Catalytic Aerobic Dehydrogenatin of N-Heterocycles by N-Hydoxyphthalimide

Article abstract of DOI:10.1002/adsc.202000767

Catalytic methods for the aerobic dehydrogenation of N-heterocycles are reported. In most cases, indoles are accessed efficiently from indolines using catalytic N-hydroxyphthalimide (NHPI) as the sole additive under air. Further studies revealed an improved catalytic system of NHPI and copper for the preparation of other heteroaromatics, for example quinolines. (Figure presented.).

Full text of DOI:10.1002/adsc.202000767

Title: Catalytic Aerobic Dehydrogenation of N-Heterocycles by N-
Hydoxyphthalimide
Authors: Weidong Chen, Hao Tang, Weilin Wang, Qiang Fu, and junfei
luo
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000767
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10.1002/adsc.202000767
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalytic Aerobic Dehydrogenation of N-Heterocycles by N-
Hydoxyphthalimide
Weidong Chen,a Hao Tang,a Weilin Wanga Qiang Fub and Junfei Luo*a
a
School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, China, E-mail:
luojunfei@nbu.edu.cn
School of Pharmacy, Southwest Medical University, Luzhou, 610041, China.
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
Catalytic
methods
for
the
aerobic
system of NHPI and copper for the preparation of other
heteroaromatics, for example quinolines.
dehydrogenation of N-heterocycles are reported. In most
cases, indoles are accessed efficiently from indolines using
catalytic N-hydroxyphthalimide (NHPI) as the sole additive
under air. Further studies revealed an improved catalytic
Keywords: Aerobic dehydrogenation; N-heterocycles; N-
hydroxyphthalimide; Indolines; Quinolines
groups of Stahl and Lei. Stahl and co-workers
designed novel, bioinspired quinone-based catalytic
systems for aerobic dehydrogenation (Scheme
1B).[5m,6a] Alternatively, Lei and co-workers used
electrochemistry in the acceptorless dehydrogenation
Introduction
The aromatization of saturated heterocycles via
dehydrogenation is a fundamental process in organic
synthesis.[1] This process has proved particularly
useful for the construction of nitrogen-containing
heteroaromatics, for example, the dehydrogenation of
indolines to indoles has been used numerous times in
the total synthesis of complex organic molecules.[2]
Accessing heteroaromatics, such as indoles and
quinolines, is an important task as they are found in
various materials, natural products and bioactive
molecules.[3] For instance, indoles and quinolines are
amongst the most frequently encountered ring
systems in medicine.[4]
of
N-heterocycles
with
TEMPO
as
an
organoelectrocatalyst (Scheme 1C).[8e]
N-hydroxyphthalimide (NHPI) has found widespread
use in the radical functionalization of C–H bonds.[9] It
is particularly useful for the oxygenation of benzylic
C–H bonds.[10] This chemistry also promotes the
dehydrogenation/oxidation of alcohols (i.e. C–O
bonds) to aldehydes under mild aerobic conditions,[11]
In recent years, there have been sustained efforts to
replace traditional methods for dehydrogenation that
use stoichiometric oxidants, such as DDQ or metal
oxides (Scheme 1A), with catalytic alternatives.
Catalytic dehydrogenations can be split into two main
categories: aerobic dehydrogenation (e.g. Scheme
1B)[5,6] and acceptorless dehydrogenation (e.g.
Scheme 1C).[7,8] In aerobic dehydrogenation, O2 is the
terminal oxidant and H2O is produced as a benign
side-product. Acceptorless dehydrogenations are
redox-neutral processes that release H2. Thus, both
strategies represent ideals in terms of atom-efficiency.
There have been great developments in catalytic
aerobic dehydrogenation and catalytic acceptorless
dehydrogenation – from early reports using precious
transition metals and heterogeneous catalysts, to more
recent techniques using electrochemical synthesis and
photoredox catalysis. We have highlighted just two of
the most recent advances in this area made by the
Scheme 1. Methods for the dehydrogenation of
indolines.
1
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10.1002/adsc.202000767
Advanced Synthesis & Catalysis
but it has not been applied to the dehydrogenation of
C–C bonds. Continuing our interest in the oxidation
of heteroaromatic compounds, we questioned
whether the radical chemistry of NHPI could be used
for the dehydrogenation of saturated N-heterocycles.
