Radical Cascade Cyclization: Reaction of 1,6-Enynes with Aryl Radicals by Electron Catalysis

Article abstract of DOI:10.1002/ejoc.201601033

The radical cascade cyclization of various 1,6-enynes with aryl radicals by electron catalysis under metal-free reaction conditions was explored. Readily available anilines were used as radical precursors, and the reactions proceeded in the absence of any transition metal. These cascades comprise three C–C bond formations, which provide polycyclic structures with extended π-systems. The photophysical properties of some of these novel compounds were investigated, and a plausible reaction mechanism is proposed.

Full text of DOI:10.1002/ejoc.201601033

A Journal of
Accepted Article
Title: Radical Cascade Cyclization - Reaction of 1,6-Enynes with Aryl Radicals via
Electron-Catalysis
Authors: Jun Xuan; Dario Gonzalez-Abradelo; Cristian Alejandro Strassert; Con-
stantin Gabriel Daniliuc; Armido Studer
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601033
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601033
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601033
COMMUNICATION
Electron-Catalysis
Radical Cascade Cyclization – Reaction of 1,6-Enynes with Aryl
Radicals via Electron-Catalysis
Jun Xuan,[a] Dario Gonzalez-Abradelo,[b] Cristian Alejandro Strassert,[b] Constantin-Gabriel Daniliuc[a]
and Armido Studer*[a]
Abstract: Radical cascade cyclization of various 1,6-enynes with
aryl radicals via electron-catalysis under metal free reaction
conditions is presented. Readily available anilines are used as
radical precursors and reactions proceed in the absence of any
transition metal. These cascades comprise three C–C bond
towards aryl radicals.[6] Moreover, the high regioselectivity of the
initial aryl radical addition (for R2 = aryl) onto the triple bond was
also astonishing to us. Therefore, we questioned whether free
aryl radicals are really involved in these cascades and we
decided to reinvestigate such transformations by using a
formations providing polycyclic structures with an extended -system. complementary metal-free approach.
Photophysical properties of some of these novel compounds are
provided and a plausible reaction mechanism is proposed.
Herein we report cascades of aryl radicals with enynes of type
1 to give the polycyclic structures 3 in moderate to good yields.
Note that compounds 3 are regioisomers of the previously
reported derivatives 2 validating our skepticism that free aryl
radicals are involved in the photoredox process. We will show
that readily accessible aryl amines that are in situ transformed to
the corresponding diazonium salts serve as efficient aryl radical
precursors in these cascades (Scheme 1, b).[7][8] Metal-free
reaction conditions and commercially available aryl radical
precursors render our approach valuable. In addition, photo
physical properties of some of these novel conjugated π-
Cascade reactions have found to be highly valuable for the
straight forward construction of complex structures with high
efficiency and high atom economy.[1] In this context, 1,n-enynes
containing both C＝C and C≡C unsaturated moieties have
been identified as interesting starting materials for cascade
reactions, especially in the field of free radical chemistry[2] and
accordingly radical cyclizations of 1,n-enynes with carbon- and
heteroatom-centered radicals have been disclosed.[3] Despite
significant advancements along these lines, challenges still
remain. For instance, photo-induced radical cyclizations of 1,n-
enynes require the use of Ruthenium or costly Iridium
complexes as photoredox catalysts[4] or direct high energy UV
light irradiation has to be applied limiting the substrate scope in
the latter case.[5] Consequently, further development of novel
and efficient 1,n-enyne radical cascade cyclizations, especially
under metal-free reaction conditions, is still highly desirable.
In 2013, Li and co-workers reported the reaction of 1,6-enynes
1 with aryl sulfonyl chlorides as radical precursors using
photoredox catalysis to afford valuable compounds of type 2
(Scheme 1, a).[4b] Authors proposed aryl radicals as
intermediates in these cascades, which are generated by single
electron reduction of the corresponding aryl sulfonyl chlorides by
the excited Ru-photoredox catalyst followed by SO2
fragmentation. To our surprise, cascades were suggested to be
initiated by chemoselective addition of an aryl radical to the CC-
triple bond of enyne 1. This is surprising since terminal alkenes,
in particular for R3 = CO2R, are known to be very reactive
systems are reported and
a revised mechanism for the
photoredox cascade is provided.
Scheme 1.Cascade radical cyclization of 1,6-enynes (bpy = 2,2'-bipyridine,
BTF = benzotrifluoride).
1,6-Enyne 1a and p-anisidine 4a were chosen as model
substrates (Table 1). Pleasingly, using isoamyl nitrite for in situ
n
diazonium salt generation, Bu4NI as a radical initiator[8e,f,9] in
[a]
[b]
Dr. J. Xuan, Dr. C.-G. Daniliuc, Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstraße 40, 48149 Münster, Germany.
