Metal-free Photocatalytic Intermolecular anti-Markovnikov Hydroamination of Unactivated Alkenes

Article abstract of DOI:10.1002/ejoc.202100049

The development of photocatalytic intermolecular hydroamination reaction between N-aminated dihydropyridines and unactivated alkenes is reported. Metal-free co-catalysts, rhodamine 6G and thiophenol, in presence of visible light are used to initiate the process. The transformation shows a broad substrate scope, both alkenes and amidyl radical can act as coupling partners. The radical strategy provides excellent anti-Markovnikov selectivity and regioselectivity in diene substrates.

Full text of DOI:10.1002/ejoc.202100049

Communications
doi.org/10.1002/ejoc.202100049
Metal-free Photocatalytic Intermolecular anti-Markovnikov
Hydroamination of Unactivated Alkenes
Gaoyuan Zhao+,[a, b] Juncheng Li+,[a] and Ting Wang*[a]
reported by Sanford,[16] Lee,[17] Studer,[18] MacMillan,[19] Yu,[20]
The development of photocatalytic intermolecular hydroamina-
Luo,[21] and Leonori[22] (Scheme 1). These methodologies have
tion reaction between N-aminated dihydropyridines and unac-
been leading broad synthetic application of amidyl radicals,
constructing CÀ N bonds, and preparing N-heterocycles.
tivated alkenes is reported. Metal-free co-catalysts, rhodamine
6G and thiophenol, in presence of visible light are used to
initiate the process. The transformation shows a broad substrate
scope, both alkenes and amidyl radical can act as coupling
partners. The radical strategy provides excellent anti-Markovni-
kov selectivity and regioselectivity in diene substrates.
The direct hydroamination reaction of unactivated alkenes
is one of the most effective approaches for the formation of
valuable nitrogen building blocks. As a result, tremendous
efforts have been made in the synthetic community on this
CÀ N bond formation by using organometallic agents as
reagents or catalysts.[23–27] In 2008, Studer reported thiol-
catalyzed hydroamination of olefins where N-aminated dihydro-
pyridines were used as amidyl radical precursors.[28] More
recently, Knowles reported an intermolecular hydroamination
of unactivated alkenes by [Ir] catalyst and thiol catalyst upon
visible-light-irradiation.[29] Continuing our interest in organic
photoredox catalysis,[30] we herein reported our application of
the N-aminated dihydropyridines to the metal-free photo-
catalytic intermolecular hydroamination reactions.
Introduction
Nitrogen-containing structural motif is prevalent in organic
compounds, such as pharmaceuticals, agrochemicals, and
modern materials.[1] Therefore, new synthetic methods towards
CÀ N bond formation have been always attractive for the
synthetic community. Comparing to the well-studied nucleo-
philic N-species, N-centered radicals would potentially offer
unique synthetic opportunities.[2–4] For example, amidyl radicals
represent a very useful class of reactive species with potentially
broad applications in the construction of CÀ N bonds and
preparation of N-containing molecules.[5–11] Ingold’s pioneering
works[5] suggested that amidyl radicals display remarkably high
electrophilic character, which gives the radical species an
umpolung reactivity comparable to the typical nucleophilic
character of N-species in classic polar reaction modes.[12] The
development of N-centered radical reaction has been limited by
the harsh requirement of the radical generation, commonly
involving hazardous radical initiators, elevated temperature, or
high energy UV irradiation. However, mild and efficient
generation of N-radicals has been achieved by visible light
photoredox catalysis recently.[13] Particularly, amidyl radicals
have been achieved by a variety of elegant designs. Besides the
challenging direct access to amidyl radical from amides by
Knowles[14] and Rovis,[15] a series of functionalized amide
precursors for the generation of amidyl radical has been
We initiated our studies by examining the hydroamination
reaction between cyclohexene 1 and N-radical precursor 2
(Table 1). A series of organic photocatalysts were carefully
investigated (entries 1–8) under blue light-emitting diode (LED)
irradiation. Among them, 9-mesityl-10-methylacridinium salts (A
and B), 4-MeÀ TPT (C), and rhodamine 6G could successfully
[a] Dr. G. Zhao,+ J. Li,+ Prof. T. Wang
Department of Chemistry, University at Albany,
State University of New York
1400 Washington Avenue, Albany, New York 12222, USA
E-mail: twang3@albany.edu
www.albany.edu/twanglab
[b] Dr. G. Zhao+
Department of Chemistry, SUNY Stony Brook
100 Nicolls Road, Stony Brook, NY 11790, USA
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100049
Scheme 1. Functionalized amides as amidyl radical precursor.