In this report, we reveal a metal-free aerobic
dehydrogenation of indolines to indoles catalyzed by
N-hydroxyphthalimide (NHPI). A related NHPI/Cu
catalyst system is also described, which expands the
scope to other heterocycles, for example to gain
access to quinolines and benzofurans. The role of
NHPI is also unique - whereas benzylic C–H bonds
tend to undergo oxygenation to give C–O bonds
under aerobic NHPI catalysis, this process leads to
dehydrogenated products.
Results and Discussion
We began by investigating the dehydrogenation of
indoline 1a to indole 2a.[12] Using N-
hydroxyphthalimide (NHPI) in acetonitrile, we
initially found that a stoichiometric quantity of NHPI
was capable of promoting dehydrogenation in 2 h
(Table 1, entry 1). Further investigation revealed that
the loading of NHPI could be lowered to catalytic
amounts (20 mol %) without affecting the efficiency
of the reaction (entry 2). This reaction was also
performed on a gram-scale to demonstrate robustness
and applicability, the recovery of NHPI was 91% in
this reaction (entry 3). Decreasing the loading of
NHPI further was possible, however, longer reaction
times (16 h) were required (entry 4). This represents a
a) Unless otherwise noted, the reactions were performed using 0.2
mmol of 1 and 0.04 mmol of NHPI in 3.0 mL of MeCN. Yields
b)
are of pure isolated products. 5 mol % of Cu(OAc)2∙H2O was
c)
d)
added. The reaction was performed at 100 °C. The reaction
was performed at 120 °C
Table 1. Optimization of the catalytic aerobic
dehydrogenation of indolines to indoles.a)
Scheme 2. Scope of the catalytic aerobic dehydrogenation
of indolines to indoles.
rare case of transition metal-free aerobic
dehydrogenation
of
heterocycles.[5,6]
By
Entry
NHPI
T (°C)
Yield (%)
experimenting with both the temperature and reaction
time (entries 5-7) a respectable yield of 50% was
obtained at room temperature (entry 7), though
carrying out the reaction with 20 mol % NHPI, at
80 °C for 2 h was considered optimal for the purposes
of this investigation (entry 2). Interestingly, the rate
and yield of the process were significantly improved
when adding catalytic Cu(OAc)2∙H2O (5 mol %), to
provide an effective method at room temperature
(entry 8). The investigation of non-toxic and
relatively abundant transition metal catalysts, such as
copper, is relatively underdeveloped in this field.5
Control experiments revealed that the reaction did not
occur in the absence of NHPI (entry 9 and 10)
With an efficient dehydrogenation in hand, we
explored the versatility of this method by examining
the scope of the indoline substrate 1 (Scheme 2). The
transition metal-free conditions were applicable to a
range of electron-rich (2b-2d) and electron-deficient
(2e-2g) indolines. We have also demonstrated that, if
desired, these yields can be improved by adding
1
2
3b
4c
5
100 mol %
20 mol %
20 mol %
15 mol %
20 mol %
20 mol %
20 mol %
20 mol %
-
80
80
80
80
50
25
25
25
80
80
85
88
85
82
80
10
50
80
0
6
7c
8d
9
10d
-
trace
a)
Unless otherwise noted, the reactions were performed
using 0.2 mmol of 1a in 3.0 mL of solvent for 2 h. Yields
are of pure isolated products. NHPI N-
hydroxyphthalimide. Gram scale (7.8 mmol) reaction.
Reacted for 16 h. d) 5 mol % of Cu(OAc)2∙H2O was added.
e) The reaction was performed under N2.
=
b)
c)
2
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10.1002/adsc.202000767
Advanced Synthesis & Catalysis
catalytic amounts of Cu(OAc)2∙H2O (5 mol %, 2b, 2c,
2f, 2g). For indolines bearing strongly electron-
withdrawing groups, NHPI alone proved inefficient,
however good yields of 2h and 2i were achieved
upon addition of the copper catalyst and raising the
temperature (100-120 °C). Substitution at various
positions (C5, 2b-2i; C4, 2j-2o, C6, 2p; C7 2q) on
the 6-membered ring of the indoline were well
tolerated in this reaction. Finally, substitution at the
C–C bond that undergoes dehydrogenation (i.e.
