A Combination of Visible-Light Organophotoredox Catalysis and Asymmetric Organocatalysis for the Enantioselective Mannich Reaction of Dihydroquinoxalinones with Ketones

Article abstract of DOI:10.1021/acs.orglett.9b02157

An enantioselective photooxidative Mannich reaction of dihydroquinoxalinones with ketones by the merger of organophotoredox and asymmetric organocatalysis is described. This protocol features very mild reaction conditions using simple and cheap catalysts (Eosin Y and (S)-Proline) for the synthesis of chiral quinoxaline derivatives with good to high yields (up to 94%) and excellent enantioselectivities (up to 99% ee).

Full text of DOI:10.1021/acs.orglett.9b02157

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Combination of Visible-Light Organophotoredox Catalysis and
Asymmetric Organocatalysis for the Enantioselective Mannich
Reaction of Dihydroquinoxalinones with Ketones
‡
,†
Jaume Rostoll-Berenguer,† Gonzalo Blay,† M. Carmen Munoz, Jose R. Pedro,* and Carlos Vila*,†
́
̃
†
̀
̀
̀
Departament de Química Organica, Facultat de Química, Universitat de Valencia, Dr. Moliner 50, 46100 Burjassot, Valencia, Spain
‡
̀
̀
̀
Departament de Física Aplicada, Universitat Politecnica de Valencia, Camino de Vera s/n, 46022 Valencia, Spain
S
* Supporting Information
ABSTRACT: An enantioselective photooxidative Mannich
reaction of dihydroquinoxalinones with ketones by the merger
of organophotoredox and asymmetric organocatalysis is
described. This protocol features very mild reaction
conditions using simple and cheap catalysts (Eosin Y and
(S)-Proline) for the synthesis of chiral quinoxaline derivatives
with good to high yields (up to 94%) and excellent enantioselectivities (up to 99% ee).
Scheme 1. Enantioselective Photooxidative Mannich
Reaction
he employment of visible-light photoredox catalysis has
become a hot topic in synthetic chemistry in the past
T
decade, due to its significant advantages such as low cost,
safety, renewability, abundance, and environmental friend-
liness.1,2 On the other hand, control of chirality is one of the
guiding principles in the chemical community over recent
decades. One of the main objectives of the organic chemistry is
exploiting the full potential of synthetic chemistry to create and
control chiral structures with different types of functions.3 In
this context, asymmetric catalysis provides vast opportunities
for an economical and efficient access to chiral compounds in
enantiomerically pure form.4 Therefore, interfacing visible-light
photochemical activation with asymmetric catalysis has
provided new opportunities for the development of synthetic
methods for efficient, convenient, and green synthesis of
nonracemic chiral molecules.5 In recent years, several examples
of the combination of visible-light photoredox catalysts and
organocatalysts have been described for the α- and β-
functionalization of carbonyl compounds6 and for the
C(sp3)−H α-functionalization of amines.7
(sp3)−H α-functionalization of other amines different from
tetrahydroisoquinolines. In particular, dihydroquinoxalinones
constitute a prevailing scaffold frequently found in many
biologically active natural and synthetic products (Figure 1).
The enantioselective synthesis of chiral amines is, generally,
a remarkable research area owing to the importance of chiral
nitrogen-containing compounds for medicinal, pharmaceutical,
and agrochemical chemistry.8 In this context, since the
pioneering report of List,9 the organocatalytic asymmetric
Mannich reaction represents a powerful methodology for the
synthesis of chiral amines.10 Besides, the enantioselective
oxidative Mannich reaction that includes C(sp3)−H α-
functionalization of amines with carbonyl compounds has
been described recently.11 However, only two examples of the
combination of visible-light photoredox catalysts and asym-
metric catalysis for the oxidative Mannich reaction of amines
(tetrahydroisoquinolines) and cyclic ketones have been
described by Luo12 and Rueping,13 independently (Scheme
1). Therefore, our attention is focused on developing a suitable
catalytic system for accomplishing the enantioselective C-
Figure 1. Selected bioactive chiral dihydroquinoxalinones.