Part of the “YourJOC Talents” Special Collection.
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Table 1. Optimization Studies of the hydroamination[a]
promote the hydroamination reaction in useful yields (en-
tries 1–4, 53%, 50%, 58%, and 65% respectively). On the other
hand, riboflavin, eosin Y, rose Bengal were only able to catalyze
the reaction inefficiently (entries 5–7). Methylene Blue is found
not effective at all in this reaction (entry 8). Screening different
thiols (aliphatic thiol, substituted phenyl thiol, sterically hin-
dered thiols) has shown that rhodamine 6G and PhSH co-
catalysts provided the best outcome (entries 4, 9–12), providing
65% isolated yield of the hydroamination product 3. In
addition, CH2Cl2 was found to be the optimal solvent after
careful screening of various solvents (CH2Cl2, THF, MeCN,
Toluene, DMSO, and ClCH2CH2Cl). Control experiments (en-
tries 13–16) have verified that photocatalyst, PhSH, and light
irradiation are necessary to keep the reaction efficiency. While
light irradiation is essential for the transformation (entry 16),
reactions without photocatalyst or PhSH (entries 13 and 14)
were able to deliver the desired product in low yields,
presumably due to non-negligible absorption of light by the N-
radical precursor 2. In addition, it is worth noting that although
blue-LEDs, comparing with white LEDs and green LEDs,
delivered the best outcome with rhodamine 6G and PhSH, we
can not rule out the possibilities that the inefficiency of other
catalysts is due to the mismatch between their absorption
spectra and the emission spectrum of blue LEDs.
Entry
Catalyst
Thiol
Yield[b] [%]
1
2
3
4
5
6
7
8
A
B
PhSH
PhSH
PhSH
PhSH
PhSH
PhSH
PhSH
PhSH
53
50
58
4-MeÀ TPT (C)
rhodamine 6G
riboflavin
eosin Y
rose bengal
methylene blue
65(68[d]
)
27
25
10
0
9
rhodamine 6G
54
10
rhodamine 6G
61
11
12
rhodamine 6G
rhodamine 6G
44
47
13
14
rhodamine 6G
–
–
–
28
25
7
PhSH
–
PhSH
15
16[c]
rhodamine 6G
0
With the optimal reaction condition in hand, we next
evaluated the scope of the photocatalytic hydroamination
reaction. Scheme 2 summarized experiments probing the scope
of olefins that can accept N-radical. In addition to cyclohexene,
a series of cycloalkenes could react with N-aminated dihydro-
pyridines to generate Boc-protected amine (Scheme 2, 3–7,
57%–72%). We were pleased to find that mono-substituted
alkene, 1,1-disubstituted, 1,2-disubstituted alkene, tri-substi-
tuted, and tetra-substituted alkene substrates all worked well
by the procedure, providing the corresponding hydroamination
[a] Reactions conducted by irradiating 1 (0.6 mmol), 2 (0.2 mmol), PhSH
(5 mol%) and photocatalyst (2 mol%) in CH2Cl2 (1 mL) with two 12 W,
450 nm light-emitting diode (LED) flood lamps for 3 h. [b] Isolated yield. [c]
Reaction conducted in the dark. [d] Yield determined by 1H NMR with
mesitylene as a quantitative internal standard.
