Electron-Catalyzed Fluoroalkylation of Vinyl Azides

Article abstract of DOI:10.1002/chem.201602855

The transition-metal free fluoroalkylation of vinyl azides is herein reported. This operationally simple reaction employs the Togni reagent as a CF₃source, Bu₄NI as an initiator, and occurs under electron catalysis. A range of readily prepared starting materials are functionalized using this approach to produce both phenanthridines and quinoxalin-2-ones.

Full text of DOI:10.1002/chem.201602855

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Title: Electron-Catalyzed Fluoroalkylation of Vinyl Azides
Authors: Emily Mackay; Armido Studer
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Electron-Catalyzed Fluoroalkylation of Vinyl Azides
Emily G. Mackay[a] and Armido Studer*[a]
[a]
Dr. Emily Mackay, Prof. Dr. A. Studer, Westfälische Wilhelms Universität, Organisch-Chemisches Institut, Corrensstrasse 40, 48149
Münster (Germany), Fax: (+49) 251-833-6523 E-mail: studer@uni-muenster.de
Abstract: The transition-metal free fluoroalkylation of vinyl azides is herein reported. This operationally simple reaction employs the Togni
reagent as a CF3 source, Bu4NI as an initiator, and occurs under electron-catalysis. A range of readily prepared starting materials are
functionalized using this approach to produce both phenanthridines and quinoxalin-2-ones.
The introduction of trifluoromethyl groups is an important area of organic chemistry, due to the unique ability of fluoroalkyl groups to
modify the chemical and physical properties of biologically active compounds,[1] often leading to drastic changes in bioavailability and
bioactivity. As a result of this, much research has been conducted in the area of trifluoromethylation. Phenanthridines[2] and
quinoxalinones[3] are important molecules on the pharmaceutical landscape (Figure 1).
Figure 1 (about here)
Typically, the synthesis of perfluoroalkylated heterocycles proceeds via the direct functionalization of the pre-formed heterocycle.[4]
An alternative approach, however, is to introduce the perfuoroalkyl group concurrently with formation of a heteroarene ring. For the
synthesis of quinoxalinones there exists only one such method.[5] In the case of phenanthridine synthesis a handful of examples have
been reported.[6] While the majority of these examples require the use of a transition metal catalyst, a select few do not.[6a-d] In one
such example, reported by our group in 2013,[6a] the trifluoromethyl group is introduced in an electron-catalyzed process using the
Togni reagent 3[7] (see Table 1) as a CF3 source, and Bu4NI as an initiator. This process employs ortho-isocyanobiaryls as substrates,
forming the C-C bond depicted in red. Further research in this area appeared later in the year.[6b-d] In a strategically different approach,
heteroarenes can be formed using the addition of a trifluoromethyl radical onto a vinyl azide,[8] this time forming the C-N bond
depicted in red. Interestingly this approach generates the trifluoromethylated phenanthridines with an extra methylene spacer,
allowing complementarity to the earlier approach. This strategic disconnection has been recently used by the groups of Chiba[6d] and
Yu[5] for the synthesis of both phenanthridines and quinoxalinones, and it was our belief that this reaction should be feasible without
the use of any transition metal, employing electron-catalysis.[9] It was with this in mind that we set about the synthesis of vinyl azide
substrates 1 and 4 according to literature procedures (see the Supporting Information).[5,6e]
Scheme 1 (about here)
We were delighted to find that upon exposure of vinyl azide 1a to the conditions previously developed for the trifluoromethylation of
ortho-isocyanobiaryls [Bu4NI (5 mol%), Togni-reagent (2 equiv.), Cs2CO3 (2 equiv.), 1,4-dioxane, 2 h, 80 °C],[6a] the target
phenanthridine 2aa was obtained in 74% isolated yield (Table 1, entry 1). The pentafluoroethyl analogue 2ab could also be accessed
using this method (Table 1, entry 2). We found that both electron-withdrawing and -donating groups were tolerated at the para-
position of the phenyl ring (see 2b and 2c, Table 1, entries 3 and 4), and a substituent at the ortho-position did not reduce the yield of
the reaction (2d, Table 1, entry 5). When a fluorine atom was introduced at the meta-position of the phenyl ring, a 1:1 mixture of
regioisomers 2ea and 2eb was formed (Table 1, entry 6). Finally, it was observed that the addition of a substituent onto the aryl ring
tether, the reaction proceeded smoothly, giving the target phenanthridine 2f in 76% yield (Table 1, entry 7).
Table 1 (about here)
Having achieved success in the preparation of phenanthridines with our electron-catalyzed reaction, our attention turned to the
synthesis of the quinoxalinones. The preparation of the starting -azidyl acrylamides 4 is described in the SI. When we exposed N-
phenyl acrylamide 4a to our standard conditions, the targeted quinoxalinone 5a was isolated in a somewhat lower yield of 51% (Table
2, entry 1). This reduced yield compared to the phenanthridine series held true for all of the quinoxalinone compounds screened. This
is not unexpected since the electrophilic trifluoromethyl radical is known to react less efficiently with electron poorer alkenes.[10]
Interestingly, in the case of the quinoxalinone series, we were unable to isolate any target material when the pentafluoroethyl Togni
reagent was used in the reaction (Table 2, entry 2). No target material was observed when either the 2,5-dimethyl 4b, or the 2-methyl
substrate 4c were screened (Table 2, entries 3 and 4), indicating that a substituent at the ortho-position hindered the reaction in this
series. Meta-isopropyl substituted analogue 4d gave the target material in 34% yield, as a 1:1 mixture of regioisomers 5da and 5db
(Table 2, entry 5). Turning now to substituents at the para position, we found that when including electron-withdrawing (Table 2,
entries 6 and 7) and electron-donating substituents (Table 2, entry 8), as well as alkyl chains (Table 2, entry 9), the reaction
proceeded smoothly, giving the target quinoxalinones 5e-h in somewhat modest yields.
Table 2 (about here)
A proposed mechanism for the heteroarene synthesis is illustrated in Scheme 2. In this mechanism, the initiator Bu4NI formally
liberates an electron, which is then able to reductively cleave the Togni reagent 3 to form the ortho-iodobenzoate anion and the

