Iodinated (Perfluoro)alkyl Quinoxalines by Atom Transfer Radical Addition Using ortho-Diisocyanoarenes as Radical Acceptors

Article abstract of DOI:10.1002/anie.201606023

A simple method for the preparation of functionalized quinoxalines is reported. Starting from readily accessible ortho-diisocyanoarenes and (perfluoro)alkyl iodides, the quinoxaline core is constructed during (perfluoro)alkylation by atom transfer radical

Full text of DOI:10.1002/anie.201606023

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201606023
German Edition: DOI: 10.1002/ange.201606023
Radical Reactions
Iodinated (Perfluoro)alkyl Quinoxalines by Atom Transfer Radical
Addition Using ortho-Diisocyanoarenes as Radical Acceptors
Dirk Leifert and Armido Studer*
Abstract: A simple method for the preparation of functional-
ized quinoxalines is reported. Starting from readily accessible
ortho-diisocyanoarenes and (perfluoro)alkyl iodides, the qui-
noxaline core is constructed during (perfluoro)alkylation by
atom transfer radical addition (ATRA), resulting in 2-iodo-3-
(perfluoro)alkylquinoxalines. The radical cascades are readily
initiated either with visible light or by using a,a’-azobisisobu-
tyronitrile (AIBN). The heteroarene products are obtained in
high yields (up to 94%), and the method can be readily scaled
up. Useful follow-up chemistry documents the value of the
novel radical quinoxaline synthesis.
T
he quinoxaline core is an important substructure[1] that can
be found in insecticides, fungicides,[2] and herbicides.[3] In
addition, quinoxalines show antibacterial,[4] anticancer,[5] and
antiplasmodial[6] activity and are also applied as class IIa
histone deacetylase (HDAC) inhibitors.[7] Considering the
broad application scope of quinoxalines in the medicinal and
agrochemical industry, the development of new methods for
their preparation is still of great importance.
Scheme 1. Construction of the quinoxaline core by ionic, transition-
metal-mediated or radical processes. TM=transition metal.
In the first reported quinoxaline synthesis, the heteroar-
ene core in 2 was constructed in an ionic process through
condensation of a 1,2-diketone with ortho-phenylene diamine
1 (Scheme 1).[8] Aside from this classical approach, different
ionic reactions or copper-catalyzed cyclizations have been
developed to access quinoxalines.[1,9,10]
In 1990, Ito and co-workers introduced an elegant
approach to the quinoxaline core. They used ortho-diisocya-
noarenes 3 as substrates that can be readily prepared from the
corresponding ortho-phenylene diamines.[11,12] Grignard addi-
tion to 3 provided quinoxalines in low yields along with
a mixture of oligomeric products.[13] Around the same time, it
was also shown that 3 can be efficiently polymerized using Pd
or Ni catalysis.[14] Addition of an organometallic species
noxalines 5 from diisocyanoarenes 3 and (perfluoro)alkyl
iodides through atom transfer radical addition[16] (ATRA).
The introduction of perfluoroalkyl substituents into
aromatic compounds of pharmaceutical and agrochemical[17]
interest is of great value because the perfluoroalkyl group
improves their lipophilicity, bioactivity, and metabolic stabil-
ity.[18] Surprisingly, only a few syntheses of perfluoroalkyl-
substituted quinoxalines have been reported. These fluori-
nated heteroarenes can be accessed by cyclization of ortho-
phenylene diamines with perfluoroalkylated bis-electro-
philes[19] and by quinoxaline post-perfluoroalkylation by
copper catalysis[20] or radical addition.[21]
Notably, isonitriles are very good radical acceptors and
have been successfully applied to the preparation of phenan-
thridines, indoles, and other heteroarenes.[22] Along these
lines, the groups of Nanni and Curran disclosed a radical
cascade for the synthesis of quinoxalines starting from
monoisocyanoarenes.[23] Despite intensive investigations,
group or atom transfer additions to isonitriles are nearly
unexplored. In a rare example, Yamago and Yoshida reported
radical PhTe group transfer processes with aryl isocyanides as
the acceptors.[24] To the best of our knowledge, radical
chemistry on ortho-diisocyanoarenes is unknown.
À
R’ TM to 3 generates the metalated quinoxaline 4, which
readily adds to another molecule of 3 in a propagation step.