Many examples are used as pharmaceuticals, including antiviral
compounds, used for the treatment of HIV,14 anticancer
compounds,15 cholesteryl ester transfer protein inhibitors,16
antiinflammatory compounds,17 antitumor agents,18 and also
as agrochemicals.19 However, enantioselective approaches to
the synthesis of chiral dihydroquinoxalin-2-ones are scarce and
limited to catalytic asymmetric hydrogenations of quinox-
alinones.20,21 In view of the few examples of the catalytic
Received: June 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
asymmetric methodologies for the synthesis of such com-
pounds, we envisioned that the corresponding quinoxalin-2-
one generated under mild conditions from 3,4-dihydroquinox-
alin-2-one by a photocatalyzed oxidation might react with
carbonyl compounds using asymmetric enamine catalysis
giving a Mannich product. Hence, continuing with our interest
in the synthesis of 1,4-dihydroquinoxalinones22 and the
photoredox functionalization of cyclic amines,23 we described
the development of a dual organocatalyst strategy for the
enantioselective oxidative alkylation of dihydroquinoxalinones
with ketones through an asymmetric Mannich reaction
(Scheme 1).
consumed and the formation of the cyclic imine quinoxalin-2-
one was observed. Then, acetone 2a (1 mL) and (S)-proline
(20 mol %) were added to the reaction mixture and stirred for
80 h under darkness, in order to avoid the over-oxidation
products. The desired product 3aa was isolated with the same
enantiomeric excess (99% ee), but much better yield (77%,
entry 2).
Next, we evaluated the light sources (entries 2−4),
observing that the oxidation was much faster, only 4 h,
under blue LED irradiation although the yield was lower
(59%) (entry 4). Other photocatalysts (Ru(bpy)3Cl2,
Fukuzumi photocatalyst, and Eosin Y) were evaluated (entries
5−7), obtaining similar reaction times, yields, and enantiose-
lectivities. In order to develop a more cost-effective and green
protocol, we decided to continue the optimization using Eosin
Y as the photocatalyst. Then, different solvents such as toluene,
CHCl3, DMSO, and DMF were evaluated (entries 8−11). In
toluene and CHCl3, the oxidation step was very slow, while,
with DMSO and DMF, the oxidation step was similar to the
case of CH3CN. Because the enantioselective Mannich
reaction was faster in DMF (2 days, entry 11), we continued
the optimization with this solvent. Lowering the photocatalyst
to 2 mol % was beneficial for both steps, obtaining product 3aa
with 74% yield and 99% ee after 21 h (entry 12). Decreasing
the amount of acetone to 10 equiv (entry 13) was detrimental
for the speed of the asymmetric Mannich reaction (3 days),
and product 3aa was isolated with 82% yield and 96% ee.
Finally, several control experiments were carried out. When the
reaction was carried out under darkness (entry 14), we did not
observe the oxidation of dihydroquinoxalin-2-one 1a to
quinoxalin-2-one after 5 days. While the reaction proceeded
without a catalyst (entry 15), giving the corresponding
oxidation of dihydroquinoxalin-2-one, it was very slow (102
h). The subsequent addition of acetone and (S)-proline led to
the formation of product 3aa with 73% yield and 99% ee.
Moreover, we performed the enantioselective Mannich
reaction using the imine (quinoxalin-2(1H)-one) as the
electrophile (entry 16) obtaining good yield and excellent
enantioselectivity (99% ee).