C2/C3 of the indole product 2) had little influence on
the efficiency of the reaction (2r, 2s and 2t).
To further show the potential of this reaction in
organic synthesis, we investigated the compatibility
of other N-substituted indolines (Scheme 3). For
example, phenyl (4a) and benzyl groups (4b, 4c)
were well tolerated in the reaction. Pivaloyl and Boc
protection was also applicable, though addition of
Cu(OAc)2∙H2O (5 mol %) was required. Some other
indolines bearing removable protecting groups, such
as tosyl (4f) and acyl (4g) groups, were unsuccessful
and we only observed recovery of starting material.
Finally, free NH-indole (4h) was also prepared from
the corresponding non-protected indoline in 40%
yield. The addition of the copper catalyst gave only a
slight improvement in reaction yield in this case.
a) The reactions were performed using 0.2 mmol of indolines (5a,
6a, 7a) and 0.04 mmol of NHPI in 3.0 mL of MeCN. Yields are
of pure isolated products.
Scheme 4. Application of the catalytic aerobic
dehydrogenation of indolines in the synthesis of
biologically active molecules.
a) Unless otherwise noted, the reactions were performed using 0.2
mmol of 3 and 0.04 mmol of NHPI in 3.0 mL of MeCN. Yields
b)
are of pure isolated products. 5 mol % of Cu(OAc)2∙H2O was
added.
Scheme 3. Scope of N-substituted indolines in the catalytic
aerobic dehydrogenation to indoles.
We then used this methodology for the synthesis of
known drug targets and intermediates (Scheme 4).
For example, the benzyl-substituted indoline 5a was
dehydrogenated to give indole 5b, a precursor of the
norepinephrine and serotonin reuptake inhibitor 5c.[13]
The glycosyl substituted indoline 6a also underwent
dehydrogenation to give indole 6b, an intermediate in
the synthesis of the cancer therapeutic 6c.[14] Finally,
we were able to prepare the cyclin dependent kinase 4
(CDK4) selective inhibitor 7b from the linked
diindoline 7a.[15]
a)
Unless otherwise noted, the reactions were performed
using 0.2 mmol of 8, 0.04 mmol of NHPI, 0.01 mmol of
Cu2O and 0.2 mmol of DMAP in 2.0 mL of solvent under
O2 atmosphere for 12 h. Yields are of pure isolated
products.
Scheme 5. Scope of tetrahydroquinolines in the catalytic
aerobic dehydrogenation to quinolines.
3
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10.1002/adsc.202000767
Advanced Synthesis & Catalysis
Having
developed
an
efficient
catalytic
under air using catalytic NHPI as the sole additive.
For more challenging substrates, and to expand the
scope to other heterocycles, a catalyst system of
NHPI and copper was developed. The process
displays good functional group compatibility and can
be used in the synthesis of bioactive compounds.
Studies to delineate this unique reactivity of NHPI
are ongoing in our laboratories.
dehydrogenation of indolines, we then looked to
expand this process to incorporate other heterocycles.
Our conditions were initially insufficient when
applied to the synthesis of quinoline 9a. However,
further optimization revealed that a combination of
NHPI (20 mol %), Cu2O (5 mol %) and DMAP under
an atmosphere of oxygen gave high yields of
dehydrogenation (scheme 5).[12] This procedure
proved applicable to substitution at every position of
the tetrahydroquinoline (9b-9h), and both electron-
withdrawing (9i-9k) and electron-donating (9l)
substituents were well tolerated. This method of
dehydrogenation was also used to prepare other
aromatic N-heterocycles, such as phenanthroline 10,
isoquinoline 11, quinoxaline 12, and pyridine 13.
Access to benzofuran 15 from 2,3-dihydrobezofuran
14 was also possible.
Some control reactions have been set up to
understand the mechanism (Scheme 6). Under an
inert (N2) atmosphere only a trace of product was
obtained (a), even when using a stoichiometric
amount of NHPI (b); reactivity was turned back
on under an oxygen atmosphere (c). These show
that oxygen is essential for the transformation,
suggesting the conversion of NHPI to an active
species, (PINO). The use of radical traps (e.g.