Gaoyuan Zhao received his B. Sc. in chemistry
from Lanzhou University in 2011 and he
pursued his Ph.D. studies at Lanzhou Univer-
sity under the supervision of Prof. Xuegong
She (2011–2016). After obtaining his Ph.D.
degree in 2016, he joined Prof. Ting Wang’s
group as a postdoctoral fellow at the Univer-
sity at Albany-SUNY (2016–2019). In 2019, he
joined Prof. Ming-yu Ngai’s group as a post-
doctoral fellow at Stony Brook University.
Currently, his research interests mainly focus
on the development of new methods to
functionalize carbohydrates.
Ting Wang graduated from Tianjin University
in Tianjin, China, where he did undergraduate
research in the laboratory of Prof. John Reiner.
In the fall of 2005, he joined Prof. Craig
Forsyth’s group for graduate studies in natural
product synthesis and earned his Ph.D. from
the Ohio State University in 2011. For his
postdoctoral work, Ting pursued studies in
the field of peptide and protein synthesis,
working with Prof. Samuel Danishefsky at
Memorial Sloan-Kettering Cancer Center. Ting
began as an Assistant Professor in the Depart-
ment of Chemistry at SUNY-Albany in 2015.
The research in the group is to explore new
synthetic opportunities through visible-light
photocatalysis, including designing new pho-
tocatalysts, understanding their unique photo-
activities, and developing novel synthetic
strategies. The newly developed synthetic
strategies will be further applied in the syn-
thesis of biologically active small molecules,
peptides, and carbohydrates.
Juncheng Li graduated from Southern Univer-
sity of Science and Technology in Shenzhen,
China. His undergraduate research included
trifluoromethylsulfation, glycosylation, and
asymmetric addition with the ligand of chiral
diene. In the fall of 2018, he joined Prof. Ting
Wang’s group for graduate studies at SUNY-
Albany. His research focuses on the develop-
ment of new photocatalysts and their applica-
tions in organic synthesis.
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Scheme 2. Scope of alkenes.
products in moderate to good yields (Scheme 2, 8–15, 54%–
73%). Moreover, this radical hydroamination process was
compatible with a variety of functional groups, such as silane,
silyl ether, unprotected alcohol, acetonides, hemiaminol, and
tertiary amide (Scheme 2, 16–20). In all cases, high anti-
Markovnikov regioselectivity was observed, which was consis-
tent with the proposed radical reaction process.
We next focused our attention on testing the scope of the
N-radicals in the coupling process (Scheme 3). Aromatic amidyl
radicals, bearing alkyl substitution, halogen substitution, and
alkoxy substitution, worked well with cyclohexene in this
transformation (Scheme 3, 21–27, 55%–78%). Particularly,
fluoro-substituted substrate provided a slightly better yield
(Scheme 3, 25, 78%). In addition, aliphatic amidyl radicals were
able to deliver the corresponding coupling products (Scheme 3,
28–30, 61%–67%). Moreover, the photocatalytic method could
also be useful to generate amines bearing common protecting
groups (Scheme 3, 31–33) and functionalized amide in complex
a molecular setting (Scheme 3, 34).
Encouraged by the success of this visible-light-driven hydro-
amination of unactivated alkenes, we next questioned that if
this radical process could differentiate different kinds of alkene
partners. Mechanistically, after the amidyl radical reacted
alkenes, the resulting carbon radical should be more stable on a
more alkyl-substituted carbon. Therefore, it might be possible
that the hydroamination reaction would favor the more
substituted alkene coupling partner. Gladly, the idea was
validated by several regioselective hydroamination reactions
(Scheme 4a). In all examples, the amidyl radicals reacted with
the tri-substituted alkene motif in the presence of mono-
substituted one, affording masked secondary amine in moder-
ate yields (36, 50%; 38, 50%; 41, 47%). We then applied the
methodology to a synthesis of pyrrolizidine 5-5-6 tricycles. The
synthesis of the heterocycles began with photocatalytic hydro-
amination between N-radical precursor 2 and 1,5-cycloocta-
Scheme 3. Scope of N-radical coupling partner.
