A visible-light photocatalytic radical addition reaction of dihydroquinoxalin-2-ones to trifluoromethyl ketones has been established using Ru(bpy)3Cl2 as photocatalyst, acetonitrile as solvent, and HP Single Blue LED as the source of light. The reaction provides a straightforward approach to the synthesis of dihydroquinoxalin-2-ones bearing a trifluoromethyl-substituted tertiary alcohol moiety in moderate to good yields under mild conditions.
A visible-light photocatalytic radical addition reaction of dihydroquinoxalin-2-ones to trifluoromethyl ketones has been established using Ru(bpy)3Cl2 as photocatalyst, acetonitrile as solvent, and HP Single Blue LED as the source of light. The reaction provides a straightforward approach to the synthesis of dihydroquinoxalin-2-ones bearing a trifluoromethyl-substituted tertiary alcohol moiety in moderate to good yields under mild conditions.
The synthesis of fluorinated
molecules is a fundamental task for
synthetic organic chemistry, due to the presence of fluorine atoms
in a vast number of pharmaceuticals, agrochemicals, and materials.[1] In this context, the trifluoromethyl group (CF3) has received a significant amount of attention and is often
used in medicinal chemistry to replace the methyl group to prevent
its metabolic oxidation, to adjust the steric and electronic properties
or to increase the lipophilicity of biological active compounds.[2] Therefore, the organic synthesis of building
blocks bearing a trifluoromethyl moiety is very attractive. One of
the most efficient and direct ways to incorporate a trifluoromethyl
group into organic molecules is the use of trifluoromethyl ketones
as reagents.[3] So, a wide range of synthetic
methodologies have been described using nucleophilic addition reactions
with trifluoromethyl ketones as electrophiles. However, the radical–radical
coupling or radical addition reactions using trifluoromethyl ketones
are less studied, and relatively few examples are known. The radical–radical
coupling and radical addition reactions are powerful C–C bond
formation processes that have been recently established using visible-light
photocatalysis, and several synthesis of secondary and tertiary alcohols
have been reported.[4] In this context, very
few examples have been described using radical reactions for the synthesis
of trifluoromethyl carbinols (Scheme ). Meggers, in 2016, described an elegant photocatalytic
enantio- and diastereoselective synthesis of 1,2-amino alcohols from
tertiary amines and trifluoromethyl ketones using a chiral iridium
photocatalyst. These authors described 15 examples with good yields
with excellent stereoselectivity.[5] In 2018,
Wang and co-workers presented a coupling reaction of tertiary N-arylamines and aldehydes, ketones, and imines using visible-light
photocatalysis, showing one example with trifluoroacetophenone.[6] Later in 2019, Liu and co-workers reported one
example (27% yield) of a radical–radical coupling of trifluoroacetophenone
and cyclohexene using fac-Ir(ppy)3 as
photocatalyst.[7] Finally in 2021, Ohmiya
and Nagao described one example of the photocatalytic synthesis of
a tertiary trifluoromethyl alcohol from the reaction of 2-phenylisobutyric
acid and trifluoroacetophenone.[8] Herein,
we present the reaction of trifluoromethyl ketones[9] and dihydroquinoxalin-2-ones using visible-light photoredox
catalysis leading to the synthesis of trifluoromethyl alcohols bearing
a dihydroquinoxalin-2-one moiety. Dihydroquinoxalin-2-ones are privileged
nitrogen heterocycles that are present in a broad assortment of biologically
active compounds such as antiviral, antibiotic, anticancer, or anti-inflammatory
drugs.[10] Consequently, the functionalization
of this class of nitrogen heterocycles is significant for medicinal
and pharmaceutical chemistry. Many methodologies have been established,
with the visible-light photocatalytic functionalization being one
of the most straightforward and sustainable approaches.[11] Continuing with our interest in the photocatalytic
functionalization of dihydroquinoxalin-2-ones,[12] we hypothesized that this class of heterocycles could be
an appropriate precursor of α-amino radicals[13] to perform the radical addition reaction to trifluoromethyl
ketones under visible-light photocatalysis.
Scheme 1
Examples of Photocatalytic
Radical Reactions Using Trifluoromethyl
Ketones
Results and Discussion
We started our studies with the reaction of 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a) with 2,2,2-trifluoroacetophenone
(2a) in the presence of different visible-light photocatalysts
in acetonitrile as a solvent at room temperature and under HP (High
Power) Single Blue LED irradiation (Table ). 4-Benzyl-3,4-dihydroquinoxalin-2(1H)-one is a challenging molecule because of the possible
formation of two α-amino radicals at the α-position to
the amide or at the benzylic position. The initial raction using 1
mol % Ru(bpy)3Cl2 under irradiation of HP Single
Blue LED (455 nm) afforded the corresponding trifluoromethyl alcohol 3aa (diastereoisomers mixture) in 73% yield after 2.5 h reaction
time (entry 1), although without diastereoselectivity. Other photocatalysts
such Eosin Y or 4-CzIPN (2,4,5,6-tetrakis(9H-carbazol-9-yl)
isophthalonitrile) were unsuccessful, and the formation of alcohol 3aa was not observed. Unexpectedly, when Ru(bpy)3(PF6)2 was used as photocatalyst, product 3aa was obtained with only 23% yield after 24 h (entry 4).
A solvent screening (entries 5–7) with Ru(bpy)3Cl2 photocatalyst did not improve the results obtained with acetonitrile.