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
and
butylated
hydroxytoluene
(BHT)
significantly decreased reactivity suggesting a
radical mechanism (d and e). The addition of
copper to the reaction allows the process to run
efficiently at lower temperatures (Table 1, entry
8). We suggest that copper promotes the
formation of PINO from NHPI. Cobalt salts are
also commonly used to promote the formation of
PINO,[16] and, like copper, they also promoted the
reaction (f). The oxidation of 5-nitro-1-
methylindoline (1i) could also be promoted by
the use of cobalt salt (g), which is similar to the
reaction using Cu salt (Scheme 2, 2i). Finally, the
formation of H2O2 was detected under mild
conditions by 1H NMR spectrum.[17]
Scheme 6. Control reactions.
A putative mechanism for this reaction is
presented in Scheme 7. First of all, oxygen
promotes the conversion of NHPI to PINO (path
a).[18] The addition of a copper catalyst can aid
this process (path b).[19] PINO can then undergo
single electron transfer (SET) with the indoline to
give the radical cation I
and the anion of NHPI.[10]
Deprotonation then leads to II and regenerates
NHPI. The trapping of radical II with ∙OOH leads
to intermediate III [21]
,
which gives to the desired
product
2
upon expulsion of H2O2.[11,17]
Conclusion
In conclusion, we have developed a catalytic aerobic
dehydrogenation of N-heterocycles. In many cases,
the conversion of indolines to indoles is possible
Scheme 7. Putative reaction mechanism.
4
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10.1002/adsc.202000767
Advanced Synthesis & Catalysis
Experimental Section
1999, 38, 1676; d) T. Sunazuka, T. Hirose, T.
Shirahata, Y. Harigaya, M. Hayashi, K. Komiyama, S.
Ōmura and A. B. Smith, J. Am. Chem. Soc. 2000, 122,
2122; e) S. P. Govek and L. E. Overman, J. Am.
Chem. Soc. 2001, 123, 9468; f) L. Wang, K. W.
Woods, Q. Li, K. J. Barr, R. W. McCroskey, S. M.
Hannick, L. Gherke, R. B. Credo, Y.-H. Hui, K.
Marsh, R. Warner, J. Y. Lee, N. Zielinski-Mozng, D.
Frost, S. H. Rosenberg and H. L. Sham, J. Med.
Chem. 2002, 45, 1697; g) F. Sarabia, L. Martín-Ortiz
and F. J. López-Herrera, Org. Lett. 2003, 5, 3927; h)
P. S. Baran, C. A. Guerrero and E. J. Corey, J. Am.
Chem. Soc. 2003, 125, 5628; i) S. P. Govek and L. E.
Overman, Tetrahedron, 2007, 63, 8499; j) Y.
Matsuda, M. Kitajima and H. Takayama, Org. Lett.
2008, 10, 125; k) J. Magolan, C. A. Carson and M. A.
Kerr, Org. Lett. 2008, 10, 1437; l) K. Okano, H.
Fujiwara, T. Noji, T. Fukuyama and H. Tokuyama,
Angew. Chemie Int. Ed. 2010, 49, 5925; m) H.
Tokuyama, K. Okano, H. Fujiwara, T. Noji and T.
Fukuyama, Chem. - An Asian J. 2011, 6, 560; n) M.
Kock and T. Lindel, Org. Lett. 2018, 20, 5444; o) S.
Suzuki, T. Asako, K. Itami and J. Yamaguchi, Org.
Biomol. Chem. 2018, 16, 3771.
General information
All reagents and solvents were purchased from commercial
suppliers and used without further purification. All the
reactions were carried out without any precautions to
exclude air and moisture. Reactions were monitored by
thin-layer chromatography (TLC) on silica gel GF-254 pre-
coated glass plates. Chromatograms were visualized by
1
fluorescence quenching with UV light at 254 nm. H NMR
spectra, recorded at 400 MHz, are referenced to the
residual solvent peak at 7.26 ppm (CDCl3). 13C NMR
spectra, recorded at 101 MHz, are referenced to the
residual solvent peak at 77.0 ppm (CDCl3).