Chemistry - A European Journal
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COMMUNICATION
trifluoromethyl radical.[11] Addition of the trifluoromethyl radical to the vinyl azide, followed by loss of nitrogen, provides iminyl radical 7.
An intramolecular addition of this radical to the pendant aryl ring leads to the cyclohexadienyl radical 8, a highly acidic species.
Following deprotonation by the ortho-iodobenzoate anion (or the stoichiometric Cs2CO3 base), the heteroarene radical anion 9 is
generated that can formally liberate an electron, propagating the catalytic cycle, and forming the product heteroarene 10.
Scheme 2 (about here)
In summary, we have presented an approach for the synthesis of fluoroalkylated phenanthridines and quinoxalinones starting with
readily prepared vinyl azides. This electron-catalyzed process uses the commercially available Togni reagent 3, along with Bu4NI as
an initiator, to form the fluoroalkyl radical. This reaction proceeds without the need for a transition metal catalyst, and forms not only
the C-CF3 bond, but also the new heteroarene ring.
Experimental Section
Typical Procedure for the Trifluoromethylation of Vinyl Azides 1 and 4: Under an argon atmosphere, vinyl azide 1a (100 mg, 0.45 mmol, 1.0 mol
equiv.), NBu4I (7.5 mg, 0.023 mmol, 5 mol%), Cs2CO3 (295 mg, 0.905 mmol, 2.0 mol equiv.), and Togni reagent (334 mg, 0.905 mmol, 2.0 mol equiv.)
were dissolved in dry dioxane (2.25 mL). The reaction vial was then sealed, and stirred at 80 °C for 2 h. The reaction mixture was then cooled to room
temperature, and dry loaded onto a silica column. Flash chromatography (silica gel, pentane to 10% EtOAc/pentane) afforded the target phenanthridine
2a as an off-white solid (87 mg, 74 %).
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (DFG) for funding this work.
Keywords: Electron catalysis • vinyl azides • phenanthridines • quinoxalinones
[1]
[2]
[3]
a) K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881-1886; S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320-
330; c) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa, H. Liu, Chem. Rev. 2016, 116, 422-518.
a) N. Hatae, E. Fujita, S. Shigenobu, S. Shimoyama, Y. Ishihara, Y. Kurata, T. Choshi, T. Nishiyama, C. Okada, S. Hibino, Bioorg. Med. Chem. Lett. 2015,
25, 2749–2752; b) L.-M. Tumir, M. R. Stojković, I.Piantanida, Beilstein J. Org. Chem. 2014, 10, 2930–2954; c) T. Ishikawa, Med. Res. Rev. 2001, 21, 61-72.
a) Y. Ramli, A. Moussaif, K. Karrouchi, E. M. Essassi, J. Che. 2014, 1-21; L. Xun, Y. Kang-hui, L. Wei-lu, X. Wen-fang, Drugs Future 2006, 31, 1-11; c) A.
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[4]
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X.-F. Wu, H. Neumann, M. Bell, Chem. Asian J. 2012, 7, 1744-1754.
T. Yang, H. Zhu, W. Yu, Org. Biomol. Chem. 2016, 14, 3376-3384.
a) B. Zhang, C. Mück-Lichtenfeld, C. G. Daniliuc, A. Studer, Angew. Chem., Int. Ed. 2013, 52, 10792-10795; b) Q. Wang, X. Dong, T. Xiao, L. Zhou, Org.
Lett. 2013, 15, 4846-4849; c) Y. Cheng, H. Jiang, Y. Zhang, S. Yu, Org. Lett. 2013, 15, 5520-5523; d) Y.-F. Wang, G. H. Lonca, M. Le Runigo, S. Chiba,
Org. Lett. 2014, 16, 4272-4275; e) H. Jiang, Y. Cheng, R. Wang, M. Zheng, Y. Zhang, S. Yu, Angew. Chem., Int. Ed. 2013, 52, 13289-13292; f) J. Rong, L.
Deng, P. Tan, C. Ni, Y. Gu, J. Hu, Angew. Chem. Int. Ed. 2016, 55, 2743-2747; g) W. Fu, M. Zhu, C. Xu, G. Zou, Z. Wang, B. Ji, J. Fluor. Chem. 2014, 168,
50-54. For a review, see h) B. Zhang, A. Studer, Chem. Soc. Rev. 2015, 44, 3505-3521.
[7]
[8]
J. Charpentier, N. Früh, A. Togni, Chem. Rev. 2015, 115, 650-682.
Other examples using vinyl azides as radical acceptors, see: a) A. Suzuki, M. Tabata, M. Ueda, Tetrahedron Lett. 1975, 2195-2198; b) S. Chiba, Chimia
2012, 66, 377-381; c) Y.-F. Wang, G. H. Lonca, S. Chiba, Angew. Chem., Int. Ed. 2014, 53, 1067-1071.
[9]
a) A. Studer, D. P. Curran, Nat. Chem. 2014, 6, 765-773; b) A. Studer, D. P. Curran, Angew. Chem. Int. Ed. 2016, 55, 58-102.
[10] M. Hartmann, Y. Li, A. Studer, Org. Biomol. Chem. 2016, 14, 206-210.
[11] The exact initiation process is not known. We currently assume that the iodide anion reacts with the Togni reagent via substitution of the carboxylate
substituent at the I(III)-atom to give an iodine(III)reagent bearing a very weak I-I-bond. Homolysis of the weak I-I-bond leads to an iodine atom, the CF3-
radical and the ortho-iodobenzoate anion.
Legends to Schemes and Tables
Figure 1. Pharmaceutically important and biologically active phenanthridines and quinoxalinones.
Scheme 1. Two distinct methods for the synthesis of trifluoromethylated phenanthridines, forming the
C-CF3 bond and the heterocycle concomitantly.
Scheme 2. Proposed mechanism for the trifluoromethylation of vinyl azides.

