Electron-Donor-Acceptor Complex-Enabled Flow Methodology for the Hydrotrifluoromethylation of Unsaturated β-Keto Esters

Article abstract of DOI:10.1021/acs.orglett.0c03187

A novel electron-donor-acceptor (EDA) complex-enabled flow photochemical hydrotrifluoromethylation of unsaturated β-keto esters is described. The developed protocol has an easy experimental procedure and does not require the use of transition-metal-based

Full text of DOI:10.1021/acs.orglett.0c03187

pubs.acs.org/OrgLett
Letter
Electron-Donor−Acceptor Complex-Enabled Flow Methodology for
the Hydrotrifluoromethylation of Unsaturated β‑Keto Esters
́
Gabriel M. F. Batista, Pedro P. de Castro, Helio F. Dos Santos, Kleber T. de Oliveira,*
and Giovanni W. Amarante*
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ABSTRACT: A novel electron-donor−acceptor (EDA) complex-enabled flow
photochemical hydrotrifluoromethylation of unsaturated β-keto esters is
described. The developed protocol has an easy experimental procedure and
does not require the use of transition-metal-based photocatalysts, allowing the
isolation of 14 new compounds in up to 86% yield. Control experiments and
computational studies revealed that the reaction proceeds through a Michael-type
1,4-addition of a trifluoromethyl radical, followed by a proton transfer step.
Furthermore, the reaction could be scaled up to 1 mmol, and the final product
could be employed in the preparation of an isoxazolone and a pyrazolone as
trifluoro-substituted heterocycles.
Scheme 1. Previous Literature Reports and Our Proposal
for Hydrotrifluoromethylation of Olefins
he formation of new carbon−carbon bonds is of great
Tinterest in organic synthesis and is usually involved in the
construction of complex molecule backbones.1 In this context,
the development of new building blocks that can be further
applied in the attainment of high-value compounds is
essential.2 Dicarbonyl derivatives have attracted the attention
of the synthetic community and have been extensively used in
the synthesis of bioactive heterocyclic scaffolds,3j,k such as
pyrazolones,3a−e furans,3f−i pyrroles,3f,j lactams,3k and isoxazo-
lones.3l
The hydrotrifluoromethylation of unsaturated β-keto esters
still appears as a challenge in organic chemistry, and novel
methodologies in this field are highly desirable to access novel
trifluoro-containing molecules. The CF3 group is known to
increase the lipophilicity and metabolic stability of pharma-
ceuticals and enhance the biological activities.4 Moreover, the
development of new methodologies for hydrotrifluoromethy-
lation is highly demanded, being a straightforward trans-
formation for the formation of C(sp3)−CF3 bonds.5 Photo-
chemical methodologies appear as valuable alternatives to the
traditional trifluoromethylation protocols, presenting several
advantages.6 Recently, important advances in the photo-
chemical-enabled synthesis were described,7 including strat-
egies involving the formation of electron-donor−acceptor
(EDA) complexes in photochemical transformations.8
methodology for hydrotrifluoromethylation at the β carbonyl
position, we envisioned that the use of an accessible tertiary
amine as an electron-donor reagent together with an electron-
acceptor CF3 source would provide the corresponding
multifunctional CF3-containing derivatives through a photo-
Received: September 22, 2020
The reported procedures for the hydrotrifluoromethylation
of olefins using an EDA approach are mainly related to
electron-rich olefins (Scheme 1a).9 Thus, the use of conjugate
Michael acceptors is still limited to either expensive iridium-
based catalysts (Scheme 1b)10 or organic photocatalysts
(Scheme 1c).11 Because of the lack of an EDA complex
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Letter
catalytic EDA complex protocol.12 Moreover, it is important to
highlight the advantages of this protocol, which was developed
under continuous photoflow conditions, with shorter reaction
times, great scalability, and better efficiency compared with
batch photoreactors (Scheme 1d).
Umemoto’s reagent (3), leading to the desired product 2a in
good yield (74%).
Having established the best flow reactor conditions, we
turned our attention to the evaluation of the reaction scope
(Scheme 2). Under the standard reaction conditions, several
The dicarbonyl compound 1a was prepared according to the
literature protocol through oxidation of the corresponding
Morita−Baylis−Hillman adduct.13 Next, a series of optimiza-
tion reactions were carried out under batch conditions (for full
details, see the Supporting Information). Although initially we
considered the use of diverse photocatalysts, such as the
commercially available [Ru(bpy)3(PF6)2], the isolated yields
were only low to moderate (up to 48%). To our delight, when
the tertiary amine N,N-dimethyl-p-toluidine (DMPT, 4) was
added, the desired product 2a was isolated in 47% yield.
Remarkably, the ruthenium complex was no longer required
for product formation, suggesting the formation of an EDA
complex, presumably with Umemoto’s reagent as the acceptor
and the amine as the donor. Moreover, the reaction in the dark
gave only a 9% yield, indicating that photoexcitation under
blue-light irradiation is required.
