Tandem addition/cyclization for access to isoquinolines and isoquinolones via catalytic carbopalladation of nitriles

Article abstract of DOI:10.1021/acs.orglett.6b03499

The first example of the palladium-catalyzed sequential nucleophilic addition followed by an intramolecular cyclization of functionalized nitriles with arylboronic acids has been achieved, providing an efficient synthetic pathway to access structurally di

Full text of DOI:10.1021/acs.orglett.6b03499

Letter
pubs.acs.org/OrgLett
Tandem Addition/Cyclization for Access to Isoquinolines and
Isoquinolones via Catalytic Carbopalladation of Nitriles
Linjun Qi, Kun Hu, Shuling Yu, Jianghe Zhu, Tianxing Cheng, Xiaodong Wang, Jiuxi Chen,*
and Huayue Wu
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, P. R. China
S
* Supporting Information
ABSTRACT: The first example of the palladium-catalyzed
sequential nucleophilic addition followed by an intramolecular
cyclization of functionalized nitriles with arylboronic acids has
been achieved, providing an efficient synthetic pathway to
access structurally diverse isoquinolines and isoquinolones.
This methodology has also been successfully applied to the
total synthesis of the topoisomerase I inhibitor CWJ-a-5 (free
base).
Scheme 1. Reactions of Organoborons with Nitriles
he cyano group is one of the most accessible polar
Tunsaturated carbon−heteroatom multiple bonds, and it is
widely used in synthetic and medicinal chemistry.1 The nitrile
may serve as a versatile precursor to structurally diverse
compounds such as amines, carboxylic acids and derivatives,
aldehydes, and heterocycles. By contrast, it is generally known
that nitriles such as acetonitrile or benzonitrile have been used
as solvents or ligands in organometallic reactions,2 presumably
due to the inherently inert nature of nitriles. Since Larock’s
pioneering contributions to the addition of arylpalladium
species to the cyano group,3 remarkable advances in
transition-metal-catalyzed additions of organoboron reagents
to nitriles have been documented, but they exclusively provide
aryl ketone products (Scheme 1a).4 We recently disclosed the
palladium-catalyzed addition of organoboron reagents to
nitriles for the synthesis of alkyl aryl ketones and diketones.5
In addition, Lu’s group and our group have also developed the
palladium-catalyzed one-pot synthesis of benzofurans by the
addition of organoboron reagents to functionalized nitriles
(Scheme 1b).5a,6 However, the nitrogen atoms of nitriles have
not been used effectively due to the hydrolysis of ketimine
intermediates. The development of a new synthetic strategy to
enhance the selectivity and step economy for the synthesis of
the target N-heterocycles products and to reduce the
generation of undesired waste products is an important goal
of chemists. Despite the prevalence of the transformation of the
cyano group into various functional groups, the development of
efficient synthetic approaches that incorporate the nitrogen
atoms of nitriles into N-heterocycles products rather than have
them follow pathways that result in hydrolysis of ketimine
intermediates still remains a challenging research area.
Figure 1. Biologically active isoquinoline and isoquinolones.
Received: November 23, 2016
Isoquinoline and isoquinolone derivatives are important N-
heterocycles found in biologically active natural products,
including pharmaceuticals such as CWJ-a-5,7 perafensine,8
moxaverine,9 and indeno[1,2-c]isoquinolone10 (Figure 1).11
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03499
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Organic Letters
Letter
Due to the substantial applicability of isoquinolines and
isoquinolones, the development of accessing isoquinolines12
and isoquinolones13 has received considerable attention. To the
best of our knowledge, nitriles as substrate candidates involved
in the transition-metal-catalyzed tandem addition and cycliza-
tion processes with organoboron reagents for the synthesis of
isoquinolines and isoquinolones have not been demonstrated
to date. This work is part of the continuing efforts in our
laboratory toward the development of novel transition-metal-
catalyzed addition or coupling reactions with organoboron
reagents14 and the synthesis of N-heterocycles.15 Herein we
describe a challenging Pd-catalyzed sequential nucleophilic
addition followed by an intramolecular cyclization of function-
alized nitriles (2-(2-oxo-2-arylethyl)benzonitriles, 2-(2-benzoyl-
phenyl)acetonitrile, and 2-(cyanomethyl)benzoate) with ar-
ylboronic acids to afford structurally diverse isoquinolines and
isoquinolones (Scheme 1c) and its application in the total
synthesis of the topoisomerase I inhibitor CWJ-a-5.
