Mn(ii)/O2-promoted oxidative annulation of vinyl isocyanides with boronic acids: Synthesis of multi-substituted isoquinolines

Article abstract of DOI:10.1039/c4cc06427e

An efficient manganese(ii)/O₂-promoted oxidative radical cascade reaction was developed for the modular synthesis of multi-substituted isoquinolines from easily accessible vinyl isocyanides and boronic acids.

Full text of DOI:10.1039/c4cc06427e

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Mn(II)/O2-promoted oxidative annulation of vinyl
isocyanides with boronic acids: synthesis of
multi-substituted isoquinolines†
Cite this:DOI: 10.1039/c4cc06427e
Received 15th August 2014,
Accepted 9th September 2014
Hao Wang,a Yang Yu,a Xiaohu Honga and Bin Xu*abc
DOI: 10.1039/c4cc06427e
www.rsc.org/chemcomm
An efficient manganese(II)/O2-promoted oxidative radical cascade reac- and have been widely applied in the formation of heterocycles.5
tion was developed for the modular synthesis of multi-substituted Sustainability contribution of isocyanides has been widely
isoquinolines from easily accessible vinyl isocyanides and boronic acids. recognized in the tandem radical cyclization reactions for the
construction of heteroarenes, where an isocyano group was well
The isoquinoline skeleton is one of the most attractive frameworks established as the radical acceptor.6 Manganese reagents, as
with a wide range of biological and pharmacological activities, and milder transition metal oxidants, have been largely used as radical
has been generally recognized as a privileged structure in medicinal generators to form electrophilic radicals or related species.7 For
chemistry.1 These compounds are structural units found in a vast example, the aryl radicals could be generated smoothly from
array of natural products with different biological activities,1a,2a arylboronic acids by manganese(III) acetate.8 Recently, an elegant new
pharmaceutical drugs,2b chiral ligands2c and important organic protocol for modular synthesis of phenanthridines was developed
materials.2d The early synthetic efforts for the construction of by Tobisu and Chatani using three equivalents of manganese(III)
the isoquinoline skeleton involve cyclization of functionalized acetylacetonate via oxidative cyclization of 2-isocyanobiphenyls
substrates, with an additional dehydrogenation step, at elevated with boronic acids (Scheme 1).9 As potentially useful synthetic
temperature under strongly acidic reaction conditions, such as precursors, vinyl isocyanides have been applied for the synthesis
traditional Bischler–Napieralski,3a Pomeranz–Fritsch3b,c and Pictet– of heterocycles, however most of these reactions are mainly focused
Spengler3d reactions. Furthermore, alternative strategies to construct on base- or visible light-promoted cycloaddition reactions,10 and
isoquinoline frameworks have been developed through the transi- much less attention has been paid to their chemistry in a transition
tion metal-catalyzed couplings of alkynes with aryl imines,4a–e metal catalysis or promotion manner. In continuation of our recent
azides,4f oximes,4g amines,4h aryl hydrazones4i or benzamidines4j research interests on the isocyanide chemistry11 and assembling
undergoing a C–H bond activation pathway. However, these pro- heterocycles through a tandem chemical bonds formation
ducts are usually less substituted or lack diversity, and the reactions strategy,4i,12 herein we describe a Mn(II)/O2-promoted oxidative
generally need noble metals, such as palladium, rhodium and radical cascade reaction, whereby a sequential double C–C
ruthenium, to promote the transformation. In this event, the bond was formed from easily accessible vinyl isocyanides and
development of efficient synthesis of multi-substituted isoquinolines boronic acids to give multi-substituted isoquinolines (Scheme 1).
from readily available starting materials with cheap metal usage,
mild conditions and operational simplicity will be highly desirable.
