Dual C(sp3)?H Bond Functionalization of N-Heterocycles through Sequential Visible-Light Photocatalyzed Dehydrogenation/[2+2] Cycloaddition Reactions

Article abstract of DOI:10.1002/anie.201710523

Herein we describe a mild method for the dual C(sp³)?H bond functionalization of saturated nitrogen-containing heterocycles through a sequential visible-light photocatalyzed dehydrogenation/[2+2] cycloaddition procedure. As a complementary approach to the well-established use of iminium ion and α-amino radical intermediates, the elusive cyclic enamine intermediates were effectively generated by photoredox catalysis under mild conditions and efficiently captured by acetylene esters to form a wide array of bicyclic amino acid derivatives, thus enabling the simultaneous functionalization of two vicinal C(sp³)?H bonds.

Full text of DOI:10.1002/anie.201710523

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Dual C(sp3)-H Bond Functionalization of N-Heterocycles
via Visible-Light Photocatalyzed Dehydrogenation/[2+2]
Cycloaddition Sequential Reaction
Authors: Guo-Qiang Xu, Ji-Tao Xu, Zhi-Tao Feng, Hui Liang, Zhu-Yin
Wang, Yong Qin, and Peng-Fei Xu
This manuscript has been accepted after peer review and appears as an
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 published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710523
Angew. Chem. 10.1002/ange.201710523
Link to VoR: http://dx.doi.org/10.1002/anie.201710523
http://dx.doi.org/10.1002/ange.201710523

10.1002/anie.201710523
Angewandte Chemie International Edition
COMMUNICATION
Dual C(sp3)-H Bond Functionalization of N-Heterocycles via
Visible-Light Photocatalyzed Dehydrogenation/[2+2]
Cycloaddition Sequential Reaction
Guo-Qiang Xu,[a][b] Ji-Tao Xu,[a] Zhi-Tao Feng,[a] Hui Liang,[a] Zhu-Yin Wang,[a] Yong Qin [b] and Peng-
Fei Xu*[a]
Abstract: Here we describe a mild method to achieve dual C(sp3)-H
bond functionalization of saturated nitrogen-containing heterocycles
via a sequential visible-light photocatalyzed dehydrogenation/[2+2]
cycloaddition procedure. As a complementary approach to the well-
established iminium ion and α-amino radical intermediates, the
elusive cyclic enamine intermediates are effectively generated via
photoredox catalysis under mild conditions, which are efficiently
captured by acetylene ester to form a wide array of bicyclic amino
acid derivatives and realize the simultaneous functionalization of two
vicinal C(sp3)-H bonds.
catalytic dehydrogenation with [2+2] cycloaddition into a
sequential process (Scheme 1a).
The direct functionalization of C-H bonds is one of the most
challenging yet highly desirable goals in modern organic
synthesis,1 and recent developments2 of direct transformations
of ubiquitous C(sp3)-H bonds, including borylation, oxidation,
amination, arylation and alkylation, have attracted lots of
attention. However, the vast majority of examples have been
focused on the single C(sp3)-H bond functionalization, and dual
C(sp3)-H bond functionalization in a single step is still unkown.