diene, providing 43 in 57% yield. A ROM strategy by using
Hoveyda-Grubbs 2G catalyst were employed to synthesize 44,
which was then cyclized to 5-5-6 tricycles 45 and 46 by treating
with Lewis acid Sn(OTf)2 (Scheme 4b).[31]
A plausible mechanism for the reaction is outlined in
Scheme 5. According to the Stern-Volmer emission quenching
studies (Supporting Information), we propose that photoexcita-
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Scheme 4. Regioselective hydroamination and synthetic application.
tion of catalyst PC afforded an oxidizing state (PC*)[32] that can
oxidize N-aminated dihydropyridine (2), generating the amino
*
À
radical cation 47 and one electron reduced photocatalyst PC .
The N-radical 48, afforded through fragmentation of 47, would
couple the alkene 50 with anti-Markovnikov selectivity. The
resulting alkyl radical 51 then abstracted a hydrogen atom from
PhSH to afford the hydroamination product 54 and generate
*
thiyl radical PhS 53 which would quickly recombine to disulfide
*
À
PhSSPh 55. PhSSPh 55 could be redox-coupled with PC to
*
À
regenerate photocatalyst and afford PhSSPh 56 which would
*
then generate PhS and PhSÀ . The resulting PhSÀ would
facilitate the proton transfer step in forming 49 and reproduce
PhSH. Although we can not rule out the possibilities of chain
reaction in the process, the light on/off experiments have
shown that continuous light irradiation is necessary for the
reaction to reach complete (Scheme S1 in the Supporting
Information). The quantum yield for this reaction is 0.2203
(Supporting Information).
In summary, we have reported a metal-free intermolecular
hydroamination reaction induced by visible light. These reac-
tions show great generality of a variety of N-radicals and
alkenes, providing direct access to various masked amines with
excellent regio-selectivity. Applications of this hydroamination
reaction in more complicated molecular settings are ongoing in
our laboratory.
Scheme 5. Proposed mechanism.
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[15] a) D. Chen, J. C. K. Chu, T. Rovis, J. Am. Chem. Soc. 2017, 139, 13897;
Acknowledgements
b) J. C. K. Chu, T. Rovis, Nature 2016, 539, 272.
[16] L. J. Allen, P. J. Cabrera, M. Lee, M. S. Sanford, J. Am. Chem. Soc. 2014,
We are grateful to the University at Albany, State University of
New York, for financial support. Support from National Science
Foundation (MRI 1726724) was acknowledged. We thank Dr.
Jason Seeley (SUNY-Albany) for his assistance and helpful
discussion about the quantum yield determination experiment.
136, 5607.
[17] H. Kim, T. Kim, D. G. Lee, S. W. Roh, C. Lee, Chem. Commun. 2014, 50,
9273.
[18] a) T. W. Greulich, D. G. Daniliuc, A. Studer, Org. Lett. 2015, 17, 254; b) H.
Jiang, A. Studer, Chem. Eur. J. 2019, 25, 7105.
[19] G. Cecere, C. M. Konig, J. L. Alleva, D. W. C. MacMillan, J. Am. Chem. Soc.
2013, 135, 11521.
[20] a) Q. Qin, S. Yu, Org. Lett. 2014, 16, 3504; b) X. An, Y. Jiao, H. Zhang, Y.
Gao, S. Yu, Org. Lett. 2018, 20, 401; c) H. Chen, L. Guo, S. Yu, Org. Lett.
2018, 20, 6255; d) X. An, H. Zhang, Q. Xu, L. Yu, S. Yu, Chin. J. Chem.
