
a more-hindered ethyl group (3e) was also shown to be possible, examined the reaction of bromo- or iodo-substituted 2-
albeit in lower yield. The reaction tolerates electron-deficient
halogen, such as fluoro (3i-3j), chloro (3k-3l), bromo (3m) and
trifluoromethyl (3n) substituents, although lower yields were
obtained. Phenyl-, and naphthyl-substituted arylboronic acids
undergo tandem reaction well, leading to the corresponding
products 3o (83%), 3p (86%), and 3q (92%), respectively. Of
note, thiophen-3-ylboronic acid was compatible for this Ni-
catalyzed tandem reaction, albeit giving the desired 3r in 66%
yield. Next, the scope of 2-(cyanomethyl)benzonitriles was
examined. Substrates bearing electron-rich methyl (3s-3u),
methoxy (3v), or electron-deficient fluoro (3w-3x), chloro (3y-
3ab), trifluoromethyl (3ac), phenyl (3ad-3ae) substituents (R1)
on the aromatic ring were compatible for this reaction to afford
the desired products in 59-90% yields. As expected, we also
found this Ni-catalyzed tandem protocol to be compatible with a
wide variety of substrates bearing either electron-donating
groups, such as methyl (3ag-3ah), methoxy (3ai), or electron-
withdrawing groups, such as fluoro (3aj), chloro (3ak), bromo
(3al) on the aromatic ring (R2 = Ar). A representative thienyl-
containing substrate, was also compatible substrate for this
tandem reaction, affording the desired product 3am in 75% yield.
The reaction of 2-(1-cyanoethyl)benzonitrile with phenylboronic
acid proceeded smoothly to produce the desired 3an in 88%
yield.
(cyanomethyl)benzonitriles with arylboronic acid to give various
bromo- or iodo-substituted aminoisoquinolines (Table 3).
Various functional groups (halogen, Me, OMe, OCH2O and
naphthyl) were well tolerated. In addition, the steric effects of
substituents had no obvious effects on the yields. For example,
the reaction with o-, m-, and p-tolylboronic acid proceeded
smoothly to afford 4h, 4i, and 4j in 68%, 65%, and 60% yields,
respectively. In general, this Ni-catalyzed tandem reaction
proceeded selectively to the desired bromo- or iodo-substituted
products, which could be amenable to further transformations.
The structure of 4o was further confirmed by single crystal X-ray
structure analysis.
Scheme 2. Synthetic applications.
Table 3. Ni-catalyzed synthesis of bromo- or iodo-substituted
aminoisoquinolines[a]
The synthetic utility of the as-synthesized aminoisoquinolines
was examined by the amenability of the amino group to further
synthetic applications (Scheme 2). We performed the
methylation, acylation, and Buchwald-Hartwig coupling of 3a
with methyl iodide (Scheme 2a), propionyl chloride (Scheme 2b)
and bromobenzene (Scheme 2c), affording the corresponding
5a, 5b and 5c in 68%, 78% and 90% yields, respectively.
We further discovered that methyl 2-(cyanomethyl)benzoates
could be used as substrates by this tandem reaction to afford a
new synthetic method for the synthesis of isoquinolones (Table
4). The desired product 3-phenylisoquinolin-1(2H)-one (7a) was
obtained in 81% yield in the presence of Ni(dppe)Cl2, ZnCl2 in 2-
MeTHF at 120 oC for 48 h under air (for optimization of the
reaction conditions, see Table S1 in ESI). A wide range of
arylboronic acids were compatible for this Ni-catalyzed tandem
reaction. Electron-donating groups (methyl-, ethyl-, iso-propyl-,
tert-butyl-, methoxy-, [1,3]-dioxolo-, and phenoxy) and electron-
withdrawing groups (fluoro, chloro, bromo, iodo, trifluoromethyl,
naphthyl and phenyl) undergo tandem reaction well, which
affords the desired products in moderate to good yields. In
addition, 2-(cyanomethyl)benzoates bearing methyl or iso-propyl
substituents, were compatible with this tandem reaction to give
the expected products 7u-7y in 54-85% yields.