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Table 1. Synthesis of phenanthridines from vinyl azides[a]
Table 2. Synthesis of quinolinones from vinyl azides 4[a]
Entry for the Table of Contents
Electrons do the job! A transition-metal free radical fluoroalkylation of vinyl azides employing the
Togni reagent as a CF3 source and Bu4NI as an initiator to give phenanthridines and quinoxalin-2-ones
in moderate to good yields is reported. Cascades occur by electron-catalysis, starting materials are
readily prepared and experiments are easy to conduct.
Table 1. Synthesis of phenanthridines from vinyl azides[a]
Substrate
Time
2 h
Product(s)
CF3
Yield[b]
74%
N3
N
1
1a
2a
CF2CF3
N3
2[c]
3 h
2 h
2 h
57%
64%
66%
N
1a
2ab
CF3
N3
N
3
1b
F
2b
F
CF3
N3
N
4
1c
t-Bu
2c
t-Bu

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CF3
N3
N
5
2 h
66%
1d
2d
CF3
N3
N
F
6
2 h
69%
2ea:2eb
= 1:1
1e
2ea
F
CF3
N
F
2eb
CF3
F
N3
F
N
7
2 h
76%
1f
2f
[a] Conditions: 2.0 equiv. Togni reagent 3, 2.0. equiv. Cs2CO3, 0.05 equiv.
Bu4NI, 1,4-dioxane, 80 °C. [b] Isolated yield. [c] Pentafluoroethyl Togni
reagent (2.0 equiv.) used in place of Togni reagent.
Table 2. Synthesis of quinolinones from vinyl azides 4[a]
Substrate
Time
1 h
Product(s)
CF3
Yield[a]
51%
O
O
N3
O
N
N
1
N
4a
5a
N3
2[b]
18 h
-
-
N
4a
O
N3
N
3
4
18 h
18 h
-
-
-
4b
O
N3
N
-
4c

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CF3
O
N3
O
N
N
5
2 h
34%
N
4d
5da
i-Pr
i-Pr
CF3
5ea:5eb
= 1:1
O
N
i-Pr
N
5db
CF3
O
N3
O
N
N
N
6
7
8
9
2 h
2 h
2 h
31%
29%
39%
41%
4e
Cl
5e
CF3
O
Cl
Br
O
N3
N
N
N
4f
Br
5f
CF3
O
N3
O
N
N
N
4g
MeO
5g
MeO
CF3
O
N3
O
N
N
2 h
N
4h
n-Oct
5h
n-Oct
[a] Conditions: 2.0 equiv. Togni reagent 3, 2.0. equiv. Cs2CO3, 0.05
equiv. Bu4NI, 1,4-dioxane, 80 °C. [b] Isolated yield. [c]
Pentafluoroethyl Togni reagent (2.0 equiv.) used in place of Togni
reagent.
Figure 1:

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Scheme 1:
Scheme 2:

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