Representative procedure for the dehydrogenation of
indolines, 1a (Scheme 2): To a 20 mL vial, 1a (26.6 mg,
0.20 mmol) and N-hydroxyphthalimide (6.6 mg, 0.04
mmol) were dissolved in MeCN (3.0 mL). The vial was
sealed and reaction mixture was stirred at 80 °C for 2 h.
After that time, the reaction mixture was cooled down to
room temperature, and the reaction solvent was evaporated
under vacuum. The crude residue was purified by flash
column chromatography (petroleum ether/EtOAc = 20/1)
to afford the 1-methyl-1H-indole (2a) as a light yellow
liquid (23.1 mg, 88% yield).
[3] a) A. F. Pozharskii, A. T. Soldatenkov and A. R.
Katritzky, Heterocycles in Life and Society, John
Wiley & Sons, Ltd, Chichester, UK, 2011. b) G. W.
Gribble, Indole Ring Synthesis, John Wiley & Sons,
Ltd, Chichester, UK, 2016.
Representative procedure for the dehydrogenation of
tetrahydroquinolines, 8a (Scheme 5):
To a 20 mL vial, 8a (25.8 mg, 0.20 mmol), Cu2O (1.4 mg,
0.01 mmol), 4-dimethylaminopyridine (24.4 mg, 1 equiv)
and N-hydroxyphthalimide (6.6 mg, 0.04 mmol) were
dissolved in MeCN (2.0 mL). The reaction mixture was
bubbled with O2 for 20 minutes and quickly sealed. The
reaction was then stirred at 120 °C for 12 h. After that time,
the reaction mixture was evaporated under vacuum. The
crude residue was purified by flash column
chromatography (petroleum ether/EtOAc = 20/1) to afford
the quinoline (9a) as a colorless liquid (24.1 mg, 95%
yield).
[4] R. D. Taylor, M. MacCoss and A. D. G. Lawson, J.
Med. Chem. 2014, 57, 5845.
[5] For select examples of transition metal-catalyzed
aerobic
dehydrogenations
of
indolines/tetrahydroquinolines see: a) K. Yamaguchi
and N. Mizuno, Angew. Chem. Int. Ed. 2003, 42,
1480; b) K. Kamata, J. Kasai, K. Yamaguchi and N.
Mizuno, Org. Lett. 2004, 6, 3577; c) S.-I. Murahashi,
Y. Okano, H. Sato, T. Nakae and N. Komiya, Synlett.
2007, 2007, 1675; d) K. Yamaguchi, J. W. Kim, J. He
and N. Mizuno, J. Catal. 2009, 268, 343; e) T.
Amaya, T. Ito, Y. Inada, D. Saio and T. Hirao,
Tetrahedron Lett. 2012, 53, 6144; f) X. Cui, Y. Li, S.
Bachmann, M. Scalone, A.-E. Surkus, K. Junge, C.
Topf and M. Beller, J. Am. Chem. Soc. 2015, 137,
10652; g) A. V. Iosub and S. S. Stahl, Org. Lett. 2015,
17, 4404; h) D. V. Jawale, E. Gravel, N. Shah, V.
Dauvois, H. Li, I. N. N. Namboothiri and E. Doris,
Chem. Eur. J. 2015, 21, 7039; i) W. Zhou, P.
Taboonpong, A. Aboo, L. Zhang, J. Jiang and J. Xiao,
Synlett, 2016, 27, 1806; j) F. Peng, M. McLaughlin,
Y. Liu, I. Mangion, D. M. Tschaen and Y. Xu, J. Org.
Chem. 2016, 81, 10009; k) W. Zhou, D. Chen, F. Sun,
J. Qian, M. He and Q. Chen, Tetrahedron Lett. 2018,
59, 949; l) R. Zhang, Y. Qin, L. Zhang and S. Luo, J.
Org. Chem. 2019, 84, 2542; m) B. Li, A. E.
Wendlandt and S. S. Stahl, Org. Lett. 2019, 21, 1176;
n) Y. Wu, Z. Chen, W.-C. Cheong, C. Zhang, L.
Zheng, W. Yan, R. Yu, C. Chen and Y. Li, Chem. Sci.
