Cobalt-catalyzed aerobic oxidative Povarov reaction of tertiary anilines with dihydrofuran for the synthesis of hexahydrofuroquinolines

Article abstract of DOI:10.1016/j.tetlet.2016.10.031

A simple and efficient cobalt-catalyzed aerobic oxidative dehydrogenative Povarov reaction of tertiary anilines with dihydrofuran has been developed for the synthesis of hexahydrofuro[3,2-c]quinolines. The one-electron-oxidation involved reaction is performed under mild conditions and only requires simple cobalt salts as a catalyst and dioxygen as a terminal oxidant.

Full text of DOI:10.1016/j.tetlet.2016.10.031

Accepted Manuscript
Cobalt-Catalyzed Aerobic Oxidative Povarov Reaction of Tertiary Anilines
with Dihydrofuran for the Synthesis of Hexahydrofuroquinolines
Congde Huo, Fengjuan Chen, Zhengjun Quan, Jie Dong, Yajun Wang
PII:
S0040-4039(16)31334-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.031
TETL 48201
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 August 2016
30 September 2016
8 October 2016
Please cite this article as: Huo, C., Chen, F., Quan, Z., Dong, J., Wang, Y., Cobalt-Catalyzed Aerobic Oxidative
Povarov Reaction of Tertiary Anilines with Dihydrofuran for the Synthesis of Hexahydrofuroquinolines,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.10.031
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1
Tetrahedron Letters
Cobalt-Catalyzed Aerobic Oxidative Povarov Reaction of Tertiary Anilines with
Dihydrofuran for the Synthesis of Hexahydrofuroquinolines
Congde Huo,* Fengjuan Chen, Zhengjun Quan, Jie Dong, Yajun Wang
a Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education; College of Chemistry and Chemical Engineering, Northwest Normal
University, Lanzhou, Gansu 730070, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient cobalt-catalyzed aerobic oxidative dehydrogenative Povarov reaction of
tertiary anilines with dihydrofuran has been developed for the synthesis of hexahydrofuro[3,2-
c]quinolines. The one-electron-oxidation involved reaction is performed under mild conditions
and only requires simple cobalt salts as a catalyst and dioxygen as a terminal oxidant.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Aerobic
Povarov Reaction
Tertiary Anilines
Dihydrofuran
Hexahydrofuroquinolines
Diels-Alder reaction is one of the most atom-economic and
efficient synthetic routes for constructing 6-membered rings.
Tetrahydroquinoline derivatives are an important class of natural
products, which exhibit both biological and pharmaceutical
activities in various fields.1-13 First discovered in 1963, the
Povarov reaction comprises a formal [4+2] cycloaddition of
imines derived from aromatic amines and electron-rich olefins.1
Since then, this imino-Diels-Alder reaction has become a
powerful synthetic tool to form tetrahydroquinoline motifs.2
described
a
Cu(OTf)2/TBHP catalyzed double-oxidative
dehydrogenative (DOD) Povarov reaction between tertiary
anilines and tetrahydrofuran.12 In this year, Guan et al presented a
FeCl3/TBHP promoted dehydrogenative Povarov reaction of
tertiary anilines and enamides for the synthesis of
tetrahydroquinolines with amido-substituted quaternary carbon
centers.13 Although these examples have achieved notable
progress in this area, stoichiometric or more amounts of chemical
oxidants were always necessary in these reactions. Therefore, the
development of new methods using low-cost catalyst with
molecular oxygen as terminal oxidant for the dehydrogenative
[4+2] cycloaddition of tertiary amines is still highly desired.
Recently, oxidative dehydrogenative Povarov reaction of
secondary amines has been well developed (Scheme 1, top). In
2011, an oxidative Povarov/aromatization tandem reaction of
glycine derivatives with alkenes using FeCl3 as the catalyst and
2,2,6,6-tetramethylpiperidin-1-yl)oxy oxoammonium salt as the
oxidant was first reported by .3 After that, some
aerobic catalytic systems, such as Cu(OTf) 2/NHPI/O2,4
Scheme 1. Oxidative Dehydrogenative Povarov Reaction of
Amines
5
TBPA+.SbCl6-/O2 , CBr4/O2,6 and even auto-oxidation,7 have been
achieved in this transformation. Since 2015, we also developed
an aerobic double-oxidative dehydrogenative (DOD) cyclization
strategy of glycine derivatives with dioxane for the synthesis of
complex quinoline motifs.8
Meanwhile, the oxidative dehydrogenative Povarov reaction
of tertiary amines was realized too (Scheme 1, bottom). In 2014,
Seidel et al reported an oxidative Povarov reaction of N-aryl
tetrahydroisoquinolines with enamides under CuBr/TBHP
conditions.9 In the next year, Xu et al demonstrated a similar
process using visible light photoredox catalysis.10 In 2009, 2
examples of oxidative aza-Diels-Alder reaction of tertiary
anilines with dihydrofuran have been mentioned by Zhang et al
using CuBr/TBHP catalytic system.11 Last year, liu et al
Herein, in this paper, we report a cobalt-catalyzed14 aerobic
oxidative dehydrogenative [4+2] cycloaddition reaction of
tertiary anilines with dihydrofuran for the synthesis of
hexahydrofuro[3,2-c]quinolines.15
Our initial investigations focused on the reaction between N,
N-dimethylaniline 1a and dihydrofuran (2) in combination with