increased the yield of the reaction to 91% (entries 4−7). The
role of the H2O in the reaction is not clear. H2O is known to be
a unique ligand in many useful palladium transformations.16
The choice of ligand was found to be important for the yield.
For example, when either N,N,N′,N′-tetramethylethylene-
diamine (L2) or 1,10-phenanthroline (L3) was used instead
of 2,2′-bipyridine (L1), no desired product or a 79% yield was
observed, respectively (entries 8−9). Replacement of Pd(acac)2
with other catalysts, including Pd(OAc)2 and Pd(CF3CO2)2,
resulted in relatively lower yields (entries 10−11). In contrast,
this reaction did not work using Pd(0) such as Pd(PPh3)4 as a
catalyst (entry 12). No desired product was observed if either
Pd(acac)2 or the ligand was absent (entries 13−14).
With the optimal reaction conditions in hand, we explored
the substrate scope of this method (Scheme 2). First, the
a
Scheme 2. Synthesis of Isoquinolines
Our study commenced by examining the reaction of 2-(2-
oxo-2-phenylethyl)benzonitrile (1a) with phenylboronic acid
(2a) using several palladium catalysts to identify the optimal
reaction conditions (Table 1). Through the screening process,
a
Table 1. Optimization of Reaction Conditions
b
entry
Pd catalyst
ligand
additive
solvent
yield (%)
1
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(OAc)2
Pd(CF3CO2)2
Pd(PPh3)4
L1
L1
L1
L1
L1
L1
L1
L2
L3
L1
L1
L1
L1
PhCO2H
HCl
THF
THF
THF
THF
DMSO
EtOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
trace
0
2
3
CF3CO2H
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
29
45
32
58
91
0
4
5
6
7
8
9
79
82
84
0
10
11
12
13
14
a
0
Conditions: 1 (0.4 mmol), 2 (1.2 mmol), Pd(acac)2 (5 mol %), bpy
Pd(acac)2
0
(10 mol %), TsOH (10 equiv), H2O (2 mL), 80 °C, 24 h, air. Isolated
yield.
a
Conditions: 1a (0.4 mmol), 2a (1.2 mmol), indicated Pd source (5
mol %), ligand (10 mol %), additive (10 equiv), solvent (2 mL), 80
b
°C, 24 h, air. Isolated yield. TsOH = p-MeC6H4SO3H, L1 = 2,2′-
bipyridine, L2 = N,N,N′,N′-tetramethylethylenediamine, L3 = 1,10-
reaction between 2-(2-oxo-2-phenylethyl)benzonitrile (1a) and
arylboronic acids was investigated under standard conditions
(3a−3i). The steric effects of substituents affected the yields of
the reaction to some extent. For example, the tandem reaction
of 1a with para- and meta-tolylboronic acid gave yields of 62%
and 73%, respectively (3c, 3d), while the ortho-tolylboronic
acid afforded a higher yield of 87% (3b). The electronic
properties of the substituents on the phenyl ring of the
arylboronic acids had little effect on the reaction. In general, the
arylboronic acids bearing an electron-donating substituent
produced a slightly higher yield of products than those
analogues bearing an electron-withdrawing substituent. 1-(4-
Methoxyphenyl)-3-phenylisoquinoline (3e) was isolated in
65% yield when p-methoxyphenylboronic acid was used as
the substrate. Introduction of the moderately electron-with-
drawing Cl group on the para-position of the arene was well
phenanthroline.