Encouraged by our previous work which realized the dual
functionalization of both C(sp3)–H and C(sp2)–H bonds via
visible-light induced oxidation and aza-Diels–Alder reaction,3 we
planned to explore the feasibility of dual C(sp3)-H bond
functionalization. The catalytic dehydrogenation process4 has
provided a new method for activing two C(sp3)-H bonds, since
the reactive alkene intermediate generated by this process could
be utilized in a secondary reaction to forge new carbon
frameworks.5 In addition, [2+2] cycloaddition is one of the most
powerful and widely applied transformations in organic
chemistry,6 which plays a remarkable role in building strained
and unusual molecular architectures that cannot be accessed
through other pathways.7 Recently, Zhou and his co-workers
developed a unprecedented catalytic enantioselective Heck
annulation of propargylic acetates and cycloalkenes to obtain
highly strained, fused cyclobutenes.8 Based on all these factors,
we decided to tackle the aforementioned difficulty by merging
Scheme 1. Dual C(sp3)-H functionalization strategy
In recent years, visible-light photoredox catalysis9 as another
powerful technology in organic synthesis has had a profound
impact on the C-H functionalization of saturated N-heterocycles
which represent a privileged motif in pharmaceuticals and
natural products10. Although a variety of synthetically useful
iminium ion11 and α-amino radical12 intermediates had been
effectively generated by photoredox catalysis and successfully
applied to various α-functionalization of amines,13 enamines as
promising intermediates for α,β-functionalization of amines are
rarely reported (Scheme 1b). Besides the general difficulties
associated with C(sp3)-H functionalization (e.g., high bond
energy and similar reactivities), it faces greater challenges to
realize dual C-H functionalization of saturated N-heterocycles: (1)
how to generate sufficient reactive cyclic enamine intermediate
and avoid forming more stable heterocyclic aromatics14, and (2)
the well-established α-functionalization13 of iminium ions11 and α-
amino radicals12 will strongly compete with this process. Herein,
we describe a mild method to generate the highly reactive cyclic
[a]
Dr. G.-Q. Xu, J.-T. Xu, Z.-T. Feng, H. Liang, Prof. Dr. Z.-Y. Wang,
Prof. Dr. P.-F. Xu
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University
Lanzhou 730000 (P.R. China)
Fax: (+86) 931-8915557
enamine intermediate via
a
visible-light photocatalytic
dehydrogenation process, and then realize dual C(sp3)-H bond
functionalization through coupling with the traditional [2+2]
cycloaddition, thus to furnish a variety of highly strained bicyclic
amino acid derivatives which are rather elusive to obtain via
other methods (Scheme 1c).
E-mail: xupf@lzu.edu.cn
[b]
Dr. G.-Q. Xu, Prof. Dr. Y. Qin
Institute of Nanoscience and Nanotechnology,
School of Physical Science and Technology,
Lanzhou University,
We initiated this novel sequential reaction with N-
phenylpyrrolidine 1a and dimethyl acetylene dicarboxylate
(DMAD, 2a), along with a variety of photocatalysts, inorganic
bases, hydrogen acceptors and light sources. To our delight, it
Lanzhou 730000, P. R. China.
Supporting information for this article is given via a link at the end of
the document. CCDC 1568396 (3aa)
This article is protected by copyright. All rights reserved.

10.1002/anie.201710523
Angewandte Chemie International Edition
COMMUNICATION
was found that the desired [2+2] cycloaddition product 3aa was
produced in a yield of 70% when Ru(bpy)3(PF6)2, nitrobenzene
and KOAc were used in the presence of a 23-W fluorescent light
bulb after 96 h photolysis at 35 oC (entry 1 of Table 1). To
improve this result, several nitrobenzene derivatives were
evaluated (entries 2-4 of Table 1) and it turned out that the
electron-withdrawing substituents on the benzene ring of
nitrobenzene gave better results, and the highest reaction
efficiency was observed when pentafluoronitrobenzene (PFNB)
was used in this system, furnishing the desired
dehydrogenation/[2+2] cycloaddition product in 99% yield.
Control experiments demonstrated that both the light and the
hydrogen acceptor were indispensable for this transformation
(entries 5, 6 of Table 1), and both of the photocatalyst and the
inorganic base were necessary to improve the reaction
desired product 3aq in good yield. Moreover, the electronic
nature of the substituents on the pyrrolidine ring played a critical
role in the efficiency of this cycloaddition reaction, which was
consistent with the observation that product 3ar bearing an
electron-rich methyl group was obtained in 98% yield while 3as
and 3at with electron-withdrawing substituents were only
produced in moderate yields (49% and 65%, respectively).
Unfortunately, other pyrrolidine derivatives, such as N-
methylpyrrolidine, N-Boc pyrrolidine, N-phenylpyrrolidin-2-one,
didn’t furnish the corresponding product under the standard
conditions.
Table 2. Scope of dehydrogenation/[2+2] cycloaddition sequential reaction
efficiency (entries 7,
8 of Table 1). Finally, the relative
configuration of product 3aa was determined by the single-
crystal X-ray diffraction, which showed that 3aa was a syn-
configuration product.