Once we had the optimized reaction conditions (entry 12),
we evaluated the scope of the enantioselective oxidative
Mannich reaction, as is shown in the Scheme 2. First we
evaluated the effect of the protecting group at the nitrogen of
the amide of dihydroquinoxalin-2-one 1. The reaction tolerates
several groups at the nitrogen atom, such as methyl, benzyl,
allyl, or CH2CO2Me, affording the corresponding chiral
quinoxalines 3 with good yields and excellent enantioselectiv-
ities. These results are remarkable, because only the oxidation
of the endocyclic CH2 was observed (3ba−3ea). 3,4-
Dihydroquinoxalin-2-one (1) bearing electron-donating (Me,
OMe) or electron-withdrawing (CF3, F, CO2H) groups on the
aromatic ring furnished the corresponding chiral ketones 3 in
good yields (58−93%) and excellent enantioselectivities (97−
99% ee), regardless of the position or the electronic character
of the substituents (3fa−3ma). Moreover, disubstituted 3,4-
dihydroquinoxalin-2-one also can be used obtaining the
corresponding chiral quinoxalin-2-ones 3na and 3oa with
excellent results in both yield and enantiomeric excess. We
next explored the asymmetric Mannich reaction with other
ketones such as butan-2-one 2b, 4-methylpentan-2-one 2c, or
undecan-2-one 2d that afford the corresponding chiral
products with excellent regio- and enantioselectivities,
although with moderate yields (42−55%). Meanwhile, cyclic
The enantioselective Mannich reaction between 3,4-
dihydroquinoxalin-2-one (1a) and acetone (2a) using (S)-
proline as an organocatalyst was selected as the model reaction
(Table 1). The initial reaction using 1 mol % of Ir(ppy)3,
a
Table 1. Optimization of the Reaction Conditions
t2
yield
b
ee
(%)
c
entry
PC (%)
solvent t1 (h) (h)
(%)
d
1
Ir(ppy)3 (1%)
Ir(ppy)3 (1%)
Ir(ppy)3 (1%)
Ir(ppy)3 (1%)
Ru(bpy)3Cl2 (1%)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
74
48
24
4
6
9
−
34
77
66
59
66
82
99
99
99
99
99
97
2
80
79
68
70
70
e
3
f
4
5
f
f
6
Fukuzumi photocat.
(5%)
f
7
Eosin Y (5%)
Eosin Y (5%)
Eosin Y (5%)
Eosin Y (5%)
Eosin Y (5%)
Eosin Y (2%)
Eosin Y (2%)
Eosin Y (5%)
−
MeCN
toluene
CHCl3
DMSO
DMF
DMF
DMF
DMF
DMF
9
86
72
72
86
46
21
65
−
63
33
86
63
75
74
82
−
98
92
98
84
98
99
96
−
f
8
78
78
9
8
7
f
9
f
10
11
12
13 ,
14
15
16
f
f
f g
7
h
120
102
−
21
15
73
95
99
99
i
−
DMF
a
Reaction conditions: A stepwise procedure where 1a (0.2 mmol)
and photocatalyst (X mol %) were dissolved in 1 mL of solvent and
stirred at rt under an air atmosphere and irradiation of 5 W white
LEDs; upon consumption of the starting material, 2a (1 mL) and (S)-
b
proline (20 mol %) were added and stirred under darkness. Yield
c
after purification by column chromatography. The enantiomeric
d
excess was determined by HPLC analysis. Reaction conditions: 1a
(0.2 mmol), 2a (1 mL), Ir(ppy)3 (1 mol %), (S)-proline (20 mol %)
in 1 mL of MeCN at rt under an air atmosphere and irradiation of 5
e
W white LEDs. Under irradiation of a 11 W fluorescent bulb light.
f
g
h
Under irradiation of blue LEDs. 10 equiv of 2a were used. Reaction
i
performed under darkness. The Mannich reaction was performed
using quinoxalin-2(1H)-one as electrophile.