[a] Conditions: 1 (0.4 mmol), 2 (0.8 mmol), Ni(dppp)Cl2 (5mol%), ZnCI2 (0.6
mmol), 2-MeTHF (2.5 mL), air, 80 oC, 4 h. Isolated yield.
In addition, the synthetic utility of this chemistry is also
indicated by the synthesis of biologically active compound 1-(4-
methyl-1,4-diazepan-1-yl)-3-phenylisoquinoline (9a) that showed
good topoisomerase I inhibitory activity (Scheme 3).[11]
The selective synthesis of bromo- or iodo-substituted N-
heterocycles has received increasing attention because they
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To gain further insight into the mechanism of the
transformation, an intermolecular competition experiment was
investigated under standard conditions (Table 5). Individual
reactions for benzonitrile (10a) and 2-phenylacetonitrile (10b)
under the same conditions afforded benzophenone (11a) and
1,2-diphenylethan-1-one (11b) in 23% and 99% yields,
respectively (entries 1-2). Competition reaction in the presence
of an equimolar amount of 10a and 10b with 2a revealed that
the transformation occurred more favourably with the substrate
10b (entry 3). This observation suggests that the reactivity of the
C(sp3)–CN is more favourable than the C(sp2)–CN in this Ni-
catalyzed addition reaction.
Table 5. Competition reaction[a]
Table 4. Ni-catalyzed synthesis of isoquinolones[a]
[a] Conditions: 2a (0.8 mmol), Ni(dppp)Cl2 (5 mol%), ZnCl2 (0.6 mmol), 2-
MeTHF (2 mL), 80 oC, 4 h, air. [b] Isolated yield.
The mechanism of this nickel-catalyzed tandem reaction of 2-
(cyanomethyl)benzonitriles with arylboronic acids for the
formation of aminoisoquinolines was proposed in Scheme 4. It
involves the following key steps: (i) transmetallation of the nickel
active species with ArB(OH)2 to produce aryl-nickel species A;
(ii) the coordination of cyano group to the Ni for the formation of
the nickel intermediate B or B’; (iii) 1,2-addition of the
coordinated aryl group to the cyano group to form the nickel
intermediate C; (iv) cyclization of D to give nickel complex E; (v)
protonation of E in the presence of ZnCl2 and water, which
affords imine intermediate F and regenerates the Ni catalyst.
Finally, tautomerism of intermediate F delivers the desired
aminoisoquinolines.
Scheme 4. Plausible mechanism.
[a] Conditions: 1 (0.4 mmol), 2 (0.8 mmol), Ni(dppe)Cl2 (10 mol%), ZnCI2 (2
mmol), 2-MeTHF (2 mL), air, 120 oC, 48 h. Isolated yield.
Scheme 3. Synthesis of biologically active compound.
Conclusions
In conclusion, we have developed a Ni-catalyzed tandem
reaction of functionalized arylacetonitriles with arylboronic acids
in 2-MeTHF, which affords a new synthetic strategy for the
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Org. Lett., 2006, 8, 5987-5990; (e) M. Behrends, J. Sävmarker, P. J. R.
Sjöberg, M. Larhed, ACS Catal., 2011, 1, 1455-1459; (f) J. Liu, X. Zhou,
H. Rao, F. Xiao, C. Li, G. Deng, Chem. Eur. J., 2011, 17, 7996-7999;
(g) J.-C. Hsieh, Y.-C. Chen, A.-Y. Cheng, H.-C. Tseng, Org. Lett., 2012,
14, 1282-1285; (h) J.-C. Wan, J.-M. Huang, Y.-H. Jhan, J.-C. Hsieh,
Org. Lett., 2013, 15, 2742-2745; (i) B. Skillinghaug, C. Skçld, J.
Rydfjord, F. Svensson, M. Behrends, J. Sävmarker, P. J. R. Sjöberg, M.