Increasing the amount of trifluoroacetophenone was detrimental for
the conversion to product 3aa (entries 8–10),
and it was isolated with lower yield (56–66%). As we described
before for a photocatalytic Giese addition of 1a,[12c] in order to improve the conversion, we decided
to use (PhO)2PO2H as a Brønsted acid additive.
Unfortunately, the obtained yield for 3aa was lower (26%).
We could perform the reaction at the 0.2 mmol scale obtaining the
same yield (entry 12). Finally, several control experiments were carried
out showing that the model reaction did not occur without the presence
of the Ru(bpy)3Cl2 photocatalyst (entry 13)
or without visible-light irradiation (entry 14).
Table 1
Optimization of the Reaction Conditionsa
Entry
Photocatalyst
Solvent
Additive
t (h)
drb
Yield (%)c
1
Ru(bpy)3Cl2·H2O (1%)
CH3CN
-
2.5
1:1
73
2
Eosin Y (5%)
CH3CN
-
24
-
-
3
4-CzIPN (2%)
CH3CN
-
24
-
-
4
Ru(bpy)3(PF6)2 (1%)
CH3CN
-
23
1:1
23
5
Ru(bpy)3Cl2·H2O (1%)
DMF
-
5
1:1
63
6
Ru(bpy)3Cl2·H2O (1%)
CH2Cl2
-
24
1:1
>5b
7
Ru(bpy)3Cl2·H2O (1%)
THF
-
24
1:1
>5b
8d
Ru(bpy)3Cl2·H2O (1%)
CH3CN
-
2.5
1:1
66
9e
Ru(bpy)3Cl2·H2O (1%)
CH3CN
-
2.5
1:1
56
10f
Ru(bpy)3Cl2·H2O (1%)
CH3CN
-
2.5
1:1
58
11
Ru(bpy)3Cl2·H2O (1%)
CH3CN
(PhO)2PO2H (10%)
24
1:1
26
12g
Ru(bpy)3Cl2·H2O (1%)
CH3CN
-
2.5
1:1
72
13
-
CH3CN
-
24
-
-
14h
Ru(bpy)3Cl2·H2O (1%)
CH3CN
-
24
-
-
Reaction
conditions: 0.13 mmol of 1a, 0.1 mmol 2a, x mol % of
photocatalyst in 1 mL of solvent at rt under an Ar atmosphere and
HP Blue LED (450 nm) irradiation.
Determined by 1H NMR.
Isolated yield of 3aa.
Reaction was performed with 0.1
mmol of 1a and 0.3 mmol 2a.
Reaction was performed with 0.1
mmol of 1a and 0.2 mmol 2a.
Reaction was performed with 0.1
mmol of 1a and 0.13 mmol 2a.
Reaction performed with 0.26 mmol
of 1a, 0.2 mmol of 2a in 2 mL of CH3CN at rt under HP Blue LED (455 nm) irradiation.
Reaction performed under darkness.
Reaction
conditions: 0.13 mmol of 1a, 0.1 mmol 2a, x mol % of
photocatalyst in 1 mL of solvent at rt under an Ar atmosphere and
HP Blue LED (450 nm) irradiation.Determined by 1H NMR.Isolated yield of 3aa.Reaction was performed with 0.1
mmol of 1a and 0.3 mmol 2a.Reaction was performed with 0.1
mmol of 1a and 0.2 mmol 2a.Reaction was performed with 0.1
mmol of 1a and 0.13 mmol 2a.Reaction performed with 0.26 mmol
of 1a, 0.2 mmol of 2a in 2 mL of CH3CN at rt under HP Blue LED (455 nm) irradiation.Reaction performed under darkness.Under the above optimized reaction
conditions (entry 1, Table ), the reaction scope
of 1,4-dihydroquinoxalin-2-one derivatives with trifluoroacetophenone 2a was first studied (Scheme ). A range of dihydroquinoxalin-2-ones were suitable
for this reaction obtaining good yields, although without diastereoselectivity
(almost 1:1 dr for all the examples). Initially, we evaluated the
effect of the protecting group at the nitrogen of the amine of dihydroquinoxalin-2-one 1. The reaction tolerates different benzylic substituents,
affording the corresponding trifluoromethyl carbinols 3ba and 3ca with good yields. Moreover, dihydroquinoxalin-2-one 1d bearing a heteroaromatic benzyl moiety furnished product 3da in good yield. Additionally, the group CH2CO2Me is allowed giving the corresponding quinoxalin-2-one 3ea, although with lower yield (55%). Moreover, 1,4-disubstituted-3,4-dihydroquinoxalin-2-ones
could be used under the optimized reaction conditions giving the corresponding
products 3fa and 3ga with good yields (60%
for both examples). The substitution in the parent aromatic ring of
3,4-dihydroquinoxalin-2-one was also examined under the optimal reaction
conditions. To our delight, 3,4-dihydroquinoxalin-2-one bearing an
electron-donating (Me) or electron-withdrawing (Br) group at the 7-position
on the aromatic ring furnished the corresponding tertiary alcohols 3ha and 3ia in good yields (59% and 68%, respectively).
Nevertheless, 3,4-dihydroquinoxalin-2-ones with a methyl substituent
at either the 5 or the 8 position were not suitable substrates for
our methodology. Interestingly, the less electron-rich substrate 1l bearing a secondary amine was found to be competent under
the reaction conditions furnishing the product 3la in
moderate yield.