2
Tetrahedron
various inexpensive first-row transition metal salts as the
dehydrogenative [4+2] cyclization of N,N-dimethylaniline with
electron deficient olefin maleimide (4).16 Moreover, using N-
phenyl 1,2,3,4-tetrahydroisoquinoline (6) and dihydrofuran (2) as
substrates, polycyclic tetrahydroquinolines (7) can be achieved
under the standard reaction conditions.9,10 These 2 kinds of ring-
fused tetrahydroquinolines are valuable precursors of many
bioactive molecules and are widely used building blocks in
organic synthesis.9,10
catalysts in acetonitrile at room temperature under aerobic
conditions (Scheme 2, entries 1-9). After screening of metal
catalysts, Co(II) Perchlorate was found to be the most effective
for implementation of the present transformation (Scheme 2,
entry 8). Screening of temperature suggested that 50oC was the
best choice for the transformation (Scheme 2, entries 8, 10-12).
The solvent effect was also explored, with acetonitrile being
identified as the optimal solvent (Scheme 2, entries 13-16). The
catalyst loading was varied too, and 10 mol % gave the best
result (Scheme 2, entries 11, 17 and 18). Finally, changing the air
atmosphere to pure oxygen atmosphere resulted in an
improvement of the efficiency (Scheme 2, entry 19). After
various reaction parameters were screened, the best results were
found to be Co(ClO4)2.6H2O (10 mol %) in MeCN at 50oC under
oxygen atmosphere (Scheme 2, entry 19). Under these reaction
conditions, a 61% yield of hexahydrofuroquinoline 3a was
obtained after 48 h.
Scheme 3. Co(II) catalyzed aerobic oxidative Povarov
reaction for the Syntheses of hexahydrofuro[3,2-c]quinolines
Scheme 2. Screening of Reaction Conditions
[a] Reaction conditions: 1a (1.0 mmol), 2a (10 mmol), solvent
(20 mL), O2, 50oC, 48 h. [b] Yields of the isolated product.
With the optimized reaction conditions in hand, we then
evaluated the scope of the reactions of various tertiary anilines
with dihydrofuran. As shown in Scheme 3, tertiary anilines with
a variety of substituents at para position including methyl, ethyl,
iso-propyl, butyl, tert-butyl, methoxyl, phenyl, and N, N-
dimethylphenyl generated the desired products in good to high
yields (Scheme 3, 3a-3j). The reaction is tolerant to fluoro,
chloro, bromo and iodo substituents on the aromatic ring of
anilines, and the corresponding target products were obtained in
good yields (Scheme 3, 3k-3n). These halogen substituted
[a] Reaction conditions: 1 (1.0 mmol), 2 (10 mmol), CH3CN
(20 mL), O2, 50oC, 48 h. [b] Yield of the isolated product.
Some control experiments were carried out in order to reveal
the mechanism of this transformation (Scheme 5). Firstly, the
reaction of 1a with 2 in the absence of molecular oxygen (argon
atmosphere) furnished no product [Eq. (1)], indicating that
dioxygen is definitely crucial for the reaction. Secondly, no
reaction occurred when a stoichiometric amount of 2,2,6,6-
examples
enable
potential
applications
in
further
functionalization. Tertiary anilines with meta-, or ortho-
substituent groups on the aryl ring gave the desired quinolines in
satisfactory yields too (Scheme 3, 3o-3t). In addition, substrates
bearing multiple substituents also worked well (Scheme 3, 3u-
3x).
tetramethylpiperidin-1-oxyl
(TEMPO)
or
butylated
hydroxytoluene (BHT) was employed in the standard reaction as
radical scavenger [Eq. (2)]. This result suggested that the present
To develop a more general and useful method, we found this
simple cobalt/O2 catalyst system is also efficient for the oxidative
reaction includes
a radical process. To account for the