Larhed, J. Org. Chem., 2014, 79, 12018-12032; (j) B. Skillinghaug, J.
Rydfjord, J. Sävmarker, M. Larhed, Org. Process Res. Dev., 2016, 20,
2005-2011; (k) K. Cheng, G. Wang, M. Meng, C. Qi, Org. Chem. Front.,
2017, 4, 398-403; (l) X. Wang, Y. Huang, Y. Xu, X. Tang, W. Wu, H.
Jiang, J. Org. Chem., 2017, 82, 2211-2218.
synthesis of diverse aminoisoquinolines with excellent
chemoselectivity and functional group tolerance. In addition, this
chemistry has also been applied to the synthesis of
isoquinolones.
Experimental Section
General Methods: Melting points are uncorrected. 1H NMR and 13C
NMR spectra were measured on a 500 MHz spectrometer using DMSO-
d6 or CDCl3 as the solvent with tetramethylsilane (TMS) as an internal
standard at room temperature. Chemical shifts are given in δ relative to
TMS, and the coupling constants J are given in hertz. High-resolution
mass spectrometry (HRMS) was recorded on an ESI-Q-TOF mass
[2]
For rhodium-catalyzed examples, see: (a) C. A. Malapit, D. R. Caldwell,
I. K. Luvaga, J. T. Reeves, I. Volchkov, N. C. Gonnella, Z. S. Han, C. A.
Busacca, A. R. Howell, C. H. Senanayake, Angew. Chem., Int. Ed.,
2017, 56, 6999-7002; (b) C. A. Malapit, J. T. Reeves, C. A. Busacca, A.
R. Howell, C. H. Senanayake, Angew. Chem., Int. Ed., 2016, 55, 326-
330; (c) T. Miura, M. Murakami, Org. Lett., 2005, 7, 3339-3341.
(a) X. Wang, M. Liu, L. Xu, Q. Wang, J. Chen, J. Ding, H. Wu, J. Org.
Chem., 2013, 78, 5273-5281; (b) S. Yu, L. Qi, K. Hu, J. Gong, T. Cheng,
Q. Wang, J. Chen, H. Wu, J. Org. Chem., 2017, 82, 3631-3638.
(a) K. Hu, L. Qi, S. Yu, T. Cheng, X. Wang, Z. Li, Y. Xia, J. Chen, H.
Wu, Green Chem., 2017, 19, 1740-1750; (b) L. Qi, K. Hu, S. Yu, J. Zhu,
T. Cheng, X. Wang, J. Chen, H. Wu, Org. Lett., 2017, 19, 218-221; (c)
Y. Zhang, Y. Shao, J. Gong, K. Hu, T. Cheng, J. Chen, Adv. Synth.
Catal., 2018, 360, 3260-3265; (d) K. Hu, Q. Zhen, J. Gong, T. Cheng, L.
Qi, Y. Shao, J. Chen, Org. Lett., 2018, 20, 3083-3087; (e) X. Yao, Y.
Shao, M. Hu, Y. Xia, T. Cheng, J. Chen, Org. Lett., 2019, 21, 7697-
7701.
spectrometer.
2-(Cyanomethyl)benzonitriles
and
methyl
2-
(cyanomethyl)benzoates were synthesized according to the literature
procedures.[12] Other commercially obtained reagents were used without
further purification. Column chromatography was performed using EM
silica gel 60 (300−400 mesh).
[3]
[4]
General procedure for the synthesis of aminoisoquinolines： 2-
(Cyanomethyl)benzonitriles 1 (0.4mmol), arylboronic acid 2 (0.8 mmol),
Ni(dppp)Cl2 (5 mol%), ZnCl2 (0.6 mmol), and 2-MeTHF (2.5 mL) were
successively added into a Schlenk reaction tube under air. The mixture
was stirred for 5 minutes at room temperature for proper mixing of the
reactants, and then heated at 80 oC with vigorous stirring for 4 hours. The
mixture was poured into ethyl acetate, which was washed with saturated
NaHCO3 (3×10 mL) and then brine (10 mL). After the aqueous layer was
extracted with ethyl acetate, the combined organic layers were dried over
anhydrous Na2SO4 and evaporated under a vacuum. The residue was
purified by flash column chromatography (hexane/ethyl acetate) to afford
3-arylisoquinolin-1-amines.