Scheme 2
Scope of the Radical Addition Reaction Regarding the
Dihydroquinoxalin-2-one
Derivatives 1
Reaction conditions: 1 (0.26 mmol), 2a (0.2 mmol), and Ru(bpy)3Cl2·H2O (1%) in 2 mL of CH3CN and stirred at rt under an Ar atmosphere and irradiation
of a HP single LED (450 nm). Isolated yields after column chromatography.
Diastereomeric ratio determined by 1H NMR.
Scope of the Radical Addition Reaction Regarding the
Dihydroquinoxalin-2-one
Derivatives 1
Reaction conditions: 1 (0.26 mmol), 2a (0.2 mmol), and Ru(bpy)3Cl2·H2O (1%) in 2 mL of CH3CN and stirred at rt under an Ar atmosphere and irradiation
of a HP single LED (450 nm). Isolated yields after column chromatography.
Diastereomeric ratio determined by 1H NMR.Subsequently, the scope and limitation of various trifluoromethyl
aryl ketones 2 were explored (Scheme ). The incorporation of either electron-donating
groups (Me, Et, or MeO) or electron-withdrawing groups (Cl or Br)
on the benzene ring of trifluoromethyl ketones 2 had
no obvious impact on the reaction, and the corresponding products
(3aa–3al) were obtained in 40–70%
yields. The presence of a MeO group in the ortho position
to the carbonyl group of 2 had a slight influence on
obtaining the trifluoromethyl alcohol 3ak with lower
yield (37%), but somewhat higher diastereoselectivity (59:41 dr).
Furthermore, trifluoromethyl ketones with two substituents at the
aromatic ring or bearing a heteroaromatic ring were tested in the
radical addition reaction, affording the products 3al and 3am with moderate yields. Besides, non-aromatic
trifluoromethyl ketone 2n was found to be able to react
under the optimized conditions but provide the expected product (3an) in low yield.
Scheme 3
Scope of the Radical Addition Reaction Regarding
the Trifluoromethyl
Aryl Ketones 2
Reaction conditions: 1 (0.26 mmol), 2 (0.2 mmol), and Ru(bpy)3Cl2·H2O (1%) in 2 mL of CH3CN and stirred at rt under an Ar atmosphere with irradiation
of a HP single LED (455 nm). Isolated yields after column chromatography.
Diastereomeric ratio determined by 1H NMR.
Scope of the Radical Addition Reaction Regarding
the Trifluoromethyl
Aryl Ketones 2
Reaction conditions: 1 (0.26 mmol), 2 (0.2 mmol), and Ru(bpy)3Cl2·H2O (1%) in 2 mL of CH3CN and stirred at rt under an Ar atmosphere with irradiation
of a HP single LED (455 nm). Isolated yields after column chromatography.
Diastereomeric ratio determined by 1H NMR.Finally, the utility of our protocol was further applied
to trifluoroacetophenone 2o resulting in the incorporation
of the indometacin core,
a nonsteroidal anti-inflammatory drug (Scheme ). Hence, indometacin was coupled with p-hydroxytrifluoroacetophenone in the presence of DCC, obtaining
the corresponding ester 2o in 97% yield. This derivative
was subjected to our photoredox radical addition protocol furnishing
the desired dihydroquinoxalin-2-one derivative bearing the indometacin
scaffold (3ao) in 64% yield.
Scheme 4
Synthesis of Indometacin-Derived
Trifluoroacetophenone 2o and Its Subsequent Radical Addition
Reaction with Dihydroquinoxalin-2-one 1a
Reaction conditions: 1a (0.26 mmol), 2o (0.2 mmol), and Ru(bpy)3Cl2·H2O (1%) in 2 mL of CH3CN and stirred at rt under an Ar atmosphere and irradiation
of a HP Single LED (455 nm). Isolated yield after column chromatography.
Diastereomeric ratio determined by 1H NMR.
Synthesis of Indometacin-Derived
Trifluoroacetophenone 2o and Its Subsequent Radical Addition
Reaction with Dihydroquinoxalin-2-one 1a
Reaction conditions: 1a (0.26 mmol), 2o (0.2 mmol), and Ru(bpy)3Cl2·H2O (1%) in 2 mL of CH3CN and stirred at rt under an Ar atmosphere and irradiation
of a HP Single LED (455 nm). Isolated yield after column chromatography.
Diastereomeric ratio determined by 1H NMR.To further expand the substrate scope of this reaction,
other trifluoromethyl
ketones were used as sources of trifluoromethyl ketyl radicals. As
disclosed in Scheme , ethyl 3,3,3-trifluoropyruvate 4 proved to be a suitable
substrate for this transformation, even though the corresponding alcohol
product 5 was isolated in low yield.
Scheme 5
Scope of the Radical
Addition Reaction Regarding the 4-Benzyl-3,4-dihydroquinoxalin-2(1H)-one 1a with Ethyl 3,3,3-trifluoropyruvate 4.
Reaction conditions: 1a (0.13 mmol), 4 (0.1 mmol), and Ru(bpy)3Cl2·H2O (1%) in 1 mL of CH3CN and
stirred at rt under an Ar atmosphere and irradiation
of a HP single LED (450 nm). 0.1 mmol
of 1a and 0.13 mmol of 4 were used. Isolated
yields after column chromatography. Diastereomeric ratio determined
by 1H NMR.