Table 1. Optimization of the reaction conditionsa
Entry
Hydrogen acceptor
Yield (%) b
d.r.c
1
2
3
4
nitrobenzene
70
42
77
99
>20:1
>20:1
>20:1
>20:1
1-methoxy-4-nitrobenzene
1-chloro-4-nitrobenzene
PFNB
Entry
Change from entry 4
Yield (%)
5
6
7
8
No light
No PFNB
No Ru(bpy)3(PF6)2
No KOAc
0
0
24
21
/
/
>20:1
>20:1
aConditions: Reactions performed with 1a (0.1 mmol), 2a (0.3 mmol),
photocatalyst (1 mol%), hydrogen acceptor (1.5 equiv.) and KOAc (4.0 equiv.)
in DCM (2 mL) at 35 °C under nitrogen atmosphere for 96 h. bIsolated yield.
CDetermined by 1H NMR. PFNB: pentafluoronitrobenzene.
Having identified the optimal conditions for this
dehydrogenation/[2+2] cycloaddition reaction, the scope of N-
phenylpyrrolidine derivatives as the cycloaddition partner was
then examined. As shown in Table 2, this sequential
transformation had high diastereoselectivity, which was
demonstrated by the fact that only syn-diastereoisomers were
produced as the major products due to the high
diastereoselectivity of the [2+2] cycloaddition process. A range
of N-arylpyrrolidines bearing electron-donating or electron-
withdrawing substituents on the para-position of the benzene
ring were suitable substrates (3ab−3ag). Some valuable
functional groups most commonly found in drug molecules were
also compatible with this system, including trifluoromethyl, ester,
and amido groups (3ah, 3ai, 3aj). Both electron-rich and
electron-deficient substituents at the ortho- and meta-sites of the
phenyl ring were well tolerated (3ak-3ap). Besides a variety of
phenyl substituents, other aromatic group substituted substrates,
such as N-naphthylpyrrolidine, also successfully delivered the
The scope of nitrogen-containing heterocycle substrates was
further evaluated for this novel protocol. As shown in Table 2b, a
range of N-phenylpiperidine derivatives smoothly delivered the
This article is protected by copyright. All rights reserved.

10.1002/anie.201710523
Angewandte Chemie International Edition
COMMUNICATION
corresponding [2+2] cycloaddition products in moderate to
excellent yields, and only one diastereoisomer was obtained for
compound 3av-3ax due to its high stability in this configuration.
Furthermore, other nitrogen-containing heterocycles, such as
Azepane and Piperazine, were also found to be suitable
substrates (3ba, 3bb). Finally, the alkyne components were
examined in this cycloaddition protocol in Table 2c. A range of
acetylene ester substrates could be smoothly transformed into
corresponding products with good yields (3bc−3be).
Encouragingly, the unsymmetrically-substituted acetylene ester
substrate also furnished the [2+2] cycloaddition product 3bf in
57% yield.
0.016, which confirmed that the reaction was not a photo-
initiated chain process, but a photocatalyzed process. In addition,
Stern-Volmer experiments (Figure 1a) illustrated that the
2+
luminescence emission of excited-state *Ru(bpy)3
was
quenched by N-phenylpyrrolidine 1a more efficiently than
pentafluoronitrobenzene (PFNB), which indicated a reduction
quenching mechanism. Furthermore, under the standard
conditions, when the amount of the radical quencher TEMPO
was added from 1.0 equiv. to 3.0 equiv., the yield of product 3aa
was sharply decreased, suggesting that this process involved
the single electron transfer process (Figure 1b). Moreover, the
dehydrogenation product 3ay was obtained in 90% yield, which
strongly demonstrated the high efficiency of this process (Figure
1c). Additionally, the fact that the dimerization product 8 was
obtained in only 10% isolated yield in absence of DMAD,
indicated that both the iminium ions and enamine III
intermediates existed in this visible-light reaction condition
(Figure 1d). Finally, a computational experiment for this [2+2]
cycloaddition process provided three possible reaction pathways
(see supporting information). The fact that similar yields of
product 3aa were obtained from the alternative transformations
under dark conditions or with the irradiations of visible light in
Figure 1e supported the conclusion that the [2+2] cycloaddition
between the enamine intermediate and DMAD was a thermal
reaction (Path I, see Supporting Information).