no desired product was detected using a Lewis acid as the
additive with a variety of parameters. To our delight, a trace
amount of the desired product 1,3-diphenylisoquinoline (3a)
was observed by GC/MS analysis using benzoic acid as an
additive in THF in the presence of Pd(OAc)2 (entry 1). The
reaction failed to give the desired product using hydrochloric
acid as an additive (entry 2). When either trifluoroacetic acid
(TFA) or p-methylbenzenesulfonic acid (TsOH) was used as
the additive, the yield of the desired product 3a was improved
to 29% and 45%, respectively (entries 3−4). Encouraged by this
promising result, we further screened the reaction parameters
including solvents, ligands, and catalysts. First, an investigation
of the effect of solvent revealed that use of H2O greatly
B
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Letter
a
tolerated, and the desired product 3f was obtained in 57% yield.
However, using a substrate bearing the strong electron-
withdrawing CF3 group at the para-position decreased the
yield of 3g to 47%. Substrate p-trifluoromethoxyphenylboronic
acid was amenable to the reaction conditions (3h). Notably,
treatment of 2-naphthylboronic acid with 1a also proceeded
smoothly and gave the desired product 3i in 64% yield. We next
examined the scope of other 2-(2-oxo-2-phenylethyl)benzo-
nitriles (3j−3q). Substrates bearing electron-donating para-
and meta-methyl substitutents gave yields of 86% and 88%,
respectively (3j, 3k), while the ortho-methyl substituted
substrate afforded a slightly lower yield of 82% due to the
lesser steric hindrance of the substituted group (3l). The
reaction worked well with the arylboronic acid containing the
bromo group (commonly used for cross-coupling reactions)
and to afford 3m in 82% yield, leading to a useful handle for
further cross-coupling reactions. Functional groups such as tert-
butyl (3n), naphthyl (3o), and ethers (3p, 3q) were well
tolerated. However, substrate 2-(2-(4-cyanophenyl)-2-
oxoethyl)benzonitrile (1r) bearing a cyano group reacted
with 2a to give phenyl(4-(1-phenylisoquinolin-3-yl)phenyl)-
methanone (3r) in 67% yield, accompanied by a trace amount
of 4-(1-phenylisoquinolin-3-yl)benzonitrile (Scheme 3). In
addition, the structure of 3r was unambiguously confirmed by
X-ray crystallography.17
Scheme 4. Synthesis of Isoquinolin-1(2H)-ones
a
Conditions: 4 (0.4 mmol), 2 (0.8 mmol), Pd(CF3CO2)2 (5 mol %),
bpy (10 mol %), TFA (0.3 mL), THF (2 mL), 80 °C, 24 h, air.
ArBF3K (0.8 mmol), Pd(CF3CO2)2 (10 mol %), bpy (20 mol %),
b
TFA (0.3 mL), 4-dimethylaminopyridine (0.4 mmol), THF (2 mL),
80 °C, 24 h, air. Isolated yield.
Scheme 5. Synthesis of CWJ-a-5
Scheme 3. Synthesis of Isoquinolines
We next turned our attention to the rapid construction of
isoquinolone. A trace amount of the desired product 3-
phenylisoquinolin-1(2H)-one (5a) was observed by GC/MS
analysis under standard conditions. We were delighted to find
that the yield of 5a was improved to 86% when the
combination of Pd(CF3CO2)2 2,2′-bipyridine (L1) and
trifluoroacetic acid (TFA) was employed in THF (for
conditions screening, see Table S2 in the Supporting
Information). As shown in Scheme 4, various isoquinolin-
1(2H)-ones 5 were obtained by the palladium-catalyzed
tandem reaction of methyl 2-(cyanomethyl)benzoate (4) with
arylboronic acids 2. Functional groups such as ethers (5e, 5f),
aryl fluorides, chlorides and bromides (5g, 5h, 5i), tert-butyl
(5j), and naphthyl (5k, 5l) were well tolerated.