Scope of the Radical
Addition Reaction Regarding the 4-Benzyl-3,4-dihydroquinoxalin-2(1H)-one 1a with Ethyl 3,3,3-trifluoropyruvate 4.
Reaction conditions: 1a (0.13 mmol), 4 (0.1 mmol), and Ru(bpy)3Cl2·H2O (1%) in 1 mL of CH3CN and
stirred at rt under an Ar atmosphere and irradiation
of a HP single LED (450 nm). 0.1 mmol
of 1a and 0.13 mmol of 4 were used. Isolated
yields after column chromatography. Diastereomeric ratio determined
by 1H NMR.To demonstrate the utility
of our photocatalytic protocol for the
synthesis of dihydroquinoxalin-2-ones bearing a trifluoromethyl alcohol,
we also performed the reaction of 1a and trifluoroacetophenone 2a at 1 mmol scale under HP Single Blue LED or sunlight irradiation
(Scheme A). Interestingly,
when the reaction was performed under sunlight irradiation, we obtained
the product 3aa with higher yield (80%). Finally, we
carried out the reduction of the amide group present in the dihydroquinoxalin-2-one
derivative 3 with LiAlH4 in THF at 70 °C,
obtaining the corresponding dihydroquinoxaline 6 with
70% yield (Scheme B). Moreover, we attempted dehydration of the product 3aa using SOCl2/pyridine;[14] however,
we obtained the quinoxalin-2-one derivative 7 in 81%
yield from the nucleophilic substitution of the OH group by Cl.
Scheme 6
(A) 1 Mmol Scale Reactions Using HP Single Blue LED or Sunlight Irradiation
an Ar Atmosphere. (B) Synthetic Transformations. Isolated Yields after
Column Chromatography
To gain insight into the mechanism of the reaction, we first examined
the reduction potential values of each component in the reaction mixture.
Ru(bpy)3Cl2 potentials in MeCN are well stablished,
and this complex can act either as an oxidant with *E1/2 = +0.77 V vs SCE or as a reductant with *E1/2= −0.81 V vs SCE.[15] Reduction potentials of several substituted 2,2,2-trifluoroacetophenones
were reported in 1990 by Liu.[16] This authors
examined the effect of several substituents at the aromatic ring and
found that the parent 2,2,2-trifluoroacetophenone (2a) has a reduction potential of −1.40 V vs SCE. Besides, we
have previously reported the reduction potential of 4-benzylquinoxalin-2-one 1a in an earlier work (+0.80 V vs SCE).[12c] Based on the thermodynamics of canonical photoredox reactivity,
we can exclude a Single Electron Transfer (SET) event between the
excited state of the ruthenium catalyst and either the trifluoroacetophenone 2a (via an oxidative quenching pathway) or 4-benzylquinoxalin-2-one 1a (via a reductive quenching pathyway). This assumption is
further confirmed by luminescence quenching studies in which both
trifluoroacetophenone 2a and 4-benzylquinoxalin-2-one 1a were unable to independently deactivate the excited state
of Ru(bpy)3Cl2 (Figure A).
Figure 1
Emission spectrum of Ru(bpy)3Cl2·6H2O (0.02 mM) for (A) solutions of increasing
concentration
of trifluoroacetophenone 2a (A0 = 0 mM; A1 = 9.6 mM;
A2 = 19.2 mM); (B) solutions of constant concentration of quinoxalin-2-one 1a (9.6 mM) and increasing concentration of trifluoroacetophenone 2a (B0 = 0 mM; B1 = 9.6 mM; B2 = 19.2 mM); and (C) solutions
of constant concentration of trifluoroacetophenone 2a (9.6 mM) and increasing concentration of quinoxalin-2-one 1a (C0 = 0 mM; C1 = 9.6 mM; C2 = 19.2 mM). (D) Stern–Volmer
plot for the emission spectrum (at 600 nm) depicted in (C).[17]
Emission spectrum of Ru(bpy)3Cl2·6H2O (0.02 mM) for (A) solutions of increasing
concentration
of trifluoroacetophenone 2a (A0 = 0 mM; A1 = 9.6 mM;
A2 = 19.2 mM); (B) solutions of constant concentration of quinoxalin-2-one 1a (9.6 mM) and increasing concentration of trifluoroacetophenone 2a (B0 = 0 mM; B1 = 9.6 mM; B2 = 19.2 mM); and (C) solutions
of constant concentration of trifluoroacetophenone 2a (9.6 mM) and increasing concentration of quinoxalin-2-one 1a (C0 = 0 mM; C1 = 9.6 mM; C2 = 19.2 mM). (D) Stern–Volmer
plot for the emission spectrum (at 600 nm) depicted in (C).[17]These findings led us
to explore other pathways dictating this
reactivity. First, we performed a Stern–Volmer quenching study
maintaining the amount of both the 4-benzylquinoxalin-2-one 1a and Ru(bpy)3Cl2 in each solution
and varying the amount of trifluoroacetophenone 2a. After
recording the emission spectrum of each sample, only a modest change
was observed, which can be attributed to experimental errors (Figure B). Then, we repeated
the same experiment but now maintain constant the amount of trifluoroacetophenone 2a and Ru(bpy)3Cl2 and vary the concentration
of 4-benzylquinoxalin-2-one 1a. This time we obtained
a set of emission spectra consistent with a Stern–Volmer relationship
(Figure C), and therefore
we can establish a Stern–Volmer constant (KSV) of 25.9 M–1 (Figure D).[17] This study
revealed that the excited state of Ru(bpy)3Cl2 can be quenched (presumably via a SET) by 4-benzylquinoxalin-2-one 1a only if trifluoroacetophenone 2a is present.