Isocyanides are uniquely versatile building blocks in organic
synthesis because of their structural and reactive properties,
a Department of Chemistry, Innovative Drug Research Center, Shanghai University,
Shanghai 200444, China. E-mail: xubin@shu.edu.cn; Fax: +86-21-66132830;
Tel: +86-21-66132830
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
c Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department
of Chemistry, East China Normal University, Shanghai 200062, China
† Electronic supplementary information (ESI) available: General experimental
procedures, characterization data and copies of the 1H, 13C and 19F NMR spectra
Scheme 1 Manganese-promoted radical cyclization of isocyanides.
for all compounds. See DOI: 10.1039/c4cc06427e
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Table 1 Optimization of the reaction conditionsa
Table 2 Scope of boronic acidsa,b
Entry Oxidant (equiv.)
Solvents Atmos. Temp. (1C) Yieldb (%)
1
2
3
4
5
6
7
8
Mn(OAc)3Á2H2O (2.0) Dioxane O2
80
80
80
80
80
80
80
80
80
80
90
70
80
80
80
80
80
80
80
50
58
64
Trace
Trace
N.R.
N.R.
Trace
95
Mn(OAc)3Á2H2O (2.0) t-AmOH O2
Mn(OAc)3Á2H2O (2.0) Toluene O2
Mn(OAc)3Á2H2O (2.0) DMSO
Mn(OAc)3Á2H2O (2.0) HOAc
O2
O2
Mn(OAc)2Á4H2O (2.0) Toluene O2
MnCl2Á4H2O (2.0)
Toluene O2
Toluene O2
Toluene O2
MnO2 (2.0)
9
Mn(acac)3 (2.0)
10
11
12
13
14
15
16
17
18
19
Mn(acac)2Á2H2O (2.0) Toluene O2
Mn(acac)2Á2H2O (2.0) Toluene O2
Mn(acac)2Á2H2O (2.0) Toluene O2
Mn(acac)2Á2H2O (2.0) Toluene O2
Mn(acac)2Á2H2O (1.5) Toluene O2
Mn(acac)2Á2H2O (1.0) Toluene O2
Mn(acac)2Á2H2O (0.5) Toluene O2
Mn(acac)2Á2H2O (2.0) Toluene Air
Mn(acac)2Á2H2O (2.0) Toluene N2
98
92
96
90c
89
81
44
88
Trace
9
—
Toluene O2
a
All reactions were performed in an oxygen-purged Schlenk tube, using
vinyl isocyanide 1a (0.5 mmol), phenylboronic acid 2a (1.0 mmol) and
oxidant in solvent (5.0 mL) at 80 1C for 2 h. Mn(acac)2Á2H2O =
b
manganese(II) acetylacetonate dihydrate. N.R. = No reaction. Isolated
yield. 2a (1.5 equiv.) was used.
c
a
All reactions were performed in an oxygen-purged Schlenk tube, using
vinyl isocyanide 1a (0.5 mmol), boronic acid 2 (1.0 mmol) and
Mn(acac)2Á2H2O (1.0 mmol) in dry toluene (5.0 mL) at 80 1C for 2 h.
Furthermore, this protocol could be successfully applied to vinyl
boronic acids which, to our knowledge, represents the first example
of manganese(II)-promoted oxidative annulation of vinyl isocyanides
with aryl or vinyl radicals in an oxygen atmosphere.
b
Isolated yield.
tolerance. A sterically hindered 2-methyl group (3b and 3p) was also
At the outset of this study, we started our investigation by incorporated without significant loss in the yields. To our delight,
exploring the reaction of vinyl isocyanide 1a with phenylboronic boronic acids with fused arenes (3q–3s) or heterocyclic substituents,
acid 2a (2.0 equiv.) in the presence of manganese(III) acetate such as furan (3t–3u), thiophene (3v), pyridine (3w) and pyrimidine
dihydrate under an oxygen atmosphere at 80 1C. Intriguingly, the (3x) moieties, were all compatible with the reaction and gave desired
isoquinoline product 3a was isolated in 50% yield (entry 1, products in good to excellent yields, which would significantly expand
Table 1). By switching the solvent from dioxane to t-AmOH or the scope of this reaction and represent a significant outcome given
toluene, the yield was slightly increased (entries 2 and 3), while the utilities of these substructures in medicinal chemistry and
DMSO or HOAc provided trace amounts of the product (entries 4 materials science. It should be noted that vinyl boronic acids were
and 5). An extensive screening of manganese sources (entries 6–10), also found to be suitable coupling partners and afforded the desired
temperature (entries 11 and 12), and the loading of boronic acid isoquinolines in good yields (3y–3z). However, no desired isoquinoline
(entry 13) or manganese reagents (entries 14–16) revealed that the products could be observed for aliphatic boronic acids, such as
use of two equivalents of Mn(acac)2Á2H2O13 as an oxidant in toluene cyclopropyl boronic acid and n-pentyl boronic acid, in the reaction
at 80 1C under an oxygen atmosphere turned out to be the best and the starting material was recovered almost quantitatively. The
choice and resulted in 3a in 98% yield. Trace amounts or very low reason may be due to the instability of generated aliphatic radicals
yield of the product was observed when the reaction was conducted in the oxygen atmosphere.