Suginome and co-workers further optimized and used this
method for the synthesis of helical polymers.[15] Encouraged
by these TM-mediated cascades, we decided to use ortho-
diisocyanoarenes as radical acceptors and report herein the
highly efficient synthesis of 2-iodo-3-(perfluoro)alkylqui-
[*] D. Leifert, Prof. Dr. A. Studer
Organisch-Chemisches Institut
We commenced our studies using ortho-diisocyanoben-
zene (3a)[11] and C4F9I (10 equiv) as reaction components to
give iodoquinoxaline 5ad (Table 1). Solvent and initiator
were varied, and the initial experiments were conducted in
acetonitrile (0.1m) with different azo initiators (8 mol%) at
908C for 3 h. V40 (1,1’-azobis(cyclohexanecarbonitrile))
Westfꢀlische Wilhelms-Universitꢀt
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: studer@uni-muenster.de
Supporting information and the ORCID identification number for an
author of this article can be found under http://dx.doi.org/10.1002/
anie.201606023.
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Table 1: Optimization.[a]
Entry
Initiator
(mol%)
C4F9I
[x equiv]
Solvent
(m)
Yield
[%][b]
1
2
3
4
5
6
7
8
V40 (8)[c]
AIBN (8)
AIBN (8)
AIBN (8)
AIBN (8)
AIBN (4)
AIBN (6)
AIBN (6)
AIBN (6)
hn
10.0
10.0
10.0
10.0
10.0
10.0
10.0
5.0
MeCN (0.1)
MeCN (0.1)
BTF (0.1)
EtOAc (0.1)
DCE (0.1)
MeCN (0.1)
MeCN (0.1)
MeCN (0.1)
MeCN (0.1)
MeCN (0.1)
74
83
67
83
83
81
82 (82)[d]
76
9
7.5
10.0
80
10[e]
85 (90)[d]
[a] The reactions (0.200 mmol) were carried out under argon. [b] Deter-
mined by 19F NMR spectroscopy with BTF as the internal standard.
[c] V40: 1,1’-azobis(cyclohexanecarbonitrile). [d] Yield of isolated prod-
uct, 3 mmol scale. [e] Hexabutylditin (5 mol%) was added, and the
reaction was conducted at 508C.
Scheme 2. Substrate scope: Variation of the iodide. [a] Iodide
(20 equiv). [b] AIBN (20 mol%).
provided the desired compound 5ad in 74% yield (Table 1,
entry 1). A higher yield was achieved with AIBN (83%,
entry 2). Changing the concentration did not lead to a better
result (0.07 or 0.2 m, not shown). A solvent screen revealed
that the yield was slightly lower in trifluorotoluene (BTF) and
the same in ethyl acetate or 1,2-dichloroethane (DCE)
compared to the reaction in acetonitrile (entries 3–5). Reduc-
ing the amount of AIBN to 6 mol% did not affect the
reaction outcome, but with 4 mol%, a slightly reduced yield
was noted (entries 6 and 7). With 7.5 or 5.0 equiv of the
perfluoroalkyl iodide, the yields slightly decreased to 80%
and 76%, respectively (entries 8 and 9). Along with the azo
initiators, we also tested initiation by simple irradiation with
visible light (400 W) at 508C. To avoid inhibition of the
radical chain by the molecular iodine formed upon irradi-
ation,[25] hexabutylditin (5 mol%) was added,[26] and product
5ad was obtained in excellent 85% yield (entry 10). Next, the
substrate scope was investigated using the AIBN method at
908C (method A; entry 7). In selected cases, the reactions
were repeated under irradiation at 508C (method B;
entry 10). The robustness of both methods was documented
by larger-scale syntheses (3 mmol) where methods A and B
led to the isolation of 5ad in 82% and 90% yield, respectively.
To study the scope of the cascade process with respect to
the alkyl iodide, diisocyanobenzene 3a was reacted with
various alkyl iodides under the optimized reaction conditions
(methods A and B; Scheme 2). As trifluoromethyl iodide and
pentafluoroethyl iodide are gases, they were first condensed
at À788C and added by syringe. Owing to their high volatility,
20 equiv of the iodide were used in these two cases, and
quinoxaline 5aa and its ethyl congener 5ab were isolated in
54% and 77% yield, respectively. The reaction with CF3I was
also conducted according to method B, with a yield enhance-
ment to 74%. Upon increasing the length of the perfluoro-
alkyl chain from C3 to C8, the yield improved from 78% to
90% (method A, 5ac–5af). However, for the C10 derivative
5ag, the yield slightly decreased (78%). The reaction with
perfluorobutyl iodide was repeated according to method B
(5ad, 85%). Even with sterically hindered 2-iodoheptafluoro-
propane, the cascade process worked well, and 5al was
isolated in 79% yield. The selectivity of this reaction
regarding the halogen atom transfer step was investigated
next. As expected, chlorine and bromine atom transfer are far
slower than the iodine atom transfer,[27] and the reactions of
ClCF2CF2I and BrCF2CF2I provided exclusively the iodine
atom transfer products 5ah and 5ai in 61 and 62% yield. With
BrCF2CF2I, the cascade process was also conducted using
method B, and the yield was improved to 85%.