These finding can be explained by admitting an interaction between 1a and 2a that makes 1a more prone
to oxidation.At this point, we wanted to explore the interaction
between 1a and 2a. We envisioned that a
solution of 4-benzylquinoxalin-2-one 1a in MeCN-d could be titrated with trifluoroacetophenone 2a while
monitoring the process by NMR.[17] Unfortunately,
we did not observe any NMR change that could be attributed to an interaction
between 1a and 2a (Figure
S1),[17] especially regarding the
amidic N–H bond of 1a and a possible Proton Coupled
Electron Transfer process like those reported by Knowles.[18]Furthermore, to confirm the participation
of a closed photoredox
cycle and to exclude a radical chain process, we determined the quantum
yield of the process. First, we determined the photon flux of our
photochemical setup using standard ferrioxalate actinometry (Figure S3),[17] and then,
we found out that the quantum yield of our methodology is as low as
Φ = 0.21 ± 0.02, showing that the participation of a chain
mechanism is unlikely (Figure S4).[17] We have also performed a light/off experiment
(Figure ) for the
reaction between 1a and 2a, showing as well
that the mechanism should be a closed photoredox cycle.
Figure 2
On/off experiment
for the radical addition reaction between dihydroquinoxalin-2-one 1a and trifluoroacetophenone 2a.
On/off experiment
for the radical addition reaction between dihydroquinoxalin-2-one 1a and trifluoroacetophenone 2a.With all this information, we were able to postulate a plausible
reaction mechanism for our photochemical protocol (Scheme ). The absorption of a 455
nm photon promotes Ru(bpy)3Cl2 to its excited
state. Then, a sort of aggregate between 1a and 2a facilitated the SET from the excited photocatalyst to 1a, yielding the corresponding radical cation A as well as the RuI form of the catalyst.[19] The radical cation A can experience Proton
Transfer (PT) to form the α-amino radical B, which
has a nucleophilic character and can react with trifluoroacetophenone 2a to generate O-centered radical C. This radical B can react with itself through an unproductive
pathway to form the dimeric compound 8.[12c] The RuI species, which has a strong reductive
behavior (EII/I1/2 = −1.33
V vs SCE), is able to reduce radical C to its corresponding
alkoxide anion D. Finally, another PT event over alkoxide D furnishes the desired product 3aa.
Scheme 7
Mechanistic
Hypothesis for the Generation of 3aa from 1a and 2a under Photoredox Conditions
Conclusion
In summary, we have described the synthesis
of trifluoromethyl
tertiary alcohols bearing a dihydroquinoxalin-2-one framework (25
examples) through a photocatalytic radical addition of dihydroquinoxalin-2-ones
to trifluoromethyl ketones enabled by a reductive quenching cycle
of Ru(bpy)3Cl2. Our protocol provides rapid
and efficient access to synthetic useful dihydroquinoxalin-2-ones
bearing trifluoromethyl and hydroxyl groups under mild reaction conditions
and simple operational protocol using HP Single LED of 455 nm. It
is also important to note that our protocol is operative in the late-stage
functionalization of a value-added indometacin-derived trifluoroacetophenone
substrate. In addition, the reaction can be scaled up to 1 mmol using
HP Single LED (455 nm) as well as sunlight irradiation. Moreover,
several synthetic transformations have been performed, and a plausible
reaction mechanism has been postulated.
Experimental
Section
General Methods
Reactions were carried out in Schlenk
tubes oven-dried overnight at 120 °C. Commercial reagents were
used as purchased. Reactions were monitored by TLC analysis using
Merck Silica Gel 60 F-254 thin layer plates. Flash column chromatography
was performed on Merck silica gel 60, 0.040–0.063 mm and visualized
using both a UV lamp (254 nm) and then a CAM solution (an aqueous
solution of ceric ammonium molybdate). Melting points were determined
in capillary tubes. NMR spectra were run at 300 MHz for 1H and 75 MHz for 13C using residual nondeuterated solvent
as internal standard (CHCl3: δ 7.26 and 77.00 ppm,
respectively). Chemical shifts are given in ppm. The carbon type was
determined by DEPT experiments. High resolution mass spectra (ESI)
were recorded on a AB SCIEX Triple TOF spectrometer equipped with
an electrospray source with a capillary voltage of 4.5 kV (ESI). MeCN
was degassed by three freeze–pump–thaw cycles and stored
over 3 Å MS for 48 h at least. Prior to use, MeCN was bubbled
with Ar for 10 min. Commercially available High Power Single LEDs
manufactured by Intelligent LED Solutions (purchased from Farnell,
internal reference 3583117) with an emission band centered at 455
nm were used as a light source. These LEDs lay on an aluminum block
to ensure proper heat dissipation. Photochemical reactions were conducted
in conventional borosilicate glass Schlenk flasks situated at 2 cm
to the HP Single LED. Ru(bpy)4Cl2·6H2O and Eosin Y were purchased by Merck-Aldrich. 4-CzIPN[20] and dihydroquinoxalinones[12c]1 were known compounds and were synthesized
according to literature-reported procedures.