under irradiation of 5 W white LEDs, gave the corresponding
chiral Mannich product 3aa with an excellent 99% ee, but low
yield (34%, entry 1). In order to avoid possible side reactions
in our system,24 we decided to attempt the activation of the
substrates separately.13 Accordingly, dihydroquinoxalin-2-one
(1a) and 1 mol % of Ir(ppy)3 were dissolved in 1 mL of
CH3CN and stirred under irradiation of 5 W white LEDs and
an air atmosphere. After 2 days, the starting material 1a was
B
DOI: 10.1021/acs.orglett.9b02157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Enantioselective Photooxidative Mannich
Reaction
Scheme 3. 5 mmol Reaction Scale Using Sun Light as
Source of Irradiation
a
To elucidate the mechanism of the reaction, control
experiments were conducted. The addition of TEMPO, a
radical scavenger, inhibited the oxidation of 1, as well as when
the reaction was run in the absence of oxygen. In addition, we
performed a Stern−Volmer quenching experiment for the
exicited Eosin Y photocatalyst with amine 1 (KSV = 79 M−1),
suggesting that the reaction might proceed through an
reductive quenching pathway.28 Therefore, under the irradi-
ation of visible light and in the presence of Eosin Y and oxygen,
dihydroquinoxalin-2-one 1 is oxidized to quinoxalin-2(1H)-
one, which reacts with the corresponding ketone affording the
Mannich product 3. On the basis of the absolute configuration
of 3aa (CCDC 1922649),29 we propose a plausible mechanism
for the enantioselective oxidative Mannich reaction, as is
shown in the Scheme 4. (S)-Proline reacts with acetone to
Scheme 4. Plausible Stereochemical Pathway
form an enamine that attacks the Re face of the cyclic imine.
The enantioselectivity is further controlled by hydrogen
bonding between the proline carboxylic acid group and the
cyclic imine.9,10
In summary, we have developed a photooxidative
enantioselective Mannich reaction of 3,4-dihydroquinoxalin-
2-one derivatives with several ketones using visible-light
organophotoredox and enamine catalysis.30 The corresponding
chiral quinoxaline products were obtained with good yields and
excellent enantioselectivities under very mild conditions. The
reaction is scalable to 5 mmol scale using sun light. Our
methodology shows a successfully combination of visible-light
organophotoredox and enantioselective organocatalysis, in
order to obtain interesting quinoxalinone derivatives.
a
The reaction was performed under sunlight irradiation.
ketones such as cyclohexanone and cyclopentanone were
examined, affording the corresponding chiral Mannich
products with excellent yields, but low diastereo- and
enantioselectivities.25 Finally, the reaction tolerates function-
alized ketones such 1-hydroxypropan-2-one or 1,1-dimethox-
ypropan-2-one, obtaining products 3ag and 3ah with excellent
results. Interestingly, the 1-hydroxypropan-2-one gave exclu-
sively the branched product, while the 1,1-dimethoxypropan-2-
one gave only the linear product. This is usual for proline
catalyzed aldol26 or Mannich9 reactions, where the less
substituted enamine is formed. In contrast to 2-butanone or
1,1-dimethoxypropan-2-one, the regioselectivity of enamine
formation in the case of the hydroxyacetone is controlled by
the π-donating OH group, which interacts with the π*-orbital
of the CC bond thereby stabilizing the hydroxyl enamine.27
Gratifyingly, the practicability and scalability of this protocol
were successfully demonstrated by performing the enantiose-
lective oxidative Mannich reaction at 5 mmol scale using sun
light and only 0.5 mol % of Eosin Y (Scheme 3). Under these
conditions, the results were similar to those obtained on small
scale (67% yield and 99% ee).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02157.
Complete experimental procedures and characterization
1
of new products, H and 13C NMR spectra and HPLC
traces for all compounds (PDF)
C
DOI: 10.1021/acs.orglett.9b02157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
For selected enantioselective reactions, see: (c) DiRocco, D. A.;
Rovis, T. J. Am. Chem. Soc. 2012, 134, 8094. (d) Bergonzini, G.;
Schindler, C. S.; Wallentin, C.-J.; Jacobsen, E. N.; Stephenson, C. R. J.