2018, 36, 1147; e) X. An, S. Yu, Synthesis 2018, 50, 3387; f) Q. Qin, Y. Han,
Y. Jiao, Y. He, S. Yu, Org. Lett. 2017, 19, 2909.
[21] L. Song, L. Zhang, S. Luo, J.-P. Cheng, Chem. Eur. J. 2014, 20, 14231.
[22] a) J. Davies, T. D. Svejstrup, D. Fernandez Reina, N. S. Sheikh, D. Leonori,
J. Am. Chem. Soc. 2016, 138, 8092; b) D. Fernandez Reina, E. M. Duncey,
S. P. Morcillo, T. D. Svejstrup, M. V. Popescu, J. Douglas, N. S. Sheikh, D.
Leonori, Eur. J. Org. Chem. 2017, 2108; c) S. P. Morcillo, E. D. Dauncey,
J. H. Kim, J. J. Douglas, N. S. Sheikh, D. Leonori, Angew. Chem. Int. Ed.
2018, 57, 12945.
[23] E. Bernoud, C. Lepori, M. Mellah, E. Schulz, J. Hannedouche, Catal. Sci.
Technol. 2015, 5, 2017.
[24] T. E. Muller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev. 2008,
108, 3795.
[25] J. Hannedouche, E. Schulz, Chem. Eur. J. 2013, 19, 4972.
[26] W. Li, X. Zhang, A. Reznichenko, A. Nawara-Hultzsch, K. Hultzsch, in
Stereoselective Formation of Amines, Springer Berlin Heidelberg, 2014,
pp. 191–260.
[27] N. Nishina, Y. Yamamoto, in Hydrofunctionalization, (Eds.: V. P. Ananikov,
M. Tanaka), Top. Organomet. Chem., Springer Berlin Heidelberg, 2013,
vol. 43, pp. 115–143.
[28] J. Guin, R. Frohlich, A. Studer, Angew. Chem. Int. Ed. 2008, 47, 779.
[29] a) Q. Zhu, D. E. Graff, R. R. Knowles, J. Am. Chem. Soc. 2018, 140, 741;
b) A. J. Musacchio, B. C. Lainhart, X. Zhang, S. G. Naguib, T. C. Sherwood,
R. R. Knowles, Science 2017, 355, 727.
[30] a) K. Wu, L. Wang, S. Colon-Rodriguez, G. Flechsig, T. Wang, Angew.
Chem. Int. Ed. 2019, 58, 1774; b) S. Kaur, G. Zhao, E. Busch, T. Wang, Org.
Biomol. Chem. 2019, 17, 1955; c) K. Wu, Y. Du, Z. Wie, T. Wang, Chem.
Commun. 2018, 54, 7443; d) K. Wu, C. Fang, S. Kaur, P. Liu, T. Wang,
Synthesis 2018, 50, 2897; e) G. Zhao, T. Wang, Angew. Chem. Int. Ed.
2018, 57, 6120; f) Y. Du, Z. Wie, T. Wang, Synthesis 2018, 50, 3379; g) K.
Wu, Y. Du, T. Wang, Org. Lett. 2017, 19, 5669; h) G. Zhao, S. Kaur, T.
Wang, Org. Lett. 2017, 19, 3291.
Conflict of Interest
The authors declare no conflict of interest.
[1] M. E. Welsch, S. A. Snyder, B. R. Stockwell, Curr. Opin. Chem. Biol. 2010,
14, 347.
[2] S. Z. Zard, Chem. Soc. Rev. 2008, 37, 1603.
[3] T. Xiong, Q. Zhang, Chem. Soc. Rev. 2016, 45, 3069.
[4] S. B. Hofling, M. R. Heinrich, Synthesis-Stuttgart 2011, 173.
[5] R. Sutcliffe, D. Griller, J. Lessard, K. U. Ingold, J. Am. Chem. Soc. 1981,
103, 624.
[6] J. Cassayre, F. Gagosz, S. Z. Zard, Angew. Chem. Int. Ed. 2002, 114, 1861.