Specific Procedure for
the Synthesis of Indometacin-Derived
Trifluoroacetophenone 2o
To a stirred solution of commercially
available indometacin (196.8 mg, 0.55 mmol, 1.1 equiv) in DCM (5 mL)
were added p-hydroxytrifluoroacetophenone (95.1 mg,
0.5 mmol, 1 equiv) and DCC (155 mg, 0.75 mmol, 1.5 equiv), and the
resulting mixture was stirred at room temperature for 16 h. Then,
the crude reaction mixture was filtered through a pad of Celite eluting
with Et2O. This yellow solution was concentrated under
reduced pressure, and the residue was purified by column chromatography
using hexane:EtOAc as eluent to afford the desired product (257 mg,
0.485 mmol, 97% yield) as a white solid.1H NMR (300
MHz, CDCl3) δ 8.29–7.93 (m, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H),
7.28 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 2.5 Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H), 6.71 (dd, J = 9.0, 2.5 Hz, 1H), 3.95 (s, 2H), 3.84 (s, 3H), 2.47 (s,
3H); 19F{1H} NMR (282 MHz, CDCl3)
δ −71.87; 13C{1H} NMR (75 MHz,
CDCl3) δ 179.2 (q, JC–F = 35.4 Hz, C), 168.3 (C), 168.2 (C), 156.1 (C), 139.4 (C), 136.4
(C), 133.6 (C), 131.9 (q, JC–F =
2.0 Hz, CH), 131.2 (CH), 130.8 (C), 130.3 (C), 129.2 (C+CH), 127.4
(C), 122.3 (CH), 116.5 (q, JC–F = 290.8 Hz, C), 115.0 (CH), 111.7 (CH), 111.2 (C), 101.2 (CH), 55.7
(CH3), 30.5 (CH2), 13.4 (CH3); HRMS
(ESI/Q-TOF) m/z [M + H]+ C27H20ClF3NO5+ Calcd for 530.0977; Found 530.0984.
General Procedure for the
Photocatalytic Radical Addition of
Quinoxalin-2-ones to Trifluoroacetophenone (GP-1)
In an oven-dried
Schlenk tube, the corresponding quinoxalin-2-one 1 (0.26
mmol, 0.13 equiv) and Ru(bpy)3Cl2·6H2O (1.5 mg, 1 mol %) were placed and the flask was evacuated
and backfilled with Ar (×3). Then, anhydrous and degassed CH3CN (2 mL), as well as the corresponding trifluoroacetophenone 2 (0.2 mmol, 0.1 equiv), was added via syringe. The reaction
mixture was stirred under the irradiation of a High-Power Blue LED
(455 nm) while being cooled with a fan to keep the temperature at
20 °C. Once the reaction was finished (TLC), the mixture was
purified by column chromatography using hexane:EtOAc or hexane:Et2O mixtures to afford compound 3.
Specific Procedure
for the Photocatalytic Radical Addition of
4-Benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a) to
Ethyl 3,3,3-trifluoropyruvate (4) (SP-1)
In an oven-dried
Schlenk tube, the corresponding 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 47.6 mg, 0.2 mmol, 0.1 equiv) and
Ru(bpy)3Cl2 (1.5 mg, 1 mol %) were placed, and
the flask was evacuated and backfilled with Ar (×3). Then, anhydrous
and degassed CH3CN (2 mL), as well as 3,3,3-trifluoropyruvate
(4, 34 μL, 0.26 mmol, 1.3 equiv), was added via
syringe. The reaction mixture was stirred under the irradiation of
a High-Power Blue LED (455 nm) while being cooled with a fan to keep
the temperature at 20 °C. Once the reaction was finished (TLC),
the mixture was purified by column chromatography using hexane:EtOAc
mixtures to afford compound 5.
Specific Procedure for
the Photocatalytic Radical Addition of
4-Benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a) to
2,2,2-Trifluoroacetophenone (2a) 1 mmol Scale Reaction (SP-2)
In an oven-dried Schlenk tube, 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 312 mg, 1.3 mmol, 1.3 equiv) and
Ru(bpy)3Cl2·6H2O (5.0 mg, 1
mol %) were placed, and the flask was evacuated and backfilled with
Ar (×3). Then, anhydrous and degassed CH3CN (7 mL),
as well as 2,2,2-trifluoroacetophenone (2a, 212 μL,
1.0 mmol 1 equiv) was added via syringe. The reaction mixture was
stirred under the irradiation of several High-Power Blue LEDs (455
nm) while being cooled with a fan to keep the temperature at 20 °C.
Once the reaction was finished (TLC), the mixture was purified by
column chromatography using hexane:EtOAc mixtures to afford compound 3aa (240 mg, 0.58 mmol, 58% yield) as a mixture of diastereoisomers
(3aa′ and 3aa″, 59:41 dr).
Specific Procedure for the photocatalytic radical addition of
4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a) to
2,2,2-trifluoroacetophenone (2a) under sunlight irradiation (SP-3)
In an oven-dried Schlenk tube, 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 465 mg, 1.95 mmol, 1.3 equiv) and
Ru(bpy)3Cl2·6H2O (7.5 mg, 1
mol %) were placed and the flask was evacuated and backfilled with
Ar (×3). Then, anhydrous and degassed CH3CN (10 mL),
as well as 2,2,2-trifluoroacetophenone (2a, 316 μL,
1.5 mmol 1 equiv) was added via syringe. The reaction mixture placed
at the upper part of the building in sunny hours and was stirred for
2.5 h. Once the reaction was finished (TLC), the mixture was purified
by column chromatography using hexane:EtOAc mixtures to afford compound 3aa (495 mg, 1.2 mmol, 80% yield) as a mixture of diastereoisomers
(3aa′ and 3aa″, 53:47 dr).