CH3CN at 70 °C for 24 h, the targeted product 3aa was obtained
in 34% isolated yield (entry 1). Encouraged by this result, the
cascade was optimized by varying initiator, solvent and reaction
time. CH3CN could be replaced by other solvents such as 1,4-
dioxane, DCE, DMF, albeit somewhat lower yields were
achieved under these conditions (Table 1, entries 2-4). The yield
of 3aa was improved to 42% upon running the cascade in
benzotrifluoride (Table 1, entry 5). Varying the radical initiator
E-mail: studer@uni-muenster.de
homepage URL(s): http://www.wwu.de/Chemie.oc/studer/
Dr. D. Gonzalez-Abradelo, Dr. C. A. Strassert
Physikalisches Institut and Center for Nanotechnology (CeNTech),
Westfälische Wilhelms-Universität
Heisenbergstraße 11, 48149 Münster, Germany.
Supporting information for this article is given via a link at the end of the
document.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601033
COMMUNICATION
revealed slightly decreased yields for NaI, KI and LiI in place of
nBu4NI (Table 1, entries 6-8). Note that the reaction proceeded
less efficiently using CuI, FeCl2 and NiCl2 as radical initiators
(Table 1, entries 9-11) and in the absence of any initiator, 3aa
was obtained in 31% yield (Table 1, entry12). Increasing the
amount of 4a and isoamyl nitrite led to a further improvement of
the yield to 56% (Table 1, entry 13), while prolonging the
reaction time did not provide a better result (Table 1, entry 14).
effect on reaction efficiency (3hb, 3ib). Importantly, this cascade
proceeds well also on heteroarene-based enynes as shown by
the successful construction of heterocycle-containing polycyclic
systems 3jb, 3kb and 3lf. As expected, the activating methyl
ester moiety can be replaced by the bulkier ethyl and tert-butyl
congeners and also the cyano group is tolerated as R3-
substituent (3mb-3ob). We also tested the diastereoselectivity of
the cyclization by installing a hydroxy group at the benzylic
position of 1. The corresponding polycyclic compounds 3pa and
Table1.Reaction optimization.[a]
[10]
3qb
were isolated in good yields with no or moderate
diastereoselectivities.
Table2.Substrate scope.[a],[b]
Entry
Initiator
Solvent
Yield[%][b]
1
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
NaI
CH3CN
1,4-dioxane
DCE
DMF
BTF
34
16
23
11
42
40
36
39
21
18
30
31
56
45
2
3
4
5
6
BTF
7
KI
BTF
8
LiI
BTF
9
CuI
BTF
10
11
12
13[c]
14[d]
FeCl2
NiCl2
--
BTF
BTF
BTF
nBu4NI
nBu4NI
BTF
BTF
[a]
Reaction conditions: 1a (0.2 mmol), 4a (0.4 mmol), isoamyl nitrite (0.5
mmol) and initiator (0.04 mmol) with solvent 2 mL was stirred at 70 oC for 24 h
[b]
under argon atmosphere.
Isolated yield. [c] After stirring for 10h, additional
0.4 mmol 4a and 0.5 mmol isoamyl nitrite were added. [d] After stirring for 24h,
additional 0.4 mmol 4a and 0.5 mmol isoamyl nitrite were added and the
reaction time was prolonged to 48h. DCE = 1,2-dichloroethane, DMF = N,N-
dimethylformamide, BTF = benzotrifluoride.
Under optimized conditions, we next probed the scope of the
cascade. As summarized in Table 2, both electron-donating and
electron-withdrawing groups are tolerated at the para-position of
the aniline, providing in the reaction with 1a the products 3ab-
3ae in moderate to good yields. The structure of 3ac was
unambiguously confirmed by X-ray diffraction analysis (see
Figure S1).[10] Ortho and meta-substituted anilines worked as
substrates albeit for the ortho-congener a lower yield resulted,
likely for steric reasons (3af, 3ag).