2019, 10, 5345.
Acknowledgements
J. Luo thanks the Natural Science Foundation of Zhejiang
Province (No. LQ19B020002), and the Ningbo Municipal
Natural Science Foundation (No. 2019A610027). Q. Fu thanks
the financial support from the Collaborative Fund of Luzhou
Government
and
Southwest
Medical
University
(2019LZXNYDJ28), and the research fund of Southwest Medical
University (2017-ZRQN-031). We also thank Dr Gregory J. P.
Perry for comments, suggestions and aiding the writing of the
manuscript.
References
[1] S. Hati, U. Holzgrabe and S. Sen, Beilstein J. Org.
Chem. 2017, 13, 1670.
[2] a) D. Zhang and L. S. Liebeskind, J. Org. Chem.
1996, 61, 2594; b) F. He, B. M. Foxman and B. B.
Snider, J. Am. Chem. Soc. 1998, 120, 6417; c) K. C.
Nicolaou, P. S. Baran, Y. Zhong, K. C. Fong, Y. He,
W. H. Yoon and H.-S. Choi, Angew. Chemie Int. Ed.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000767
Advanced Synthesis & Catalysis
[6] For select examples of transition metal-free aerobic
dehydrogenations of indolines/tetrahydroquinolines
see: a) A. E. Wendlandt and S. S. Stahl, J. Am. Chem.
Soc. 2014, 136, 506; b) N. Morimoto, Y. Takeuchi
and Y. Nishina, Chem. Lett. 2016, 45, 21; c) M. K.
Sahoo, G. Jaiswal, J. Rana and E. Balaraman, Chem.
Eur. J. 2017, 23, 14167; d) J. Zhang, S. Chen, F.
Chen, W. Xu, G.-J. Deng and H. Gong, Adv. Synth.
Catal. 2017, 359, 2358; e) K. Mullick, S. Biswas, A.
M. Angeles-Boza and S. L. Suib, Chem. Commun.
2017, 53, 2256; f) R. Yang, S. Yue, W. Tan, Y. Xie
and H. Cai, J. Org. Chem. 2020, 85, 7501.
361, 3958; g) L. Yang, F. Ma, F. Xu, D. Li, L. Su, H.
Xu and C. Wang, Chem. Asian J. 2019, 14, 3557; h)
T. Liu, K. Wu, L. Wang and Z. Yu, Adv. Synth. Catal.
2019, 361, 3958.
[9] See reviews: a) L. Melone and C. Punta, Beilstein J.
Org. Chem. 2013, 9, 1296; b) F. Recupero and C.
Punta, Chem. Rev. 2007, 107, 3800; c) Y. Ishii, S.
Sakaguchi and T. Iwahama, Adv. Synth. Catal. 2001,
343, 393; See selected examples: d) J. Luo and J.
Zhang, J. Org. Chem. 2016, 81, 9131; e) L. Vanoye,
M. Abdelaal, K. Grundhauser, B. Guicheret, P.
Fongarland, C. D. Bellefon and A. Favre-Rꢀguillon,
Org. Lett. 2019, 21, 10134; f) M. Bietti, O.
Lanzalunga, A. Lapi, T. Martin, M. Mazzonna, M.
Polin and M. Salamone, J. Org. Chem. 2017, 82,
5761.
[7] For select examples of transition metal-catalyzed
acceptorless
dehydrogenations
of
indolines/tetrahydroquinolines see: a) T. Hara, K.
Mori, T. Mizugaki, K. Ebitani and K. Kaneda,
Tetrahedron Lett. 2003, 44, 6207; b) S. Muthaiah and
S. H. Hong, Adv. Synth. Catal. 2012, 354, 3045; c)
K.-N. T. Tseng, A. M. Rizzi and N. K. Szymczak, J.
Am. Chem. Soc. 2013, 135, 16352; d) J. Wu, D.
Talwar, S. Johnston, M. Yan and J. Xiao, Angew.
Chem. Int. Ed. 2013, 52, 6983; e) D. Damodara, R.
Arundhathi and P. R. Likhar, Adv. Synth. Catal. 2014,
356, 189; f) S. Chakraborty, W. W. Brennessel and W.