Scheme 6. Plausible Reaction Mechanism
Then, the utility of this methodology was further applied to
the total synthesis of CWJ-a-5 (free base), which was the
representative compound identified as a topoisomerase 1
inhibitor.7 In the key step, the commercially available methyl
2-(cyanomethyl)benzoate (CAS: 5597-04-6) and phenylbor-
onic acid (CAS: 98-80-6) were chosen as the starting material
to undergo sequential nucleophilic addition followed by an
intramolecular cyclization to deliver CWJ-a-5 (free base) in
total yield of 73% (Scheme 5). Compared with other synthetic
procedures, this process was easy to handle with commercially
available starting materials.
arylboronic acids would generate the aryl palladium species,
which would be followed by the coordination of the cyano
group giving intermediate A. Next, carbopalladation of the
cyano group would result in formation of a palladium ketimine
intermediate B. The intermediate B could undergo intra-
molecular cyclization to palladium complex C. Protonation of
the intermediate C by TsOH would afford the dihydro-
isoquinolin-3-ol (D) and regenerate the palladium catalyst.
Finally, dehydration of the dihydroisoquinolin-3-ol (D) would
A possible mechanism for the synthesis of isoquinolines from
the tandem reaction between 2-(2-oxo-2-arylethyl)benzonitriles
and arylboronic acids as a representative example is proposed in
Scheme 6. First, transmetalation of the palladium species with
C
DOI: 10.1021/acs.orglett.6b03499
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(8) Perafensine: Prous, J. R.; Serradell, M. N.; Castaner, J. Drugs
Future 1982, 7, 580.
deliver the corresponding isoquinolines 3 as the products.
However, a detailed mechanism of the formation of the
isoquinolines remains unclear currently.
In summary, we have developed an original approach for the
synthesis of isoquinolines and isoquinolones by the Pd-
catalyzed tandem addition/cyclization of functionalized nitriles
with arylboronic acids. In addition, the protocol was
successfully applied to the total synthesis of CWJ-a-5 (free
base). This chemistry may find further applications for the
construction of other useful N-heterocycles.
(9) (a) Bayer, R.; Plewa, S.; Borcescu, E.; Claus, W. Arzneim.-Forsch.
1988, 38, 1765. (b) Resch, H.; Weigert, G.; Karl, K.; Pemp, B.;
Garhofer, G.; Schmetterer, L. Acta Ophthalmol. 2009, 87, 731.
(10) (a) Jagtap, P. G.; Baloglu, E.; Southan, G. J.; Mabley, J. G.; Li,
H.; Zhou, J.; van Duzer, J.; Salzman, A. L.; Szabo, C. J. Med. Chem.
́
2005, 48, 5100. (b) Virag, L.; Szabo, C. Pharmacol. Rev. 2002, 54, 375.
(11) For selected reviews, see: (a) Khan, A. Y.; Kumar, G. S. Biophys.
Rev. 2015, 7, 407. (b) Heravi, M. M.; Nazari, N. Curr. Org. Chem.
2015, 19, 2358. (c) Dembitsky, V. M.; Gloriozova, T. A.; Poroikov, V.
V. Phytomedicine 2015, 22, 183. (d) Chrzanowska, M.; Rozwadowska,
M. D. Chem. Rev. 2004, 104, 3341. (e) Giri, P.; Suresh Kumar, G.
Mini-Rev. Med. Chem. 2010, 10, 568. For selected book, see:
(f) Bentley, K. W. The Isoquinoline Alkaloids, Vol. 1; Hardwood
Academic: Amsterdam, 1998. For selected examples, see: (g) Morrell,
A.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. J. Med.