Specific Procedure for the reduction of 3a (SP-4)
In
a 50 mL round bottomed flask equipped with a condenser, compound 3aa (78.4 mg, 0.19 mmol, 1 equiv) was placed. The flask was
purged with N2 and then dry THF (5 mL) was added. The solution
was cooled to 0 °C and LiAlH4 (125 μL, 0.76
mmol, 4 equiv., 4 M in THF) was added dropwise. The reaction mixture
was progressively warmed up and heated (in an oil bath) at reflux
temperature for 2 h. After this period, the reaction mixture was cooled
again to 0 °C and the excess LiAlH4 was quenched with
sat. aq. NH4Cl (5 mL) and the organics were extracted with
DCM (×3). The combined organic layers were washed with brine
(×1) and dried over anhydrous MgSO4. After evaporating
the solvent, the residue was purified by column chromatography using
hexane:EtOAc mixtures, obtaining quinoxaline derivative 6.
Specific Procedure for the Chlorination of 3aa (SP-5)
In
a 10 mL round bottomed flask equipped with a condenser, compound 3aa (26.9 mg, 0.07 mmol, 1 equiv) was placed. The flask was
purged with N2 and then DCM (2 mL) was added. SOCl2 (10 μL, 0.13 mmol, 2 equiv) and pyridine (11 μL,
0.13 mmol, 2 equiv) were successively added and the reaction mixture
was stirred at room temperature under N2 for 2 h. The reaction
mixture was directly purified by column chromatography using hexane:Et2O mixture to afford compound 7.
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol,
1 equiv), according to GP-1, compound 3aa was obtained
as a mixture of diastereoisomers (50:50 dr) that were separated by
column chromatography using hexane:EtOAc mixtures (from 9:1 to 7:3): 3aa′ (29.7 mg, 0.07 mmol, 36% yield, brown oil) and 3aa″ (30.1 mg, 0.07 mmol, 36% yield, brown oil).
Using 4-benzyl-7-methyl-3,4-dihydroquinoxalin-2(1H)-one (1h, 65.6 mg, 0.26 mmol, 1.3 equiv)
and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2
mmol, 1 equiv), according to GP-1, compound 3ha was obtained
as a mixture of diastereoisomers (51:49 dr) that were separated by
column chromatography using hexane:EtOAc mixtures (from 9:1 to 7:3): 3ha′ (25.7 mg, 0.06 mmol, 30% yield, colorless oil)
and 3ha″ (24.7 mg, 0.06 mmol, 29% yield, colorless
oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
2,2,2-trifluoro-1-(p-tolyl)ethan-1-one (2b, 31 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ab was obtained as a mixture of diastereoisomers (60:40 dr)
that were separated by column chromatography using hexane:EtOAc mixtures
(from 95:5 to 75:25): 3ab′ (28.0 mg, 0.06 mmol,
30% yield, brown oil) and 3ab″ (18.7 mg, 0.04
mmol, 20% yield, brown oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
1-(4-ethylphenyl)-2,2,2-trifluoroethan-1-one (2c, 33
μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ac was obtained as a mixture of diastereoisomers (53:47 dr) that were
separated by column chromatography using hexane:EtOAc mixtures (from
95:5 to 75:25): 3ac′ (13.6 mg, 0.03 mmol, 15%
yield, yellow oil) and 3ac″ (12.1 mg, 0.03 mmol,
14% yield, yellow oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
2,2,2-trifluoro-1-(4-methoxyphenyl)ethan-1-one (2d, 31
μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ad was obtained as a mixture of diastereoisomers (54:46 dr) that were
separated by column chromatography using hexane:EtOAc mixtures (from
95:5 to 75:25): 3ad′ (22.7 mg, 0.05 mmol, 27%
yield, yellow oil) and 3ad″ (20.2 mg, 0.05 mmol,
23% yield, yellow oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
2,2,2-trifluoro-1-(4-chlorophenyl)ethan-1-one (2e, 30
μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ae was obtained as a mixture of diastereoisomers (50:50 dr) that were
separated by column chromatography using hexane:EtOAc mixtures (from
95:5 to 75:25): 3ae′ (24.1 mg, 0.05 mmol, 27%
yield, yellow oil) and 3ae″ (24.4 mg, 0.05 mmol,
27% yield, yellow oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one (2f, 30
μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3af was obtained as a mixture of diastereoisomers (58:42 dr) that were
separated by column chromatography using hexane:EtOAc mixtures (from
95:5 to 75:25): 3af′ (36.3 mg, 0.08 mmol, 37%
yield, yellow oil) and 3af″ (26.4 mg, 0.05 mmol,
27% yield, yellow oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
2,2,2-trifluoro-1-(m-tolyl)ethan-1-one (2g, 31 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ag was obtained as a mixture of diastereoisomers (58:42 dr)
that were separated by column chromatography using hexane:EtOAc mixtures
(from 95:5 to 75:25): 3ag′ (24.8 mg, 0.06 mmol,
31% yield, yellow oil) and 3ag″ (19.6 mg, 0.05
mmol, 24% yield, yellow oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
2,2,2-trifluoro-1-(3-methoxyphenyl)ethan-1-one (2h, 32
μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ah was obtained as a mixture of diastereoisomers (53:47 dr) that were
separated by column chromatography using hexane:EtOAc mixtures (from
95:5 to 75:25): 3ah′ (23.1 mg, 0.05 mmol, 26%
yield, yellow oil) and 3ah″ (20.6 mg, 0.05 mmol,
24% yield, yellow oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
1-(3-chlorophenyl)-2,2,2-trifluoroethan-1-one (2i, 29
μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ai was obtained as a mixture of diastereoisomers (55:45 dr) that were
separated by column chromatography using hexane:EtOAc mixtures (from
95:5 to 75:25): 3ai′ (30.0 mg, 0.07 mmol, 33%
yield, yellow oil) and 3ai″ (24.6 mg, 0.05 mmol,
28% yield, yellow oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
1-(3-bromophenyl)-2,2,2-trifluoroethan-1-one (2j, 30
μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3aj was obtained as a mixture of diastereoisomers (54:46 dr) that were
separated by column chromatography using hexane:EtOAc mixtures (from
95:5 to 75:25): 3aj′ (33.9 mg, 0.07 mmol, 35%
yield, yellow oil) and 3aj″ (28.8 mg, 0.06 mmol,
29% yield, yellow oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and
2,2,2-trifluoro-1-(thiophen-2-yl)ethan-1-one (2m, 26
μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3am was obtained as a mixture of diastereoisomers (58:42 dr) that were
separated by column chromatography using hexane:EtOAc mixtures (from
95:5 to 75:25): 3am′ (25.1 mg, 0.06 mmol, 30%
yield, yellow oil) and 3am″ (18.4 mg, 0.04 mmol,
22% yield, yellow oil).