[7] J. Kemper, A. Studer, Angew. Chem. Int. Ed. 2005, 44, 4914.
[8] S. Zhuang, K. Liu, C. Li, J. Org. Chem. 2011, 76, 8100.
[9] W. Kong, N. Fuentes, A. Garcia-Dominguez, E. Merino, C. Nevado, Angew.
Chem. Int. Ed. 2015, 54, 2487.
[10] H. C. Xu, J. M. Campbell, K. D. Moeller, J. Org. Chem. 2014, 79, 379.
[11] N. J. Race, A. Faulkner, M. H. Shaw, J. F. Bower, Chem. Sci. 2016, 7, 1508.
[12] N. J. Gesmundo, J. M. Grandjean, D. A. Nicewicz, Org. Lett. 2015, 17,
1316.
[13] For recent reviews, see: a) C. K. Prier, D. A. Rankic, D. W. MacMillan,
Chem. Rev. 2013, 113, 5322; b) M. N. Hoplinson, B. Sahoo, J. L. Li, F.
Glorius, Chem. Eur. J. 2014, 20, 3874; c) M. D. Karkas, J. A. Porco, Jr., C. R.
Stephenson, Chem. Rev. 2016, 116, 9683; d) J. Xuan, W.-J. Xiao, Angew.
Chem. Int. Ed. 2012, 51, 6828; e) T. P. Yoon, ACS Catal. 2013, 3, 895;
f) D. A. Nicewicz, T. M. Nguyen, ACS Catal. 2014, 4, 355; g) S. Fukuzumi,
K. Ohkubo, Org. Biomol. Chem. 2014, 12, 6059; h) D. P. Hari, B. König,
Chem. Commun. 2014, 50, 6688; i) D. A. Nicewicz, N. A. Romero, Chem.
Rev. 2016, 116, 10075; j) J.-R. Chen, X.-Q. Hu, L.-Q. Lu, W.-J. Xiao, Chem.
Soc. Rev. 2016, 45, 2044; k) P. Wang, Q. Zhao, H. Qian, W.-J. Xiao, J.-R.
Chen, Green Synth. Catal. 2020, 1, 42; l) X. Y. Yu, Q. Q. Zhao, J. Chen,
W. J. Xiao, J. R. Chen, Acc. Chem. Res. 2020, 53, 1066; m) L. Xiao, J. Li, T.
Wang, Acta Chim. Sin. 2019, 88, 841; n) H. Jiang, A. Studer, Chem. Soc.
Rev. 2020, 49, 1790; o) E. C. Gentry, R. R. Knowles, Acc. Chem. Res. 2016,
49, 1546; p) H. Jiang, A. Studer, CCS Chem. 2019, 1, 38; q) J. Davies, S. P.
Morcillo, J. J. Douglas, D. Leonori, Chem. Eur. J. 2018, 24, 12154.
[14] a) D. C. Miller, G. J. Choi, H. S. Orbe, R. R. Knowles, J. Am. Chem. Soc.
2015, 137, 13492; b) G. J. Choi, Q. Zhu, D. C. Miller, C. J. Gu, R. R.
Knowles, Nature 2016, 539, 268; c) Q. Zhu, D. E. Graff, R. R. Knowles, J.
Am. Chem. Soc. 2018, 140, 741; d) S. T. Nguyen, Q. Zhu, R. R. Knowles,
ACS Catal. 2019, 9, 4502.
[31] M. Diaz-Gavilan, W. R. J. D. Galloway, K. M. G. O’Connell, J. T. Hodking-
son, D. R. Spring, Chem. Commun. 2010, 46, 776–778.
[32] E. Yoshioka, S. Kohtani, T. Jichu, T. Fukazawa, T. Nagai, Y. Takemoto, H.
Miyabe, Synlett 2015, 26, 265.
Manuscript received: January 17, 2021
Revised manuscript received: April 19, 2021
Accepted manuscript online: April 21, 2021
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