[5]
[6]
(a) M. Yousuf, S. Adhikari, Org. Lett., 2017, 19, 2214-2217; (b) H. Yu, L.
Xiao, X. Yang, L. Shao, Chem. Commun., 2017, 53, 9745-9748.
For reviews on Ni-catalyzed, see: (a) S. Ikeda, Acc. Chem. Res., 2000,
33, 511-519; (b) H. M. Pan, D. Song, Y. Li, Chem. Rev., 2015, 115,
12091-12137; (c) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang,
A. Resmerita, N. K. Garg, V. Percec, Chem. Rev., 2011, 111, 1346-
1416; (d) N. A. Eberhardt, Hairong Guan, Chem. Rev., 2016, 116,
8373-8426; (e) V. Ritleng, M. Henrion, Michael J. Chetcuti, ACS Catal.,
2016, 6, 890-906; (f) M. Henrion, V. Ritleng, M. J. Chetcuti, ACS Catal.,
2015, 5, 1283-1302; (g) R. Jana, T. P. Pathak, M. S. Sigman, Chem.
Rev., 2011, 111, 1417-1492; (h) J. Schranck, J. Rotzler, Org. Process
Res. Dev., 2015, 19, 1936-1943.
General procedure for the synthesis of isoquinolones：Methyl 2-
(cyanomethyl)benzoates 6 (0.4 mmol), arylboronic acid 2 (0.8 mmol),
Ni(dppe)Cl2 (10 mol%), ZnCl2 (2 mmol), and 2-MeTHF (2 mL) were
successively added into a Schlenk reaction tube under air. The reaction
mixture was stirred for 5 minutes at room temperature for proper mixing
of the reactants, and then heated at 120 oC with vigorous stirring for 48
hours. The mixture was poured into ethyl acetate, which was washed
with saturated NaHCO3 (3×10 mL) and then brine (10 mL). After the
aqueous layer was extracted with ethyl acetate, the combined organic
layers were dried over anhydrous Na2SO4 and evaporated under a
vacuum. The residue was purified by flash column chromatography
(hexane/ethyl acetate) to afford 3-arylisoquinolin-1(2H)-ones.
[7]
For Ni-catalyzed reactions of alkyne, see: (a) J. Montgomery, Acc.
Chem. Res., 2000, 33, 467-473; (b) J. Huang, C. Ho, Angew. Chem.,
Int. Ed., 2019, 58, 5702-5706; (c) A. García-Domínguez, S. Müller, C.
Nevado, Angew. Chem., Int. Ed., 2017, 56, 9949-9952; (d) Z. Li, A,
García-Domínguez, C. Nevado, Angew. Chem., Int. Ed., 2016, 55,
6938-6941; (e) P. Liu, J. Montgomery, K. N. Houk, J. Am. Chem. Soc.,
2011, 133, 6956-6959; (f) X. Zhang, X. Xie, Y. Liu, Chem. Sci., 2016, 7,
5815-5820; (g) H. A. Malik, G. J. Sormunen, J. Montgomery, J. Am.
Chem. Soc., 2010, 132, 6304-6305; (h) Y. Yoshino, T. Kurahashi, S.
Matsubara, J. Am. Chem. Soc., 2009, 131, 749-757; (i) A. Herath, W. Li,
J. Montgomery, J. Am. Chem. Soc., 2008, 130, 469-471.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21572162), and the Natural Science Foundation of
Zhejiang Province (Nos. LY20B020015 and LQ18B020006) for
financial support.
[8]
[9]
(a) V. K. Chenniappan, S. Silwal, R. J. Rahaim, ACS Catal., 2018, 8,
4539-4544; (b) J.-C. Hsieh, Y.-C. Chen, A.-Y. Cheng, H.-C. Tseng, Org.