D. Jones, J. Am. Chem. Soc. 2014, 136, 8564; g) R.
Xu, S. Chakraborty, H. Yuan and W. D. Jones, ACS
Catal. 2015, 5, 6350; h) D. Talwar, A. Gonzalez-de-
Castro, H. Y. Li and J. Xiao, Angew. Chem. Int. Ed.
2015, 54, 5223; i) J. M. Stubbs, R. J. Hazlehurst, P. D.
Boyle and J. M. Blacquiere, Organometallics, 2017,
36, 1692; j) M. A. Esteruelas, V. Lezáun, A. Martínez,
M. Oliván and E. Oñate, Organometallics, 2017, 36,
2996; k) S. K. Moromi, S. M. A. H. Siddiki, K. Kon,
T. Toyao and K. Shimizu, Catal. Today, 2017, 281,
507; l) S. Kato, Y. Saga, M. Kojima, H. Fuse, S.
Matsunaga, A. Fukatsu, M. Kondo, S. Masaoka and
M. Kanai, J. Am. Chem. Soc. 2017, 139, 2204; m) K.-
H. He, F.-F. Tan, C.-Z. Zhou, G.-J. Zhou, X.-L. Yang
and Y. Li, Angew. Chem. Int. Ed. 2017, 56, 3080; n)
J.-W. Zhang, D.-D. Li, G.-P. Lu, T. Deng and C. Cai,
ChemCatChem 2018, 10, 4966; o) Q. Wang, H. Chai
and Z. Yu, Organometallics 2018, 37, 584; p) M. K.
Sahoo and E. Balaraman, Green Chem. 2019, 21,
2119; q) G. Jaiswal, M. Subaramanian, M. K. Sahoo
and E. Balaraman, ChemCatChem 2019, 11, 2449; r)
J.-J. Zhong, W.-P. To, Y. Liu, W. Lu and C.-M. Che,
Chem. Sci. 2019, 10, 4883.
[10] See selected examples since 2018: a) Y. Wang, X.
Chen, H. Jin, and Y. Wang, Chem. Eur. J. 2019, 25,
14273; b) X. Liu, X.-S. Luo, H.-L. Deng, W. Fan, S.
Wang, C. Yang, X.-Y. Sun, S.-L. Chen, and M.-H.
Huang, Chem. Mater. 2019, 31, 5421; c) J. Luo, K.
Xuan, Y. Wang, F. Li, F. Wang, Y. Pu, L. Li, N.
Zhao, and F. Xiao, New J. Chem. 2019, 43, 8428; d)
C. Zhang, Z. Huang, J. Lu, N. Luo, and F. Wang, J.
Am. Chem. Soc. 2018, 140, 2032.
[11] a) T. Iwahama, S. Sakaguchi, and Y. Ishii, Org.
Process Res. Dev. 2000, 4, 94; b) T. Iwahama, Y.
Yoshino, T. Keitoku, S. Sakaguchi, and Y. Ishii, J.
Org. Chem. 2000, 65, 6502; c) F. Minisci, C. Punta, F.
Recupero, F. Fontana and G. F. Pedulli, Chem.
Commun. 2002, 688; d) M. Jafarpour, A. Rezaeifard,
V.Yasinzadeh and H. Kargar, RSC Adv. 2015, 5,
38460; e) R. Hasanpour, F. Feizpour, M. Jafarpour
and A. Rezaeifard, New J. Chem. 2018, 42, 7383.
[12] See the supporting information for further details of
the optimization.
[13] P. E. Mahaney, A. T. Vu, C. C. McComas, P. Zhang,
L. M. Nogle, W. L. Watts, A. Sarkahian, L. Leventhal,
N. R. Sullivan, A. J. Uveges, E. J. Trybulski, Bioorg.
Med. Chem. 2006, 14 8455.
[14] M. Sassatelli, F. Bouchikhi, S. Messaoudi, F. Anizon,
E. Debiton, C. Barthomeuf, M. Prudhomme, P.
Moreau, Eur. J. Med. Chem. 2006, 41, 88.
[15] C. Aubry, A. J. Watson, D. Emmerson, E. Murphy, Y.