Chem. 2006, 49, 7740. (h) Chen, L.; Conda-Sheridan, M.; Reddy, P.;
Morrell, A.; Park, E.; Kondratyuk, T.; Pezzuto, J.; van Breemen, R.;
Cushman, M. J. Med. Chem. 2012, 55, 5965. (i) Khadka, D. B.; Cho,
W.-J. Bioorg. Med. Chem. 2011, 19, 724. (j) Kaila, N.; Follows, B.;
Leung, L.; Thomason, J.; Huang, A.; Moretto, A.; Janz, K.; Lowe, M.;
Mansour, T. S.; Hubeau, C.; Page, K.; Morgan, P.; Fish, S.; Xu, X.;
Williams, C.; Saiah, E. J. Med. Chem. 2014, 57, 1299.
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.6b03499.
Experimental procedures, characterization data, NMR
spectra and X-ray data for product 3r (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jiuxichen@wzu.edu.cn.
ORCID
(12) For reviews of isoquinolines synthesis, see: (a) He, R.; Huang,
Z.; Zheng, Q.; Wang, C. Tetrahedron Lett. 2014, 55, 5705 and
references therein. For selected examples, see: (b) Sun, B.; Yoshino,
T.; Kanai, M.; Matsunaga, S. Angew. Chem., Int. Ed. 2015, 54, 12968.
(c) Zhou, S.; Wang, M.; Wang, L.; Chen, K.; Wang, J.; Song, C.; Zhu,
J. Org. Lett. 2016, 18, 5632. (d) Yuan, Z.; Cheng, R.; Chen, P.; Liu, S.;
Liang, S. H. Angew. Chem., Int. Ed. 2016, 55, 11882. (e) Pawar, A. B.;
Agarwal, D.; Lade, D. M. J. Org. Chem. 2016, 81, 11409.
(13) For reviews of isoquinolones synthesis, see: (a) Glushkov, V. A.;
Shklyaev, Y. V. Chem. Heterocycl. Compd. 2001, 37, 663. (b) Nakamura,
I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. For selected examples,
see: (c) Wu, Y.; Sun, P.; Zhang, K.; Yang, T.; Yao, H.; Lin, A. J. Org.
Chem. 2016, 81, 2166. (d) Grigg, R.; Elboray, E. E.; Akkarasamiyo, S.;
Chuanopparat, N.; Dondas, H. A.; Abbas-Temirek, H. H.; Fishwick, C.
W. G.; Aly, M. F.; Kongkathip, B.; Kongkathip, N. Chem. Commun.
2016, 52, 164. (e) Dhanasekaran, S.; Suneja, A.; Bisai, V.; Singh, V. K.
Org. Lett. 2016, 18, 634. (f) Wang, D.; Zhang, R.; Deng, R.; Lin, S.;
Guo, S.; Yan, Z. J. Org. Chem. 2016, 81, 11162. (g) Li, L.; Zhou, B.;
Wang, Y.; Shu, C.; Pan, Y.; Lu, X.; Ye, L. Angew. Chem., Int. Ed. 2015,
54, 8245. (h) Pan, Y.; Chen, G.; Shen, C.; He, W.; Ye, L. Org. Chem.
Front. 2016, 3, 491.
(14) (a) Zheng, X.; Ding, J.; Chen, J.; Gao, W.; Liu, M.; Wu, H. Org.
Lett. 2011, 13, 1726. (b) Lu, W.; Chen, J.; Liu, M.; Ding, J.; Gao, W.;
Wu, H. Org. Lett. 2011, 13, 6114. (c) Zhang, J.; Chen, J.; Liu, M.;
Zheng, X.; Ding, J.; Wu, H. Green Chem. 2012, 14, 912. (d) Zheng, H.;
Zhang, Q.; Chen, J.; Liu, M.; Cheng, S.; Ding, J.; Wu, H.; Su, W. J. Org.
Chem. 2009, 74, 943. (e) Chen, J.; Peng, Y.; Liu, M.; Ding, J.; Su, W.;
Wu, H. Adv. Synth. Catal. 2012, 354, 2117. (f) Shen, Y.; Chen, J.; Liu,
M.; Ding, J.; Gao, W.; Huang, X.; Wu, H. Chem. Commun. 2014, 50,
4292.