Perfluoroalkylethyl iodides are less reactive, and the
corresponding products 5aj (33%) and 5ak (36%) were
isolated in significantly lower yields. Addition of the per-
fluoroalkylethyl radicals to the isonitrile is likely to be slower
than the corresponding additions with the reactive, pyrami-
dalized perfluoroalkyl radicals.[28] A good result was obtained
for the reaction of ethyl iododifluoroacetate with 3a to give
quinoxaline 5am (74%). As for the alkyl radical series,
removing the activating fluorine substituents led to reduced
yields also in the ester series, and with ethyl iodoacetate, 5an
was obtained in 58% yield. For this substrate, method B
provided a slightly lower yield. The non-fluorinated sub-
strates 2-iodo-2-methylpropionitrile and cyclohexyl iodide
provided the corresponding ATRA products 5ao and 5ap in
moderate yields.
We continued our studies by varying the diisonitrile
moiety using C4F9I as the alkyl iodide component (Scheme 3).
The regioselectivity was low for all tested unsymmetric
diisonitriles. Methyl 3,4-diisocyanobenzoate (3b) provided
the two regioisomers of 5bd in 64% overall yield with 1.2:1
regioselectivity (method A). Electron-withdrawing substitu-
2
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Scheme 4. Proposed mechanism by ATRA.
Scheme 3. Substrate scope: Variation of the isonitrile (regioisomers
not assigned).
ents on the arene do not influence the regioselectivity but
seem to reduce the reactivity towards the electrophilic
perfluoroalkyl radical as compared to the reaction with 3a.
Indeed, with electron-rich, methoxy-substituted diisonitrile
3d, the yield increased, and 5dd was isolated with poor
regioselectivity in 86% yield. Method B provided a similar
result. Even a bulky tert-butyl group could not induce any
regioselectivity, and 5ed was isolated as a 1:1 mixture of
regioisomers (80%), and a similar result was obtained for
ortho-methyl diisonitrile 3c to give 5cd. The bulky terphenyl
derivative 3 f provided 5 fd in 76% yield, supporting the
finding that the steric bulk of substituents on the diisonitrile
moiety has only a small influence on the reaction. Tetramethyl
substrate 3g showed the highest reactivity, and 5gd was
isolated in excellent 94% yield (method A). Method B also
provided access to this product in high yield.
Scheme 5. Follow-up chemistry.
reaction conditions provided alkynyl quinoxaline 6 in 86%
yield. Iodine–magnesium exchange and subsequent formyla-
tion with dimethylformamide (DMF) afforded the corre-
sponding aldehyde 7.[30] Nucleophilic aromatic substitution
with methyl thioglycolate gave thioether 8 in 93% yield.
In summary, we have presented a method for the
preparation of (perfluoro)alkyl quinoxalines by atom transfer
radical addition starting form readily accessible diisonitriles
and various inexpensive and commercially available alkyl
iodides. Two different modes of initiation, AIBN or light, are
reported, which both delivered the targeted heteroarenes in
high yields (up to 94%). Notably, the reactions can be easily
scaled up, and the iodoquinoxalines obtained in these
cascades are valuable substrates for follow-up chemistry.
The suggested mechanism for the cascade process is
depicted in Scheme 4. Methods A and B differ only in the
initiation step. In the AIBN approach (method A), the azo
compound is thermally cleaved to give, after N2 fragmenta-
tion, the 2-cyanopropyl radical, which reacts with diisonitrile
Acknowledgements
À
3a and Rf I to quinoxaline A and the chain-initiating
perfluoroalkyl radical Rf. The perfluoroalkyl radical is also
We thank the Deutsche Forschungsgemeinschaft (DFG) for
supporting our work.
À
accessible by light-induced Rf I bond homolysis using
initiation method B. The thus generated radical Rf then
adds to 3a in a chain reaction to give imidoyl radical B, which
leads to quinoxalinyl radical C through a 6-endo cyclization.
Keywords: (perfluoro)alkylation · atom transfer ·
cascade reactions · quinoxalines · radical addition
À
Iodine atom transfer from Rf I to aryl radical C eventually
provides product 5 along with the chain-propagating per-
fluoroalkyl radical.