Y. Chan, M. P. Dickens, M. D. Garcia, P. R. Jenkins,
S. Mahale, B. Chaudhuri, Bioorg. Med. Chem. 2009,
17, 6073.
[8] For select examples of transition metal-free
acceptorless
dehydrogenations
of
indolines/tetrahydroquinolines see: a) A. F. G. Maier,
S. Tussing, T. Schneider, U. Flörke, Z.-W. Qu, S.
Grimme and J. Paradies, Angew. Chem. Int. Ed. 2016,
55, 12219; b) M. Kojima and M. Kanai, Angew.
Chem. Int. Ed. 2016, 55, 12224; c) M. Zheng, J. Shi,
T. Yuan and X. Wang, Angew. Chem. Int. Ed. 2018,
57, 5487; d) Y. Han, Z. Wang, R. Xu, W. Zhang, W.
Chen, L. Zheng, J. Zhang, J. Luo, K. Wu, Y. Zhu, C.
Chen, Q. Peng, Q. Liu, P. Hu, D. Wang and Y. Li,
Angew. Chem. Int. Ed. 2018, 57, 11262; e) Y. Wu, H.
Yi and A. Lei, ACS Catal. 2018, 8, 1192; f) T. Liu, K.
Wu, L. Wang and Z. Yu, Adv. Synth. Catal. 2019,
[16] a) C. Annunziatini, M. F. Gerini, O. Lanzalunga, and
M. Lucarini, Org. Chem. 2004, 69, 3431; b) B.
Karimi and J. Rajabi, Org. Lett. 2004, 6, 2841; c) Z.
Yao, X. Hu, J. Mao and H. Li, Green Chem. 2009, 11,
2013; d) E. Gaster, S. Kozuch, and D. Pappo, Angew.
Chem. Int. Ed. 2017, 56, 5912.
[17] See the supporting information for further details of
the indication of H2O2 formation and NHPI recovery
by 1H NMR spectrum.
6
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10.1002/adsc.202000767
Advanced Synthesis & Catalysis
[18] a) R. A. Sheldon and I. W. C. E. Arends, Adv. Synth.
Catal. 2004, 346, 1051; b) Y. Yan, P. Feng, Q.-Z.
Zheng, Y.-F. Liang, J.-F. Lu, Y. Cui and N. Jiao,
Angew. Chem. Int. Ed. 2013, 52, 1521; c) S. Wertz
and A. Studer, Green Chem. 2013, 15, 3116; d) Y.-F.
Liang, X. Li, X. Wang, Y. Yan, P. Feng and N. Jiao,
ACS Catal. 2015, 5, 1956; e) Y.-F. Liang, X. Wang,
C. Tang, T. Shen, J. Liu and N. Jiao, Chem. Commun.
2016, 52, 1416.
[20] a) W.-J. Zhou, G.-M. Cao, G. Shen, X.-Y. Zhu, Y.-Y.
Gui, J.-H. Ye, L. Sun, L.-L. Liao, J. Li and D.-G. Yu,
Angew. Chem. Int. Ed. 2017, 56, 15683; b) M.
Parasram, P. Chuentragool, Y. Wang, Y. Shi and V.
Gevorgyan, J. Am. Chem. Soc. 2017, 139, 14857.
[21] a) J. M. Lee, E. J. Park, S. H. Cho and S. Chang, J.
Am. Chem. Soc. 2008, 130, 7824; b) S. l W. Lardy and
V. A. Schmidt, J. Am. Chem. Soc. 2018, 140, 12318.
[19] a) Y. Ishii, S. Sakaguchi and T. Iwahamab, Adv.
Synth. Catal. 2001, 343, 393; b) R. Bag, D. Sar and T.
Punniyamurthy, Org. Lett. 2015, 17, 2010.
7
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10.1002/adsc.202000767
Advanced Synthesis & Catalysis
FULL PAPER
Catalytic Aerobic Dehydrogenation of N-
Heterocycles by N-Hydoxyphthalimide
Adv. Synth. Catal. Year, Volume, Page – Page
Weidong Chen, Hao Tang, Weilin Wang and Junfei
Luo*
A mild and efficient aerobic dehydrogenation of N-
heterocycles is reported using catalytic N-
hydroxyphthalimide (NHPI).
8
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