Jiuxi Chen: 0000-0001-6666-9813
Huayue Wu: 0000-0003-3431-561X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21572162, 21472140, and 21272176), Natural Science
Foundation of Zhejiang Province (Nos. LY14B020009 and
LY16B020012), Science and Technology Project of Zhejiang
Province (No. 2016C31022), and the Xinmiao Talent Planning
Foundation of Zhejiang Province (Nos. 2015R426063,
2016R426058, and 2016R426059) for financial support.
REFERENCES
■
(1) (a) Kukushkin, V. Y.; Pombeiro, A. J. L. Chem. Rev. 2002, 102,
1771. (b) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359. For
selected books, see: (c) Rappoport, Z. The Chemistry of the Cyano
Group; Wiley-Interscience: London, 1970. (d) Larock, R. C.
Comprehensive Organic Transformations: A Guide to Functional Group
Preparations; VCH: New York, 1989.
(2) (a) Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103, 2035.
(b) Rach, S. F.; Kuhn, F. E. Chem. Rev. 2009, 109, 2061.
̈
(3) (a) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999,
121, 3238. (b) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
2302. (c) Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551.
(4) (a) Zhao, B.; Lu, X. Tetrahedron Lett. 2006, 47, 6765. (c) Yousuf,
M.; Das, T.; Adhikari, S. New J. Chem. 2015, 39, 8763. (d) Wong, Y.-
C.; Parthasarathy, K.; Cheng, C.-H. Org. Lett. 2010, 12, 1736. (e) Tsui,
G. C.; Glenadel, Q.; Lau, C.; Lautens, M. Org. Lett. 2011, 13, 208.
(5) (a) Wang, X.; Liu, M.; Xu, L.; Wang, Q.; Chen, J.; Ding, J.; Wu,
H. J. Org. Chem. 2013, 78, 5273. (b) Chen, J.; Ye, L.; Su, W. Org.
Biomol. Chem. 2014, 12, 8204.
(6) (a) Zhao, B.; Lu, X. Org. Lett. 2006, 8, 5987. (b) Wang, X.; Wang,
X.; Liu, M.; Ding, J.; Chen, J.; Wu, H. Synthesis 2013, 45, 2241.
(7) CWJ-a-5: (a) Cho, W. J.; Park, M.-J.; Chung, B.-H.; Lee, C.-O.
Bioorg. Med. Chem. Lett. 1998, 8, 41. (b) Kim, K.-E.; Cho, W.-J.;
Chang, S.-J.; Yong, C.-S.; Lee, C.-H.; Kim, D.-D. Int. J. Pharm. 2001,
217, 101.
(15) (a) Yang, W.; Chen, J.; Huang, X.; Ding, J.; Liu, M.; Wu, H. Org.
Lett. 2014, 16, 5418. (b) Yang, W.; Qiao, R.; Chen, J.; Huang, X.; Liu,
M.; Gao, W.; Ding, J.; Wu, H. J. Org. Chem. 2015, 80, 482. (c) Chen,
Z.; Chen, J.; Liu, M.; Ding, J.; Gao, W.; Huang, X.; Wu, H. J. Org.
Chem. 2013, 78, 11342.
(16) (a) Yu, A.; Li, J.; Cui, M.; Wu, Y. Synlett 2007, 2007, 3063.
(b) Deledda, S.; Motti, E.; Catellani, M. Can. J. Chem. 2005, 83, 741.
(c) Zhao, Y.-B.; Mariampillai, B.; Candito, D. A.; Laleu, B.; Li, M. Z.;
Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 1849. (d) Jiao, L.; Bach,
T. J. Am. Chem. Soc. 2011, 133, 12990.
(17) Crystallographic data for compound 3r have been deposited
with the Cambridge Crystallographic Data Centre as entry CCDC
1518575.
D
DOI: 10.1021/acs.orglett.6b03499
Org. Lett. XXXX, XXX, XXX−XXX