To underline the potential of our method, three follow-up
reactions were conducted with quinoxaline 5ad as the
substrate (Scheme 5). Sonogashira coupling[29] under standard
[1] a) S. Gobec, U. Urleb in Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations, Vol. 16 (Ed.: Y. Yama-
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
Chemie
moto), Thieme, Stuttgart, pp. 845 – 911; b) V. A. Mamedov in
Quinoxalines: Synthesis, Reactions, Mechanisms and Structure,
Springer, Heidelberg, 2016; A. K. Patidar, M. Jeyakandan, A. K.
Mobiya, G. Selvam, Int. J. PharmTech Res. 2011, 3, 386.
[2] K. Sasse, R. Wegler, G. Unterstenhçfer, F. Grewe, Angew. Chem.
1960, 72, 973.
Cushman, H. Patel, A. McKenzie, J. Org. Chem. 1988, 53,
5088; c) H. Watanabe, F. Yamashita, K. Uneyama, Tetrahedron
Lett. 1993, 34, 1941.
[20] a) M. G. Mormino, P. S. Fier, J. F. Hartwig, Org. Lett. 2014, 16,
1744; b) X. Lin, C. Hou, H. Li, Z. Weng, Chem. Eur. J. 2016, 22,
2075.
[3] G. Sakata, K. Makino, Y. Kurasawa, Heterocycles 1988, 27, 2481.
[4] O. I. El-Sabbagh, M. E. El-Sadek, S. M. Lashine, S. H. Yassin,
S. M. El-Nabtity, Med. Chem. Res. 2009, 18, 782.
[5] A. Carta, G. Paglietti, M. E. Rahbar Nikookar, P. Sanna, L.
Sechi, S. Zanetti, Eur. J. Med. Chem. 2002, 37, 355.
[6] N. Primas, P. Suzanne, P. Verhaeghe, S. Hutter, C. Kieffer, M.
Laget, A. Cohen, J. Broggi, J.-C. Lancelot, A. Lesnard, P.
Dallemagne, P. Rathelot, S. Rault, P. Vanelle, N. Azas, Eur. J.
Med. Chem. 2014, 83, 26.
[7] R. W. Bꢀrli, C. A. Luckhurst, O. Aziz, K. L. Matthews, D. Yates,
K. A. Lyons, M. Beconi, G. McAllister, P. Breccia, A. J. Stott,
S. D. Penrose, M. Wall, M. Lamers, P. Leonard, I. Mꢀller, C. M.
Richardson, R. Jarvis, L. Stones, S. Hughes, G. Wishart, A. F.
Haughan, C. OꢁConnell, T. Mead, H. McNeil, J. Vann, J.
Mangette, M. Maillard, V. Beaumont, I. Munoz-Sanjuan, C.
Dominguez, J. Med. Chem. 2013, 56, 9934.
[8] O. Hinsberg, Ber. Dtsch. Chem. Ges. 1884, 17, 318.
[9] For selected examples, see: a) P. Ghosh, A. Mandal, Green
Chem. Lett. Rev. 2013, 6, 45; b) Y.-H. Cho, K.-H. Kim, C.-H.
Cheon, J. Org. Chem. 2014, 79, 901; c) Y. Chen, K. Li, M. Zhao,
Y. Li, B. Chen, Tetrahedron Lett. 2013, 54, 1627.
[10] For selected examples, see: a) W. Wang, Y. Shen, X. Meng, M.
Zhao, Y. Chen, B. Chen, Org. Lett. 2011, 13, 4514; b) T. Chen, X.
Chen, J. Wei, D. Lin, Y. Xie, W. Zeng, Org. Lett. 2016, 18, 2078.
[11] Y. Ito, A. Ohnishi, H. Ohsaki, M. Murakami, Synthesis 1988, 714.
[12] M. Suginome, Y. Ito in Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations, Vol. 19 (Ed.: S.-I.
Murahashi), Thieme, Stuttgart, pp. 445.
[21] a) Y. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S. Su,
D. G. Blackmond, P. S. Baran, Proc. Natl. Acad. Sci. USA 2011,
108, 14411; b) A. G. OꢁBrien, A. Maruyama, Y. Inokuma, M.
Fujita, P. S. Baran, D. G. Blackmond, Angew. Chem. Int. Ed.
2014, 53, 11868; Angew. Chem. 2014, 126, 12062.
[22] For the use of isonitriles as radical acceptors, see: a) I. Ryu, N.
Sonoda, D. P. Curran, Chem. Rev. 1996, 96, 177; b) B. Zhang, A.
Studer, Chem. Soc. Rev. 2015, 44, 3505; for double additions to
isonitriles, see: c) D. Leifert, D. G. Artiukhin, J. Neugebauer, A.