3
aforementioned results, a proposed mechanism for the cobalt-
catalyzed dehydrogenative [4+2] cyclization of tertiary anilines 1
with dihydrofuran 2 is shown in Scheme 6. First, a cobalt(III)
peroxide radical generated by a combination of molecular oxygen
with cobalt(II) might abstract a hydrogen atom of 1 to form
radical intermediate A. The iminium type intermediate B could
then be formed through a single electron transfer (SET) from A.
Subsequently, cycloaddition of B with 2 results in the desired
product 3 (path A). Path B was also possible because electron-
deficient maleimide (4) was suitable substrate for this
transformation too.
dimethylanilines with dihydrofuran. The reaction proceeds
through cobalt-catalyzed dehydrogenation of tertiary amines
followed by nucleophilic addition/intramolecular cyclization with
dihydrofuran to afford hexahydrofuroquinoline motifs in good
yields. The use of low-cost simple cobalt salts as the catalyst and
molecular oxygen as the oxidant makes this transformation
sustainable and practical.
Acknowledgment
We thank the National Natural Science Foundation of China
(21262029, 21562037) and the Natural Science Foundation of
Gansu Province (1506RJZA122) for financially supporting this
work.
Scheme 4. Other applications
References and notes
1.
(a) Povarov, L.-S.; Mikhailov, B.-M. Izv. Akad. Nauk SSSR
Otd. Khim. Nauk. 1963, 953–956; (b) Povarov, L.-S.; Grigos,
V. -I.; Mikhailov, B.-M. Izv. Akad. Nauk SSSR Otd. Khim.
Nauk. 1963, 2039–2041; (c) Povarov, L.-S. Russian. Chem.
Rev. 1967, 36, 656–670.
2.
Recent review, see: Kouznetsov, V.-V. Tetrahedron. 2009, 65,
2721–2750.
3.
4.
Richter, H.; Mancheño, O. G. Org. Lett. 2011, 13, 6066–6069.
Xie, Z. Y.; Jia, J.; Liu, X. G.; Liu, L. Adv. Synth. Catal. 2016,
358, 919-925.
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Scheme 5. Control experiments
6.
Huo, C.; Xie, H.; Wu, M.; Jia, X.; Wang. X.; Chen, F.; Tang,
J. Chem. Eur. J. 2015, 21, 5723−5726.
7.
Huo, C.; Yuan, Y.; Wu, M.; Jia, X.; Wang, X., Chen, F.; Tang,
J. Angew. Chem. Int. Ed. 2014, 53, 13544–13547.
Huo, C.; Xie, H.; Chen, F.; Tang, J.; Wang, Y. Adv. Synth.
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Min, C.; Sanchawala, A.; Seidel, D. Org. Lett. 2014, 16,
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Scheme 6. Proposed mechanism
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In summary, we have demonstrated a cobalt-catalyzed,
aerobic oxidative dehydrogenative formal [4+2] reaction of N,N-

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Cobalt-Catalyzed Aerobic Oxidative
Povarov Reaction of Tertiary Anilines with
dihydrofuran for the synthesis of
Hexahydrofuroquinolines
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Congde Huo,* Fengjuan Chen, Zhengjun Quan, Jie Dong, Yajun Wang

4
Tetrahedron
Highlights
Cobalt-catalyzed aerobic oxidative dehydrogenative Povarov reaction was developed.
Hexahydrofuro[3,2-c]quinolines were synthesized efficiently.
One-electron-oxidation involved reaction mechanism was proposed.