We next turned our attention to explore the scope with respect
to the 1,6-enyne component. Substituted aryl, heteroaryl as well
as alkyl groups are tolerated as alkyne substituents to give in the
reaction with aniline the corresponding -systems 3bb-3gb in
52-68% yield. The electronic nature of the substituents of the
arene ring tethering the ene/yne-functionalities showed little
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol + 0.6 mmol), isoamyl nitrite
(0.75 mmol + 0.75 mmol) and nBu4NI (0.06 mmol) with BTF 3 mL was stirred
at 70 oC under argon atmosphere. [b] Isolated yield.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601033
COMMUNICATION
A
plausible reaction mechanism exemplified for the
Since our chemistry, clearly comprising aryl radicals, provides
a regioisomeric product as compared to the photoredox process,
it can be concluded that free aryl radicals are not generated in
the previously reported visible light-induced cyclizations of 1,6-
enynes with arylsulfonyl chlorides.[4b] To explain the formation of
regioisomeric product 2, a revised mechanism is suggested in
Scheme 3. The aryl sulfonyl radical G, which is formed via single
electron reduction of arylsulfonyl chloride with the excited RuII
species,[13] adds to the terminal alkene of 1 to generate the
tertiary alkyl radical H. 5-exo-cyclization leads to vinyl radical I
that further reacts via 1,5-aryl migration and subsequent SO2
fragmentation to the primary alkyl radical J.[14] Cyclization onto
the arene gives cyclohexadienyl radical K which is oxidized by
the Ru(III)-complex providing a cyclohexadienyl cation thereby
regenerating the Ru(II)-catalyst. Deprotonation finally affords the
isolated product 2.
construction of 3aa is depicted in Scheme 2. The p-anisidine is
first transferred to the corresponding diazonium salt A with
isoamyl nitrite. Single electron reduction of A with TBAI
generates aryl radical B in the initiation step.[8e] Chemoselective
addition of radical B to the terminal activated alkene provides
the tertiary alkyl radical C, which undergoes 5-exo-cyclization to
vinyl radical D. Radical D adds to the arene to generate
cyclohexadienyl radical E which in turn gets deprotonated[11] by
the alcoholate derived from isoamyl nitrite to the arene radical
anion F. F is eventually oxidized to give final product 3aa
formally liberating an electron to complete the catalytic cycle.[12]
The determination of the photophysical properties of species
3aa, 3ab, 3ad, 3gb and 3kb served as a first approach to the
comprehension of the fluorescent characteristics of the family of
compounds. Some of the techniques used involved absorption
spectroscopy, determination of photoluminescence quantum
yields as well as fluorescence lifetimes, excitation and emission
spectra in degassed solutions at room temperature (the results
can be found in the ESI). A summary of the photophysical data
is listed in Table 3. Emission spectra were in all cases broad and
unstructured as expected for excited states with a sizeable
charge-transfer contribution. Small shifts of the fluorescence to
the red were favoured by a π-donor substituent in the R3 position.
Compound 3kb displayed the most energetic transition due to
the increase of the energy of the LUMO caused by the
thiophene ring. Fluorescence lifetimes decreased from 3ab to
3aa and 3ad which indicated a small heavy atom effect.
Fluorescence quantum yields were low because of fast
radiationless deactivation processes.
Scheme 2. Suggested mechanism of the electron-catalyzed cascade
cyclization.
Table 3. Summary of photophysical data.
3ab
3aa
3ad
3gb
3kb
λabs [nm]
324
328
326
321
7.8
317
7.6
ε [L·mol-1·cm-1]/103
λem [nm]
21.8
21.3
23.8
438
4.03
440
1.04
440
0.34
391
1.43
423
6.77
τF (± 0.05) [ns]
ΦF (± 0.005)
0.018
0.015
0.010
0.015
0.004
In summary, we have developed a cascade radical cyclization
of 1,6-enynes by using commercially available aryl amines as
n
radical precursors and Bu4NI as a chain initiator. Aryl radicals
are generated by in situ formation of aryl diazonium salts with
commercial isoamyl nitrite and subsequent one-electron
reduction. The novel method allows accessing a broad range of
polycyclic compounds in moderate to good yields. Reactions are
experimentally easy to conduct by just mixing and stirring of all
components. Transition-metals are not required to run these
transformations and cascades proceed via electron-catalysis.
Scheme 3. Revised mechanism for the reported visible light-induced
cyclization of 1,6-enynes with arylsulfonyl chlorides (ref. 4b).
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601033
COMMUNICATION
[4]
[5]
a) J. W. Tucker, J. D. Nguyen, J. M. R. Narayanam, S. W. Krabbe, C. R.
J. Stephenson, Chem. Commun. 2010, 46, 4985-4987; b) G.-B. Deng,
Z.-Q. Wang, J.-D. Xia, P.-C. Qian, R.-J. Song, M. Hu, L.-B. Gong, J.-H.
Li, Angew. Chem. 2013, 125, 1575-1578; Angew. Chem. Int. Ed. 2013,
52, 1535-1538; c) Y. Li, B. Liu, R.-J. Song, Q.-A. Wang, J.-H. Li, Adv.