under a nitrogen atmosphere (entry 18) or in the absence of the
manganese salt (entry 19), which implied that manganese(II) tion, a variety of vinyl isocyanides with different substitutions were
and oxygen are crucial for this transformation. next explored, and the results are illustrated in Table 3. For the
To further evaluate the generality and scope of this transforma-
With the optimized reaction conditions in hand, we then substrates having ester (4a–4m) and amide (4n–4p) substituents,
extended the reaction to a range of substrates. A wide variety of the reactions were successfully coupled with 2a to afford the
substitution patterns and functionalities were tolerated, as shown in corresponding isoquinolines in good to excellent yields. Vinyl
Table 2. Substrates containing both electron-donating (3b–d, 3g–j, 3o isocyanides which were derived from diaryl ketones (4a–4e), alkyl
and 3p) and electron-withdrawing groups (3e, 3f and 3k–n), or aryl ketones (4f and 4g), and aryl aldehydes (4h–4m), all proceeded
bearing ortho (3b), meta (3c–3f) and para (3g–3n) groups proceeded smoothly with phenylboronic acid 2a and produced the desired
efficiently in good to excellent yields with good functional group isoquinolines, regardless of their different electronic properties
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Table 3 Scope of vinyl isocyanidesa,b
Scheme 2 Preliminary mechanistic studies.
Manganese(II) was initially oxidized to manganese(III) in the
presence of oxygen,15 which reacted with phenylboronic acid 2a
by one-electron oxidation to generate a phenyl radical.8,9 The given
phenyl radical underwent intermolecular addition to isocyanide 1a
to form the corresponding imidoyl radical A.16 Intramolecular attack
of the imidoyl radical on the aromatic ring subsequently provided a
cyclohexadienyl type radical B, which is ultimately transferred to the
corresponding cationic intermediate C through a single-electron
oxidation process by manganese(III). The generated intermediate C
subsequently aromatized to afford the desired isoquinoline product
3a by a deprotonation step.
a
All reactions were performed in an oxygen-purged Schlenk tube, using
vinyl isocyanide 1 (0.5 mmol), phenylboronic acid 2a (1.0 mmol) and
Mn(acac)2Á2H2O (1.0 mmol) in dry toluene (5.0 mL) at 80 1C for 2 h.
b
Isolated yield.
In conclusion, we have developed an efficient manganese(II)/
O2-promoted oxidative radical cascade reaction from easily avail-
able vinyl isocyanides and boronic acids, which enables the rapid
divergent synthesis of valuable multi-substituted isoquinolines
and their p-extended analogues with operational simplicity. The
characteristics of a broad substrate scope, good functional group
tolerance, and synthesis modularity will provide the described
reaction broad utility in organic synthesis. Further insight into the
mechanism, reaction scope, and the synthetic applications for
bioactive compounds are now under investigation in our group.
and substitution positions. Furthermore, the regioselectivity of
this reaction mainly depends on the steric hindrance of sub-
strates. For example, good regioselectivity of 4m-A/4m-B (1 : 3.4)
was observed for a di-methoxyl substituent containing sub-
strate (1m), and the major product (4m-B) corresponds to the
C–C coupling at a less hindered position.