Scheme 2. Scope of the Hydrotrifluoromethylation of
Dicarbonyl Compounds under Flow Conditions
Furthermore, during the batch optimization, a screening of
the tertiary amine and its loading was carried out. When only 2
equiv of the tertiary amine was employed, the Umemoto
reagent was not completely consumed, suggesting that after
some reaction time no free tertiary amine was available to
generate the corresponding EDA complex. On the other hand,
the use of a higher amine loading (10 equiv) considerably
decreased the yield. Thus, the best results were obtained with
two consecutive additions (2 + 1 equiv) of DMPT, leading to
product 2a in 61% yield after 4.5 h under batch conditions.14
Considering that continuous flow photoreactors have more
efficient irradiation and that the ratio of the tertiary amine to
Umemoto’s reagent is critical for the attainment of higher
yields, we hypothesized that the transposition of this reaction
to continuous conditions would greatly enhance the yield.15
Therefore, a second optimization was conducted in a
photoflow reactor (setup details are available in the Supporting
Information), taking into account the flow rate and the amine
loading (Table 1). As a result, the best reaction conditions are
given in entry 4 of Table 1, with a flow rate of 1.0 mL min−1
and a residence time of 30 min. It is important to highlight that
only 2 equiv of DMPT was employed with just 1.1 equiv of
aryl-substituted derivatives were well-tolerated. For example,
the presence of an electron-donating methyl group even at a
sterically hindered ortho position led to the desired product 2c
in 86% yield. Despite the well-known bond dissociation energy
related to halogenated adducts under photochemical reaction
conditions, para-, meta-, and even ortho-halogenated products
were synthesized in good yields (2f−k). Furthermore, a
substrate with an electron-withdrawing p-trifluoromethyl group
afforded 2e in 30% yield. It is important to notice that
although 2e was synthesized in a lower yield (30%), this
product contains two trifluoromethyl groups in its structure.
Particularly, in this case, the starting material was not
completely consumed. Finally, the use of heteroaryl sub-
stituents was also evaluated, affording products 2l and 2m in
46% and 44% yield, respectively. The use of a sterically
hindered trisubstituted olefin (diethyl 2-benzylidenemalonate)
was also evaluated under the optimized reaction conditions but
failed to provide the desired product, suggesting that the use of
terminal olefins might be crucial for this transformation.
To experimentally confirm the formation of an EDA
complex, UV−vis spectra of both Umemoto’s reagent and
DMPT in separate solutions and their corresponding mixtures
were obtained. When the spectrum of the mixture is
deconvoluted from the individual spectra, the EDA complex
spectrum appears at λmax = 400 nm (Scheme 3a). Besides, a
titration of DMPT into a solution of Umemoto’s reagent was
also performed (Scheme 3b), and in agreement with the Le
Table 1. Optimization of the Hydrotrifluoromethylation
Reaction under Flow Conditions
flow rate
residence time
(min)
DMPT loading
(equiv)
yield
(%)
a
entry
(mL min−1
)
1
2
3
4
5
3.0
2.0
0.5
1.0
1.0
10
15
60
30
30
2
2
2
2
4
66
72
72
74
60
b
a
̂
Chatelier’s principle, a shift in the equilibrium toward the
All of the reactions were carried out in a 30 mL flow reactor with 120
formation of the EDA complex occurs. Accordingly, it is
possible to observe that the solution will possess an increased
absorbance.
W blue LEDs (λmax = 450 nm) using 0.2 mmol of 1a, 1.1 equiv (0.22
mmol) of Umemoto’s reagent, DMPT, and DCM/DMSO (39:1) as
b
the solvent (2 mL). Average isolated yield (duplicates).
B
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Scheme 3. (a) UV−Vis Spectra Demonstrating the
Scheme 4. Studies Regarding the Mechanistic Proposal: (a)
Reaction Employing TEMPO as a Radical Scavenger; (b)
Reaction Employing DMSO-d6; (c) Proposed Reaction
Mechanism with ΔG along the Reaction Pathway
Formation of an EDA Complex between Umemoto’s
Reagent (3) and DMPT (4); (b) UV−Vis Spectra of the
EDA Obtained at Different Concentrations of DMPT; (c)
EDA Complex Solution and DFT Data for the Formation of
the EDA Complex; (d) Natural Transition Orbitals (NTOs)
a
a
of the EDA Complex
a
All of the given values were calculated at the B3LYP-D3/6-
31G(d,p)//M06-2X-D3/6-31G(d) level of theory with insertion of
b
solvent (DCM) using the SMD model. Detected by 19F NMR
analysis of the crude reaction mixture using fluorobenzene as an
c
1
internal standard. Calculated from H NMR analysis of the crude
reaction mixture.
a
All of the given structures, orbitals, and values were calculated at the
B3LYP-D3/6-31G(d,p)//M06-2X-D3/6-31G(d) level of theory with
insertion of solvent (DCM) using the SMD model.
carried out and revealed 30% deuterium incorporation
(Scheme 4b), suggesting proton transfer from the solvent.