Synth. Catal. 2016, 358, 1219-1228.
Acknowledgements
This work was supported by the Alexander von Humboldt
Foundation (postdoctoral fellowship to J.X. and D.G.). A.S.
thanks the ERC (ERC Advanced Grant agreement No. 692640)
for financial support. We thank Dirk Leifert for helpful
discussions.
a) I. V. Alabugin, S. V.Kovalenko, J. Am. Chem. Soc. 2002, 124, 9052-
9053; b) M. Schmittel, G. Viola, F. DalìAcqua, G.Morbach, Chem.
Commun. 2003, 646-647; c) M. Schmittel, A. A. Mahajan, G. Bucher, J.
Am. Chem. Soc. 2005, 127, 5324-5325; d) M. Schmittel, C. Vavilala, J.
Org. Chem. 2005, 70, 4865-4868; e) G. Bucher, A. A. Mahajan, M.
Schmittel, J. Org. Chem. 2008, 73, 8815-8828.
Keywords: radical cyclization • metal free • electron catalysis •
1,6-enynes • polycyclic compounds
[6]
[7]
a) M. Heinrich, Chem. Eur. J. 2009, 15, 820-833; b) S. Kindt, M. R.
Heinrich, Synthesis, 2016, 48, 1597-1606.
[1]
For selected reviews, see: a) K. C. Nicolaou, D. J. Edmonds, P. G.
Bulger, Angew. Chem. 2006, 118, 7292-7344; Angew. Chem. Int. Ed.
2006, 45, 7134-7186; b) C. Grondal, M. Jeanty, D. Enders, Nat. Chem.
2010, 2, 167-178; c) L.-Q. Lu, J.-R. Chen, W.-J. Xiao, Acc. Chem. Res.
2012, 45, 1278-1293; d) C. M. R. Volla, I. Atodiresei, M. Rueping,
Chem. Rev. 2014, 114, 2390-2431; e) Y. Wang, H. Lu, P.-F. Xu, Acc.
Chem. Res. 2015, 48, 1832-1844.
For reviews, a) F. Mo, G. Dong, Y. Zhang, J. Wang, Org. Biomol. Chem.
2013, 11, 1582-1593; b) D. P. Hari, B. König, Angew. Chem. 2013, 125,
4832-4842; Angew. Chem. Int. Ed. 2013, 52, 4734-4743; c) L. He, G.
Qiu, Y. Gao, J. Wu, Org. Biomol. Chem. 2014, 12, 6965-6971.
For selected papers, a) D. Qiu, H. Meng, L. Jin, S. Wang, S. Tang, X.
Wang, F. Mo, Y. Zhang, J. Wang, Angew. Chem. 2013, 125, 11795-
11798; Angew. Chem. Int. Ed. 2013, 52, 11581-11584; b) X. Wang, Y.
Xu, F. Mo, G. Ji, D. Qiu, J. Feng, Y. Ye, S. Zhang, Y. Zhang, J. Wang, J.
Am. Chem. Soc. 2013, 135, 10330-10333; c) F. P. Crisóstomo, T.
Martín, R. Carrillo, Angew. Chem. 2014, 126, 2213-2217; Angew.
Chem. Int. Ed. 2014, 53, 2181-2185; d) M. Hartmann, A. Studer, Angew.
Chem. 2014, 126, 8319-8322; Angew. Chem. Int. Ed. 2014, 53, 8180-
8183; e) M. Hartmann, C. G. Daniliuc, A. Studer, Chem. Commun.
2015, 51, 3121-3123; f) H. Zang, J.-G. Sun, X. Dong, P. Li, B. Zhang,
Adv. Synth. Catal. 2016, 358, 1746-1752.
[8]
[2]
[3]
For selected reviews, see: a) L. Yet, Chem. Rev. 2000, 100, 2963-3007;
b) C. Aubert, L. Fensterbank, V. Gandon, M. Malacria, Top. Organomet.
Chem. 2006, 19, 259-294; c) P. A. Inglesby, P. A. Evans, Chem. Soc.
Rev. 2010, 39, 2791-2805; d) F. Lopez, J. L. Mascarenas, Beilstein J.
Org. Chem. 2011, 7, 1075-1094; e) U. Wille, Chem. Rev. 2013, 113,
813-853.
For selected examples, see: a) D. L. J. Clive, S. R. Magnuson, H. W.
Manning, D. L. Mayhew, J. Org. Chem. 1996, 61, 2095-2108; b) M. A.
Leeuwenburgh, R. E. J. N. Litjens, J. D. C. Codée, H. S. Overkleeft, G.