Lett., 2012, 14, 1282-1285; (c) Y. C. Wong, K. Parthasarathy, C. H.
Cheng, Org. Lett., 2010, 12, 1736-1739; (d) X. Yang, H. Yu, Y. Xu, L.
Shao, J. Org. Chem., 2018, 83, 9682-9695; (e) S. Fang, H. Yu, X. Yang,
J. Li, L. Shao, Adv. Synth. Catal., 2019, 361, 3312-3317.
Keywords: Nickel • Aminoisoquinolines • Isoquinolones •
Arylacetonitriles • 2-MeTHF
For reviews, see: (a) R. López, C. Palomo, Angew. Chem., Int. Ed.,
2015, 54, 13170-13184; (b) D. A. Culkin, J. F. Hartwig, Acc. Chem.
Res., 2003, 36, 234-245.
[1]
For palladium-catalyzed examples, see: a) C. Zhou, R. C. Larock, J.
Am. Chem. Soc., 2004, 126, 2302-2303; (b) C. Zhou, R. C. Larock, J.
Org. Chem., 2006, 71, 3551-3558; (c) J. Lindh, P. Sjçerg, M. Larhed,
Angew. Chem., Int. Ed., 2010, 49, 7733-7737; (d) B. W. Zhao, X. Y. Lu,
[10] For selected examples of 2-MeTHF, see: (a) D. F. Aycock, Org.
Process Res. Dev., 2007, 11, 156-159; (b) V. Pace, P. Hoyos, L.
Castoldi, P. Domínguez de María, . . lc ntara ChemSusChem,
2012, 5, 1369-1379; (c) V. Antonucci, J. Coleman, J. B. Ferry, N.
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Johnson, M. Mathe, J. P. Scott, J. Xu, Org. Process Res. Dev., 2011,
15, 939-941; (d) Y. Gu, F. Jérôme, Chem. Soc. Rev., 2013, 42, 9550-
9570; (e) A. D. Mamuye, S. Monticelli, L. Castoldi, W. Holzer, V. Pace,
Green Chem., 2015, 17, 4194-4197; (f) S. D. Ramgren, L. Hie, Y. Ye, N.
K. Garg, Org. Lett., 2013, 15, 3950-3953; (g) P. Pavez, G. Oliva, D.
Millán, ACS Sustainable Chem. Eng., 2016, 4, 7023-7031; (h) C. J.
Clarke, W. Tu, O. Levers, A. Bröhl, J. P. Hallett, Chem. Rev., 2018, 118,
747-800; (i) O. Al Musaimi, Y. E. Jad, A. Kumar, A. El-Faham, J. M.
Collins, A. Basso, B. G. de la Torre, F. Albericio, Org. Process Res.
Dev., 2018, 22, 1809-1816.
[11] W. Cho, S. Y. Min, T. N. Le, T. S. Kim, Bioorg. Med. Chem. Lett., 2003,
13, 4451-4154.
[12] (a) J. Kankanala, C. Marchand, M. Abdelmalak, H. Aihara, Y. Pommier,
Z. Wang, J. Med. Chem., 2016, 59, 2734-2746; (b) Y. Wan, W. Niu, W.
J. Behof, Y. Wang, P. Boyle, C. B. Gorman, Tetrahedron, 2009, 65,
4293-4297; (c) R. Doi, I. Abdullah, T. Taniguchi, N. Saito, Y. Sato,
Chem. Commun., 2017, 53, 7720-7723.
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10.1002/asia.201901442
Chemistry - An Asian Journal
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Qianqian Zhen, Lepeng Chen, Linjun Qi,
Kun Hu, Yinlin Shao, Renhao Li and
Jiuxi Chen*
Page No. – Page No.
Nickel-catalyzed tandem reaction of
functionalized arylacetonitriles with
arylboronic acids in 2-MeTHF: eco-
friendly
synthesis
of
aminoisoquinolines
isoquinolones
and
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