The energy barriers involved in the proposed pathway were
also determined through DFT calculations (Scheme 4c). Thus,
on the basis of the experimental and computational evidence
that the trifluoromethyl radical is formed independently from
2a, the proposed reaction mechanism initiates through the
Michael-type addition of the trifluoromethyl radical to the
conjugated olefin. This step proceeds through a considerably
low energy transition state (TS1) with a reaction barrier of
only 4.6 kcal mol−1. Moreover, this step is greatly
thermodynamically favored (ΔG = −26.9 kcal mol−1),
probably related to the formation of a more stable α-dicarbonyl
radical species (CM2). Finally, the reaction pathway then
follows with the proton transfer (from DMSO), leading to the
formation of the final product 2a. This step is rate-limiting and
proceeds through a second transition state (TS2) with a
reaction barrier of 23.2 kcal mol−1.
Next, DFT calculations were performed to confirm the EDA
complex formation (Scheme 3c). The data allowed the
calculation of ΔGf (and consequently KEDA), which enabled
the theoretical determination of the concentration of EDA
complex in solution. The combination of these data with the
experimental absorbance determined during the titration UV−
vis experiments allowed the prediction of the molar
absorptivity of the EDA complex (ε400 = (2366
71) L
mol−1 cm−1) (see the Supporting Information for full details).
Finally, the natural transition orbitals (NTOs) for the EDA
complex ground state and its first singlet−singlet transition was
simulated and indicated that the absorption at 400 nm
corresponds to a charge transfer band (Scheme 3d).
We then turned our attention toward the hydrotrifluor-
omethylation reaction mechanism. Since a radical pathway was
expected, attempts to trap CF3 radical were carried out in the
presence of TEMPO and led to the TEMPO−CF3 product
(detected through 19F NMR analysis of the crude reaction
mixture) (Scheme 4a).
Finally, to highlight the synthetic applicability of product 2a,
a scale-up to 1 mmol was performed, affording the desired
product without considerable loss of yield (68%). The
preparation of two heterocycles employing product 2a as the
substrate was also demonstrated. First, 2a was employed in the
synthesis of trifluoromethyl-substituted isoxazolone derivative
To obtain further insight into the proton source in the final
products, a control reaction employing DMSO-d6 was also
C
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Letter
5 in 87% yield. Moreover, 2a was also used in the preparation
of highly functionalized pyrazolone 6 in 68% yield (Scheme 5).
Pedro P. de Castro − Department of Chemistry, Federal
University of Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil
́
Helio F. Dos Santos − Department of Chemistry, Federal
University of Juiz de Fora, 36036-900 Juiz de Fora, MG,
Scheme 5. Reactions Employing 2a as a Building Block
Brazil; orcid.org/0000-0003-0196-2642
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03187
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for generous financial support from CAPES
(Finance Code 001), CNPq (310514/2018-5), FAPEMIG,
FAPESP (Grants 2018/00106-7 and 2013/07276-1), and
́
Rede Mineira de Quimica. Furthermore, we are grateful to Dr.
Angelina de Almeida (Instituto Federal de Sergipe) and Dr.
Arthur Carpanez (Universidade Federal de Juiz de Fora) for all
of their help in the early studies.
In summary, a photochemical flow hydrotrifluoromethyla-
tion methodology for unsaturated β-keto esters is described
herein. To the best of our knowledge, this constitutes the first
photoflow protocol with an EDA approach to CF3 radical
conjugate additions into these dicarbonyl derivatives. The
method does not require the use of any metal-based catalyst
and proceeds through an EDA approach. Furthermore, under
the optimized reaction conditions, a substrate scope of 14
derivatives was described in up to 86% yield. Control reactions
and DFT calculations were performed and suggested a
mechanism involving EDA formation followed by conjugate
addition of trifluoromethyl radical and a proton transfer step. A
scale-up to 1 mmol could be accomplished, leading to product
2a in 68% yield. Finally, product 2a could be successfully
employed in the synthesis of two trifluoromethyl-substituted
heterocycles that may serve as valuable bioactive molecules,
opening up further synthetic transformations for these
dicarbonyl trifluoro derivatives.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03187.
Experimental procedures, pictures of the reactor setup,
copies of NMR spectra, computational data, and batch
reaction conditions optimization study (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
Kleber T. de Oliveira − Department of Chemistry, Federal
University of Sao Carlos, 13565-905 Sao Carlos, SP, Brazil;
̃ ̃
orcid.org/0000-0002-9131-4800; Email: kleber.oliveira@
ufscar.br
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̈
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Angew. Chem., Int. Ed. 2016, 55, 15549.
Giovanni W. Amarante − Department of Chemistry, Federal
University of Juiz de Fora, 36036-900 Juiz de Fora, MG,
Brazil; orcid.org/0000-0003-1004-5395;
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Email: giovanni.amarante@ufjf.edu.br
Authors
Gabriel M. F. Batista − Department of Chemistry, Federal
University of Juiz de Fora, 36036-900 Juiz de Fora, MG,
Brazil; Department of Chemistry, Federal University of Sao
Carlos, 13565-905 Sao Carlos, SP, Brazil
̃
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