Galstyan, C. A. Strassert, A. Studer, Chem. Commun. 2016, 52,
5997.
[23] a) D. Nanni, P. Pareschi, C. Rizzoli, P. Sgarabotto, A. Tundo,
Tetrahedron 1995, 51, 9045; b) D. P. Curran, H. Liu, H. Josien, S.-
B. Ko, Tetrahedron 1996, 52, 11385; c) C. M. Camaggi, R.
Leardini, D. Nanni, G. Zanari, Tetrahedron 1998, 54, 5587; see
also: d) X. Sun, J. Li, Y. Ni, D. Ren, Z. Hu, S. Yu, Asian J. Org.
Chem. 2014, 3, 1317.
[24] a) S. Yamago, H. Miyazoe, T. Sawazaki, R. Goto, J.-i. Yoshida,
Tetrahedron Lett. 2000, 41, 7517; b) S. Yamago, H. Miyazoe, R.
Goto, M. Hashidume, T. Sawazaki, J.-i. Yoshida, J. Am. Chem.
Soc. 2001, 123, 3697; c) S. Yamago, H. Miyazoe, T. Nakayama, M.
Miyoshi, J.-i. Yoshida, Angew. Chem. Int. Ed. 2003, 42, 117;
Angew. Chem. 2003, 115, 121; d) C. Wakselman, M. Tordeux, J.
Org. Chem. 1979, 44, 4219.
[25] A. Studer, D. P. Curran, Angew. Chem. Int. Ed. 2016, 55, 58;
Angew. Chem. 2016, 128, 58.
[26] D. P. Curran, M.-H. Chen, D. Kim, J. Am. Chem. Soc. 1986, 108,
2489.
[13] Y. Ito, E. Ihara, M. Hirai, H. Ohsaki, A. Ohnishi, M. Murakami,
J. Chem. Soc. Chem. Commun. 1990, 403.
[27] D. P. Curran, E. Bosch, J. Kaplan, M. Newcomb, J. Org. Chem.
1989, 54, 1826.
[14] a) Y. Ito, E. Ihara, M. Murakami, M. Shiro, J. Am. Chem. Soc.
1990, 112, 6446; b) Y. Ito, E. Ihara, M. Murakami, Polym. J. 1992,
24, 297.
[15] M. Suginome, S. Collet, Y. Ito, Org. Lett. 2002, 4, 351.
[16] a) T. Pintauer, K. Matyjaszewski in Encyclopedia of Radicals in
Chemistry, Biology and Materials (Eds.: C. Chatgilialoglu, A.
Studer), Wiley, Chichester, 2012, pp. 1851; b) T. Pintauer, K.
Matyjaszewski, Chem. Soc. Rev. 2008, 37, 1087.
[28] M. Hartmann, Y. Li, A. Studer, Org. Biomol. Chem. 2016, 14,
206.
[29] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 16, 4467; b) M. Armengol, J. A. Joule, J. Chem. Soc. Perkin
Trans. 1 2001, 154.
[30] a) P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F.
Kopp, T. Korn, I. Sapountzis, V. A. Vu, Angew. Chem. Int. Ed.
2003, 42, 4302; Angew. Chem. 2003, 115, 4438; b) W. Lin, I.
Sapountzis, P. Knochel, Angew. Chem. Int. Ed. 2005, 44, 4258;
Angew. Chem. 2005, 117, 4330.
[17] a) M. Schlosser, Angew. Chem. Int. Ed. 2006, 45, 5432; Angew.
Chem. 2006, 118, 5558; b) W. K. Hagmann, J. Med. Chem. 2008,
51, 4359.
[18] a) K. Mꢀller, C. Faeh, F. Diederich, Science 2007, 317, 1881; b) S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev.
2008, 37, 320.
[19] For selected examples, see: a) M. Cushman, W. C. Wong, A.
Bacher, J. Chem. Soc. Perkin Trans. 1 1986, 1043; b) M.
Received: June 21, 2016
Published online: && &&, &&&&
4
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Communications
Radical Reactions
D. Leifert, A. Studer*
&&&& — &&&&
Iodinated (Perfluoro)alkyl Quinoxalines
by Atom Transfer Radical Addition Using
ortho-Diisocyanoarenes as Radical
Acceptors
Radical cascade reactions: Diisocyanoar-
enes react as acceptors with various alkyl
iodides in atom transfer radical additions
to give alkylated iodoquinoxalines in good
to excellent yields. Initiation was achieved
thermally with AIBN or under irradiation
with visible light.
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