Scheme 2. Application and transformation of product 3aa.
To demonstrate the applicability of this photocatalytic protocol
in organic synthesis, we carried out this reaction at 10 mmol
scale under the irradiation of four 23-W fluorescent light bulbs.
As expected, the cycloaddition product 3aa was smoothly
obtained in 97% yield based on the recovered starting material
after two visible-light irradiation experiments (Scheme 2a).
Furthermore, it was found that this versatile scaffold could be
used to construct more complex polycyclic compounds via a
Diels-Alder reaction (Scheme 2b). Under mild conditions, the
C(sp2)-H benzylation of this scaffold was accomplished via
installing a valuable 2-hydroxy-5-nitrobenzyl segment (Scheme
2c).
3.5
N-Ph-Pyrrolidine
PFNB
DMAD
3.0
2.5
2.0
1.5
1.0
Figure 2. Proposed mechanism
Based on a series of mechanistic experiments, a detailed
description of the prospective mechanism for this visible-light
photocatalyzed dehydrogenation/ [2+2] cycloaddition sequential
reaction is shown in Figure 2. It is well-known that Ru(bpy)32+ (I)
has a strong absorption cross section in the visible light range,
0
2
4
6
8
C (mM)
2+
and the exited state *Ru(bpy)3 (II) (*RuII/RuI= 0.84 V) will be
highly populated via accepting a photon from a variety of light
sources. Subsequently, this high-energy intermediate (II)
primarily undergoes a single electron transfer (SET) with the
amine substrate (1a) (EOX= 0.74 V versus SCE in CH3CN) to
initiate the first catalytic cycle and provide the highly reducing
Figure 1. Mechanistic investigations
To further confirm our hypothesis, a series of mechanistic
investigations were conducted as shown in Figure 1. First, the
quantum yield of the reaction of 1a and 2a was determined to be
+
Ru(bpy)3 (III) and the amine radical cation (IV). Given that
Ru(bpy)3+ (III) has been shown to be a potent reductant (RuII/RuI
=–1.33 V versus SCE in CH3CN), commercially available
This article is protected by copyright. All rights reserved.

10.1002/anie.201710523
Angewandte Chemie International Edition
COMMUNICATION
[3]
[4]
G.-Q. Xu, C.-G. Li, M.-Q. Liu, J. Cao, Y.-C. Luo, P.-F. Xu, Chem.
Commun. 2016, 52, 1190–1193.
nitrobenzene (VI) (the reductive potential of PFNB is -0.96 V
versus SCE in CH3CN), as an electron and hydrogen acceptor,
+
For selected reviews of dehydrogenation, see: a) G. E. Dobereiner, R. H.
Crabtree, Chem. Rev. 2010, 110, 681–703. b) J. Choi, A. H. MacArthur,
M. Brookhart, A. S. Goldman, Chem. Rev. 2011, 111, 1761–1779.
For selected examples of dehydrogenation/cycloaddition, see: a) H. Du,
W. Yuan, B. Zhao, Y. Shi, J. Am. Chem. Soc. 2007, 129, 7496–7497. b)
E. M. Stang, M. C. White, J. Am. Chem. Soc. 2011, 133, 14892–14895.
c) Y. Nakao, E. Morita, H. Idei, T. Hiyama, J. Am. Chem. Soc. 2011,
133, 3264–3267.
enables the Ru(bpy)3 (III) to back to the ground state and
produce a high activated nitrobenzene anion radical (VII). Under
the cooperation between the nitrobenzene anion radical (VII)
and weak base KOAc, the amine radical cation (IV) is effectively
transformed into the desired enamine intermediates (V). Finally,
a thermal [2+2] cycloaddition reaction between the enamine
intermediate (V) and dimethyl acetylenedicarboxylate (DMAD,
2a) successfully occurs to deliver dual C-H functionalized
product 3aa.