To define the possible reaction pathway, several control experi-
ments were carried out, as shown in Scheme 2. When a mixed
substrate containing both electron-rich 2g and electron-deficient
2m was treated with 1a, isoquinoline 3g with electron-rich proper-
ties was isolated predominately in 73% yield (Scheme 2a), which
suggested that electron-rich arylboronic acids reacted faster than
electron-deficient ones.9 Boronic acids have been reported to
decompose into aryl radicals through a single-electron transfer in
the presence of an oxidant.8,9,14 In the experiment involving the
addition of 2,2,6,6-tetramethyl-piperidine-1-oxy (TEMPO) under
optimized reaction conditions, the use of phenylboronic acid 2a
afforded exclusively a mixture of 5a and biphenyl 5b (Scheme 2b),
which implied the existence of a phenyl radical and a single
electron transfer pathway during the reaction.
Although a detailed reaction pathway remains to be clarified, a
plausible mechanism for the current manganese(II)/O2-mediated
annulation of vinyl isocyanide with boronic acid is depicted in
Scheme 3, which is based on the above results and the radical
cyclization mechanism proposed by Chatani and Tobisu.9
Scheme 3 Proposed mechanism for synthesis of 3a (ligands are omitted
for clarity).
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7 For reviews, see: (a) B. B. Snider, Chem. Rev., 1996, 96, 339; (b) G. G.
Melikyan, Aldrichimica Acta, 1998, 31, 50; (c) A. S. Demir and
M. Emrullahoglu, Curr. Org. Synth., 2007, 4, 323; (d) X. Q. Pan,
J. P. Zou and W. Zhang, Mol. Diversity, 2009, 13, 421; (e) B. B. Snider,
in Radicals in Organic Synthesis, ed. P. Renaud and M. P. Sibi,
Wiley-VCH, Weinheim, 2001, ch. 2.3, vol. 2, pp. 198–218; ( f ) B. B.
Snider, in Transition Metals for Organic Synthesis, ed. M. Beller and
C. Bolm, Wiley-VCH, Weinheim, 2nd edn, 2004, vol. 1, pp. 483–490.
We thank the National Natural Science Foundation of China
(No. 21272149) and the Innovation Program of Shanghai Municipal
Education Commission (No. 14ZZ094) for financial support. The
authors thank Prof. Hongmei Deng (Laboratory for Microstruc-
tures, SHU) for assistance with spectral measurements.
¨
8 A. S. Demir, O. Reis and M. Emrullahoglu, J. Org. Chem., 2003,
68, 578.
Notes and references
1 (a) K. W. Bentley, The Isoquinoline Alkaloids, Harwood Academic,
Amsterdam, The Netherlands, 1998, vol. 1; (b) A. Zhang, J. L.
9 M. Tobisu, K. Koh, T. Furukawa and N. Chatani, Angew. Chem., Int.
Ed., 2012, 51, 11363.
Neumeyer and R. J. Baldessarini, Chem. Rev., 2006, 107, 274; 10 (a) D. S. Matteson and R. A. Bailey, J. Am. Chem. Soc., 1968, 90, 3761;
(c) P. G. Baraldi, M. A. Tabrizi, S. Gessi and P. A. Borea, Chem.
Rev., 2008, 108, 238.
(b) R. B. King and R. B. Effraty, J. Am. Chem. Soc., 1971, 93, 564;
(c) D. Van Leusen, E. Van Echten and A. M. Van Leusen, J. Org.