A. van der Marel, J. H. van Boom, Org. Lett. 2000, 2, 1275-1277; c) M.
Chen, Y. Weng, M. Guo, H. Zhang, A. Lei, Angew. Chem. 2008, 120,
2311-2314; Angew. Chem. Int. Ed. 2008, 47, 2279-2282; d) S. Mondal,
R. K. Mohamed, M. Manoharan, H. Phan, I. V. Alabugin, Org. Lett.
2013, 15, 5650-5653; e) J.-Y. Luo, H.-L. Hua, Z.-S. Chen, Z.-Z. Zhou,
Y.-F. Yang, P.-X. Zhou, Y.-T. He, X.-Y. Liu, Y.-M. Liang, Chem.
Commun. 2014, 50, 1564-1566; f) Y. Liu, J.-L. Zhang, R.-J. Song, P.-C.
Qian, J.-H. Li, Angew. Chem. 2014, 126, 9163-9166; Angew. Chem. Int.
Ed. 2014, 53, 9017-9020; g) S. Mondal, B. Gold, R. Mohamed, H. Phan,
I. V. Alabugin, J. Org. Chem. 2014, 79, 7491-7501; h) W. Kong, N.
Fuentes, A. García-Domínguez, E. Merino, C. Nevado, Angew. Chem.
2015, 127, 2517-2521; Angew. Chem. Int. Ed. 2015, 54, 2487-2491; i)
N. Fuentes, W. Q. Kong, L. Fernandez-Sanchez, E. Merino, C. Nevado,
J. Am. Chem. Soc. 2015, 137, 964-973; j) M. Hu, R.-J. Song, J.-H. Li,
Angew. Chem. 2015, 127, 618-622; Angew. Chem. Int. Ed. 2015, 54,
608-612; k) J.-K. Qiu, B. Jiang, Y.-L. Zhu, W.-J. Hao, D.-C. Wang, J.
Sun, P. Wei, S.-J. Tu, G.-G. Li, J. Am. Chem. Soc. 2015, 137, 8928-
8931; l) Y.-L. Zhu, B. Jiang, W.-J. Hao, J.-K. Qiu, J. Sun, D.-C. Wang, P.
Wei, A.-F.Wang, G.-G. Li, S.-J. Tu, Org. Lett. 2015, 17, 6078-6081; m)
Y. Zhao, Y. Hu, H. Wang, X. Li, B. Wan, J. Org. Chem. 2016, 81, 4412-
4420; n) Y.-L. Zhu, B. Jiang, W.-J. Hao, A.-F. Wang, J.-K. Qiu, P. Wei,
D.-C. Wang, G. Li, S.-J. Tu, Chem. Commun. 2016, 52, 1907-1910.
[9]
a) P. Finkbeiner, B. J. Nachtsheim, Synthesis 2013, 979-999; b) X.-F.
Wu, J.-L. Gong, X. Qi, Org. Biomol. Chem. 2014, 12, 5807-5817.
[10] CCDC 1495853 (3ac) and CCDC 1495854 (3qb, major isomer) contain
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre.
[11] A. Studer, D. P. Curran, Angew. Chem. 2011, 123, 5122 -5127; Angew.
Chem. Int. Ed. 2011, 50, 5018-5022.
[12] a) A. Studer, D. P. Curran, Nat. Chem. 2014, 6, 765-773; b) A. Studer,
D. P. Curran, Angew. Chem. 2016, 128, 58-106; Angew. Chem. Int. Ed.
2016, 55, 58-102.
[13] a) C.-J. Wallentin, J. D. Nguyen, P. Finkbeiner, C. R. J. Stephenson, J.
Am. Chem. Soc. 2012, 134, 8875-8884; b) H. Jiang, X. Chen, Y. Zhang,
S. Yu, Adv. Synth. Catal. 2013, 355, 809-813.
[14] a) A. Studer, M. Bossart, Tetrahedron 2001, 57, 9649-9667; b) T. J.
Snape, Chem. Soc. Rev. 2008, 37, 2452-2458.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601033
COMMUNICATION
COMMUNICATION
Jun Xuan, Dario Gonzalez-Abradelo,
Cristian Alejandro Strassert, Constantin-
Gabriel Daniliuc, Armido Studer*
Page No. – Page No.
Radical Cascade Cyclization –
Reaction of 1,6-Enyneswith Aryl
Radicals via Electron-Catalysis
Mix and stir! Radical cascade cyclization of 1,6-enynes with aryl amines via
electron-catalysis to give -systems is described. Reactions proceed in the absence
of any transition metal and commercially available anilines act as aryl radical
precursors.
This article is protected by copyright. All rights reserved