[5]
[6]
For selected reviews of [2+2] cycloaddition, see: a) B. Alcaide, P.
Almendros, C. Aragoncillo, Chem. Soc. Rev. 2010, 39, 783–816. b) T.
Bach, J. P. Hehn, Angew. Chem. Int. Ed. 2011, 50, 1000 –1045. Angew.
Chem. 2011, 123, 1037–1077. c) T. P. Yoon, ACS Catal. 2013, 3,
895−902. d) S. Poplata, A. Trꢀster, Y.-Q. Zou, T. Bach, Chem. Rev.
2016, 116, 9748−815.
In summary, we have developed
a novel visible-light
photocatalyzed dehydrogenation/[2+2] cycloaddition sequential
reaction to achieve dual functionalization of two C(sp3)-H bonds.
In this transformation, an array of elusive cyclic enamines were
formed under mild conditions, which opens a new way for
developing further transformations. In situ building small strained
cyclobutene skeletons on saturated N-heterocycles to furnish a
variety of complex bicyclic amino acid derivatives was
successfully realized via this sequential process.
[7]
For selected recent examples of [2+2] cycloaddition, see: a) J. M. Hoyt,
V. A. Schmidt, A. M. Tondreau, P. J. Chirik, Science 2015, 349,
960−963. b) M. A. Ischay, M. E. Anzovino, J. Du, T. P. Yoon, J. Am.
Chem. Soc. 2008, 130, 12886–12887. c) E. Kumarasamy, R.
Raghunathan, S. K. Kandappa, A. Sreenithya, S. Jockusch, R. B Sunoj,
J. Sivaguru, J. Am. Chem. Soc. 2017, 139, 655–662. d) J. Zhao, J. L.
Brosmer, Q. Tang, Z. Yang, K. N. Houk , P. L. Diaconescu , O. Kwon,
J. Am. Chem. Soc. 2017, 139, 9807–9810.
[8]
Z. Jiao, Q. Shi, J. S. Zhou, Angew. Chem. Int. Ed. 2017, 56, 14567–
14571; Angew.Chem. 2017, 129,14759–14763.
Acknowledgements
[9] For selected reviews of visible-light photoredox catalysis, see: a) J. Xuan,
W.-J. Xiao, Angew. Chem. Int. Ed. 2012, 51, 6828–6838. b) C. K. Prier,
D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013, 113, 5322–5363.
c) M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org. Chem. 2016, 81,
6898–6926. d) M. D. Kärkäs, J. A. Porco, C. R. J. Stephenson, Chem.
Rev. 2016, 116, 9683–9747.
We are grateful to the NSFC (21632003, and 21572087), the
key program of Gansu province (17ZD2GC011) and the
“111”program from the MOE of P. R. China, and Syngenta
Company for financial support.
[10] a) V. M. Dembitsky, J. Nat. Med. 2008, 62, 1–33. b) C. M. Marson, Chem.
Soc. Rev. 2011, 40, 5514–5533. c) R. D. Taylor, M. MacCoss, A. D. G.
Lawson, J. Med. Chem. 2014, 57, 5845−5859. d) E. Vitaku, D. T. Smith,
J. T. Njardarson, J. Med. Chem. 2014, 57, 10257−10274.
Keywords: C-H bond functionalization • dehydrogenation • [2+2]
cycloaddition • visible-light photocatalysis
[11] For selected examples of α-functionalization of amines via iminium ion,
see: a) A. G. Condie, J. C. Gonzꢁlez-Gꢂmez, C. R. J. Stephenson, J.
Am. Chem. Soc. 2010, 132, 1464−1465. b) D. A. DiRocco, T. Rovis, J.
Am. Chem. Soc. 2012, 134, 8094−8097. c) G. Bergonzini, C. S.
Schindler, C.-J. Wallentin, E. N. Jacobsen, C. R. J. Stephenson, Chem.
Sci. 2014, 5, 112−116.
[1]
For selected reviews of C(sp3)-H functionalization, see: a) J. A. Labinger,
J. E. Bercaw, Nature 2002, 417, 507−514. b) H. M. L. Davies, J. R.
Manning, Nature 2008, 451, 417–424. c) J. Yamaguchi, A. D.
Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2012, 51, 8960–9009.
Angew. Chem. 2012, 124, 9092–9142. d) J. Wencel-Delord, F. Glorius,
Nat. Chem. 2013, 5, 369–375. e) J. F. Hartwig, J. Am. Chem. Soc.
2016, 138, 2−24.
[12]
For selected examples of α-functionalization of amines via α-amino
radical, see: a) A. McNally, C. K. Prier, D. W. C. MacMillan, Science
2011, 334, 1114−1117. b) S. Zhu, A. Das, L. Bui, H. Zhou, D. P. Curran,
M. Rueping, J. Am. Chem. Soc. 2013, 135, 1823−1829. c) Y. Miyake, K.
Nakajima, Y. Nishibayashi, J. Am. Chem. Soc. 2012, 134, 3338−3341.
d) L. Ruiz Espelt, I. S. McPherson, E. M. Wiensch, T. P. Yoon, J. Am.
Chem. Soc. 2015, 137, 2452−2455. e) J. J. Murphy, D. Bastida, S.
Paria, M. Fagnoni, P. Melchiorre, Nature 2016, 532, 218−222.
[2] For selected excellent examples of C(sp3)-H functionalization, see: a) H.
Chen, S. Schlecht, T. C. Semple, J. F. Hartwig, Science 2000, 287,
1995–1997. b) M. S. Chen, M. C. White, Science 2010, 327, 566–571.
c) E. M. Simmons, J. F. Hartwig, Nature 2012, 483, 70-73. d) E. J. Horn,
B. R. Rosen, Y. Chen, J. Tang, K. Chen, M. D. Eastgate, P. S. Baran,
Nature 2016, 533, 77–81. e) E. T. Hennessy, T. A. Betley, Science
2013, 340, 591-595. f) A. McNally, B. Haffemayer, B. S. L. Collins, M. J.
Gaunt, Nature 2014, 510, 129–338. g) F.-L. Zhang, K. Hong, T.-J. Li, H.
Park, J.-Q. Yu, Science 2016, 351, 252-256. h) J. J. Topczewski, P. J.
Cabrera, N. I. Saper, M. S. Sanford, Nature 2016, 531, 220–224. i) M.
H. Shaw, V. W. Shurtleff, J. A. Terrett, J. D. Cuthbertson, D. W. C.
MacMillan, Science 2016, 352, 1304-1308. j) G. J. Choi, Q. Zhu, D. C.
Miller, C. J. Gu, R. R. Knowles, Nature 2016, 539, 268–271. k) J. C. K.
Chu, T. Rovis, Nature 2016, 539, 272–275.
[13] For selected reviews of α-functionalization of amines via visible-light
photocatalysis, see: a) J. W. Beatty, C. R. J. Stephenson, Acc. Chem.
Res. 2015, 48, 1474−1484. b) L. Shi, W. Xia, Chem. Soc. Rev. 2012,
41, 7687−7697.
[14] S. Kato, Y. Saga, M. Kojima, H. Fuse, S. Matsunaga, A. Fukatsu, M.
Kondo, S. Masaoka, M. Kanai, J. Am. Chem. Soc. 2017, 139,
2204−2207.
This article is protected by copyright. All rights reserved.

10.1002/anie.201710523
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
G.-Q. Xu, J.-T. Xu, Z.-T. Feng, H. Liang,
Pro. Dr. Z.-Y. Wang, Y. Qin, P.-F. Xu*
Page No. – Page No.
Dual C(Sp3)-H Bond Functionalization
of N-Heterocycles via Visible-Light
Photocatalyzed Dehydrogenation/
[2+2] Cycloaddition Sequential
Reaction
Here, we describe a novel dual C(sp3)-H bonds functionalization strategy via
merging visible-light photocatalyzed dehydrogenation and [2+2] cycloaddition
reaction into a sequential process, which provides a valuable method to install a
variety of cyclobutene scaffolds onto various saturated nitrogen-containing
heterocycles to produce a series of cyclic amino acid derivatives.
This article is protected by copyright. All rights reserved.