Chem., 1992, 57, 2245; (d) M. Yamada, T. Fukui and K.-I. Nunami,
Tetrahedron Lett., 1995, 36, 257; (e) J. E. Baldwin, D. Chen and
A. T. Russell, Chem. Commun., 1997, 2389; ( f ) C. J. Helal and
J. C. Lucas, Org. Lett., 2002, 4, 4133; (g) B. Henkel, Tetrahedron Lett.,
2 (a) K. W. Bentley, Nat. Prod. Rep., 2006, 23, 444; (b) F. Dzierszinski,
A. Coppin, M. Mortuaire, E. Dewailly, C. Slomianny, J.-C. Ameisen,
F. DeBels and S. Tomavo, Antimicrob. Agents Chemother., 2002, 46, 3197;
(c) C. W. Lim, O. Tissot, A. Mattison, M. W. Hooper, J. M. Brown,
A. R. Cowley, D. I. Hulmes and A. J. Blacker, Org. Process Res. Dev., 2003,
7, 379; (d) A. Tsuboyama, H. Iwawaki, M. Furugori, T. Mukaide,
J. Kamatani, S. Igawa, T. Moriyama, S. Miura, T. Takiguchi, S. Okada,
M. Hoshino and K. Ueno, J. Am. Chem. Soc., 2003, 125, 12971.
3 (a) A. Bischler and B. Napieralski, Ber. Dtsch. Chem. Ges., 1893,
26, 1903; (b) P. Fritsch, Ber. Dtsch. Chem. Ges., 1893, 26, 419;
(c) C. Pomeranz, Monatsh. Chem., 1893, 14, 116; (d) A. Pictet and
T. Spengler, Chem. Ber., 1911, 44, 2030.
¨
2004, 45, 2219; (h) A. Domling and K. Illgen, Synthesis, 2005, 662;
(i) H. Jiang, Y. Cheng, R. Wang, Y. Zhang and S. Yu, Chem. Commun.,
2014, 50, 6164.
11 (a) S. Xu, X. Huang, X. Hong and B. Xu, Org. Lett., 2012, 14, 4614;
(b) X. Huang, S. Xu, Q. Tan, M. Gao, M. Li and B. Xu, Chem.
Commun., 2014, 50, 1465; (c) X. Hong, H. Wang, G. Qian, Q. Tan
and B. Xu, J. Org. Chem., 2014, 79, 3228; (d) T. Fang, Q. Tan, Z. Ding,
B. Liu and B. Xu, Org. Lett., 2014, 16, 2342.
4 For selected examples on isoquinoline synthesis via C–H activation, see: 12 (a) C. Sun and B. Xu, J. Org. Chem., 2008, 73, 7361; (b) W. Ye, J. Mo,
(a) N. Guimond and K. Fagnou, J. Am. Chem. Soc., 2009, 131, 12050;
(b) P. C. Too, Y.-F. Wang and S. Chiba, Org. Lett., 2010, 12, 5688;
(c) P. C. Too, S. H. Chua, S. H. Wong and S. Chiba, J. Org. Chem., 2011,
76, 6159; (d) J. Jayakumar, K. Parthasarathy and C.-H. Cheng, Angew.
Chem., Int. Ed., 2012, 51, 197; (e) R. He, Z.-T. Huang, Q.-Y. Zheng and
C. Wang, Angew. Chem., Int. Ed., 2014, 53, 4950; ( f ) Y.-F. Wang, K. K. Toh,
J.-Y. Lee and S. Chiba, Angew. Chem., Int. Ed., 2011, 50, 5927;
(g) R. K. Chinnagolla, S. Pimparkar and M. Jeganmohan, Org. Lett.,
T. Zhao and B. Xu, Chem. Commun., 2009, 3246; (c) T. Zhao and
B. Xu, Org. Lett., 2010, 12, 212; (d) G. Li, Z. Ding and B. Xu, Org. Lett.,
2012, 14, 5338; (e) B. Liu, X. Hong, D. Yan, S. Xu, X. Huang and
B. Xu, Org. Lett., 2012, 14, 4398; ( f ) J. Shao, X. Huang, X. Hong,
B. Liu and B. Xu, Synthesis, 2012, 1798; (g) J. Sun, B. Liu and B. Xu,
RSC Adv., 2013, 3, 5824; (h) G. Qian, B. Liu, Q. Tan, S. Zhang and
B. Xu, Eur. J. Org. Chem., 2014, 4837; (i) J. Sun, Q. Tan, W. Yang,
B. Liu and B. Xu, Adv. Synth. Catal., 2014, 356, 388.
2012, 14, 3032; (h) P. Villuendas and E. P. Urriolabeitia, J. Org. Chem., 13 [Mn(acac)2Á2H2O] and [Mn(acac)3] were purchased from TCI Co.,
2013, 78, 5254; (i) W. Liu, X. Hong and B. Xu, Synthesis, 2013, 2137;
( j) X. Wei, M. Zhao, Z. Du and X. Li, Org. Lett., 2011, 13, 4636.