Chem. Sci. 2014, 5, 112. (e) Perepichka, I.; Kundu, S.; Hearne, Z.; Li,
CCDC 1922649 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
̌
C.-J. Org. Biomol. Chem. 2015, 13, 447. (f) Wei, G.; Zhang, C.; Bures,
F.; Ye, X.; Tan, C.-H.; Jiang, Z. ACS Catal. 2016, 6, 3708.
(g) Uraguchi, D.; Kinoshita, N.; Kizu, T.; Ooi, T. J. Am. Chem. Soc.
2015, 137, 13768. (h) Murphy, J. J.; Bastida, D.; Paria, S.; Fagnoni,
M.; Melchiorre, P. Nature 2016, 532, 218. (i) Wang, C.; Qin, J.; Shen,
X.; Riedel, R.; Harms, K.; Meggers, E. Angew. Chem., Int. Ed. 2016, 55,
685.
AUTHOR INFORMATION
Corresponding Authors
■
(8) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and
Applications; Wiley-VCH: Weinheim, 2010.
*E-mail: jose.r.pedro@uv.es.
*E-mail: carlos.vila@uv.es.
(9) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
́
(10) (a) Cordova, A. Acc. Chem. Res. 2004, 37, 102. (b) Ting, A.;
ORCID
Schaus, S. E. Eur. J. Org. Chem. 2007, 2007, 5797. (c) Verkade, J. M.
M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T.
Chem. Soc. Rev. 2008, 37, 29. (d) Arend, M.; Westermann, B.; Risch,
N. Angew. Chem., Int. Ed. 1998, 37, 1044.
Gonzalo Blay: 0000-0002-7379-6789
́
Jose R. Pedro: 0000-0002-6137-866X
Carlos Vila: 0000-0001-9306-1109
(11) (a) Zhang, G.; Zhang, Y.; Wang, R. Angew. Chem., Int. Ed.
2011, 50, 10429. (b) Zhang, J.; Tiwari, B.; Xing, C.; Chen, X.; Chi, Y.
R. Angew. Chem., Int. Ed. 2012, 51, 3649. (c) Zhang, G.; Ma, Y.;
Wang, S.; Kong, W.; Wang, R. Chem. Sci. 2013, 4, 2645. (d) Tan, Y.;
Yuan, W.; Gong, L.; Meggers, E. Angew. Chem., Int. Ed. 2015, 54,
13045.
(12) Yang, Q.; Zhang, L.; Ye, C.; Luo, S.; Wu, L.-Z.; Tung, C.-H.
Angew. Chem., Int. Ed. 2017, 56, 3694.
(13) Hou, H.; Zhu, S.; Atodiresei, I.; Rueping, M. Eur. J. Org. Chem.
2018, 2018, 1277.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
Financial support from the Agencia Estatal de Investigacion
(AEI, Spanish Government) and Fondo Europeo de Desarrollo
Regional (FEDER, European Union) (CTQ2017-84900-P) is
acknowledged. J.R.-B. thanks the Ministerio de Ciencia,
́
Innovacion y Universidades for an FPU predoctoral contract,
and C.V. thanks the Agencia Estatal de Investigacion (AEI,
Spanish Government) for an RyC contract (RYC-2016-
20187). Access to NMR, MS, and X-ray facilities from the
Servei Central de Suport a la Investigacio Experimental
̈
(14) (a) Rosner, M.; Billhardt-Troughton, U.-M.; Kirsh, R.; Kleim,
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J.-P.; Meichsner, C.; Riess, G.; Winkler, I. U.S. Patent 5,723,461,
1998. (b) Abraham, C. J.; Paull, D. H.; Scerba, M. T.; Grebinski, J.
W.; Lectka, T. J. Am. Chem. Soc. 2006, 128, 13370. (c) Ren, J.;
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(SCSIE)-UV is also acknowledged.
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E
DOI: 10.1021/acs.orglett.9b02157
Org. Lett. XXXX, XXX, XXX−XXX