Using 4-(4-methoxybenzyl)-3,4-dihydroquinoxalin-2(1H)-one (1c, 69.8 mg, 0.26 mmol, 1.3 equiv)
and 1-(4-chlorophenyl)-2,2,2-trifluoroethan-1-one (2d, 30 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3cd was obtained as a mixture of diastereoisomers (60:40 dr)
that were separated by column chromatography using hexane:EtOAc mixtures
(from 95:5 to 75:25): 3cd′ (35.3 mg, 0.07 mmol,
37% yield, yellow oil) and 3cd″ (23.7 mg, 0.05
mmol, 25% yield, yellow oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 4-(2,2,2-trifluoroacetyl)phenyl
2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate
(2o, 106 mg, 0.2 mmol, 1 equiv), according to GP-1, compound 3ao was obtained as a mixture of diastereoisomers (55:45 dr)
that were separated by column chromatography using DCM:EtOAc mixtures
(from 99:1 to 95:5): 3ao′ (54.1 mg, 0.07 mmol,
35% yield, yellow oil) and 3ao″ (44.2 mg, 0.06
mmol, 29% yield, yellow oil).
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 23.8 mg, 0.1 mmol, 1 equiv) and ethyl 3,3,3-trifluoropyruvate
(4, 17 μL, 0.13 mmol, 1.3 equiv), according to
SP-1, compound 5 was obtained as a mixture of diastereoisomers
(54:46 dr) that were separated by column chromatography using hexane:EtOAc
mixtures (from 95:5 to 75:25): 5′ (5.5 mg, 0.014
mmol, 14% yield, yellow oil) and 5″ (4.7 mg, 0.011
mmol, 11% yield, yellow oil).
Using 4-benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3aa, 78.4 mg, 0.19 mmol, 1 equiv),
according to SP-4, compound 6 was obtained as a mixture
of diastereoisomers (52:48 dr) that were separated by column chromatography
using hexane:EtOAc mixtures (from 95:5 to 75:25): 6′ (27.8 mg, 0.068 mmol, 36% yield, yellow oil) and 6″ (25.7 mg, 0.062 mmol, 34% yield, yellow oil).
Using 4-benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3aa, 26.9 mg, 0.05 mmol, 1 equiv),
according to SP-5, compound 7 was obtained as a mixture
of diastereoisomers (50:50 dr) that were separated by column chromatography
using hexane:Et2O mixtures (from 5:5 to 2:8): 7′ (11.3 mg, 0.025 mmol, 40% yield, yellow oil) and 7″ (11.5 mg, 0.025 mmol, 40% yield, yellow oil).
Authors: Chuanyong Wang; Jie Qin; Xiaodong Shen; Radostan Riedel; Klaus Harms; Eric Meggers Journal: Angew Chem Int Ed Engl Date: 2015-12-02 Impact factor: 15.336
Authors: C Todd Eary; Zachary S Jones; Robert D Groneberg; Laurence E Burgess; David A Mareska; Mark D Drew; James F Blake; Ellen R Laird; Devan Balachari; Michael O'Sullivan; Andrew Allen; Vivienne Marsh Journal: Bioorg Med Chem Lett Date: 2007-02-08 Impact factor: 2.823
Authors: Jiang Wang; María Sánchez-Roselló; José Luis Aceña; Carlos del Pozo; Alexander E Sorochinsky; Santos Fustero; Vadim A Soloshonok; Hong Liu Journal: Chem Rev Date: 2013-12-03 Impact factor: 60.622
Authors: Andreas Mavroskoufis; Keerthana Rajes; Paul Golz; Arush Agrawal; Vincent Ruß; Jan P Götze; Matthew N Hopkinson Journal: Angew Chem Int Ed Engl Date: 2020-01-09 Impact factor: 15.336
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Figure 1
Figure 2
Scheme 7