Inc. with approximately $193/500 g and $363/500 g, respectively.
14 (a) O. Riant, O. Samuel, T. Flessner, S. Taudien and H. B. Kagan,
J. Org. Chem., 1997, 62, 6733; (b) A. Dickschat and A. Studer, Org.
Lett., 2010, 12, 3972; (c) I. B. Seiple, S. Su, R. A. Rodriguez,
R. Gianatassio, Y. Fujiwara, A. L. Sobel and P. S. Baran, J. Am. Chem.
Soc., 2010, 132, 13194; (d) Y. Fujiwara, V. Domingo, I. B. Seiple,
R. Gianatassio, M. D. Bel and P. S. Baran, J. Am. Chem. Soc., 2011,
133, 3292; (e) J. W. Lockner, D. D. Dixon, R. Risgaard and P. S. Baran,
Org. Lett., 2011, 13, 5628; ( f ) N. Uchiyama, E. Shirakawa,
R. Nishikawa and T. Hayashi, Chem. Commun., 2011, 47, 11671;
(g) J. Wang, S. Wang, G. Wang, J. Zhang and X.-Q. Yu, Chem.
Commun., 2012, 48, 11769; (h) P. P. Singh, S. K. Aithagani,
M. Yadav, V. P. Singh and R. A. Vishwakarma, J. Org. Chem., 2013,
78, 2639.
5 For reviews, see: (a) M. Tobisu and N. Chatani, Chem. Lett., 2011,
40, 330; (b) A. V. Lygin and A. de Meijere, Angew. Chem., Int. Ed., 2010,
49, 9094; (c) R. M. Wilson, J. L. Stockdill, X. Wu, X. Li, P. A. Vadola,
P. K. Park, P. Wang and S. J. Danishefsky, Angew. Chem., Int. Ed., 2012,
51, 2834; (d) V. Nenajdenko, Isocyanide Chemistry: Applications in
Synthesis and Material Science, Wiley-VCH, Weinheim, 2012.
6 (a) D. P. Curran and H. Liu, J. Am. Chem. Soc., 1992, 114, 5863;
(b) D. P. Curran, S.-B. Ko and H. Josien, Angew. Chem., Int. Ed. Engl.,
1995, 34, 2683; (c) D. Nanni, P. Pareschi, C. Rizzoli, P. Sgarabotto and
A. Tundo, Tetrahedron, 1995, 51, 9045; (d) S. Yamago, H. Miyazoe,
R. Goto, M. Hashidume, T. Sawazaki and J.-i. Yoshida, J. Am. Chem.
Soc., 2001, 123, 3697. For reviews: (e) I. Ryu, N. Sonoda and
D. P. Curran, Chem. Rev., 1996, 96, 177; ( f ) D. Nanni, in Radicals 15 (a) K. Oisaki, J. Abe and M. Kanai, Org. Biomol. Chem., 2013,
in Organic Synthesis, ed. P. Renaud and M. P. Sibi, Wiley-VCH,
Weinheim, 2001, ch. 1.3, vol. 2, pp. 44–61; (g) D. Spagnolo and
11, 4569; (b) F. Zhang, L. Wang, C. Zhang and Y. Zhao, Chem.
Commun., 2014, 50, 2046.
D. Nanni, in Encyclopedia of Radicals in Chemistry, Biology and 16 (a) M. D. Bachi and D. Denenmark, J. Am. Chem. Soc., 1989,
Materials, ed. C. Chatgilialoglu and A. Studer, Wiley-Blackwell,
Chichester, 2012, vol. 2, pp. 1019–1057.
111, 1886; (b) M. Minozzi, D. Nanni and P. Spagnolo, Curr. Org.
Chem., 2007, 11, 1366.
Chem. Commun.
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