Enantioselective Copper-Catalyzed Synthesis of Trifluoromethyl-Cyclopropylboronates

Article abstract of DOI:10.1021/acs.orglett.1c02420

A copper-catalyzed enantioselective cyclopropanation involving trifluorodiazoethane in the presence of alkenyl boronates has been developed. This transformation enables the preparation of 2-substituted-3-(trifluoromethyl)cyclopropylboronates with high levels of stereocontrol. The products are valuable synthetic intermediates by transformation of the boronate group. This methodology can be applied to the synthesis of novel trifluoromethylated analogues of trans-2-arylcyclopropylamines, which are prevalent motifs in biologically active compounds.

Full text of DOI:10.1021/acs.orglett.1c02420

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Enantioselective Copper-Catalyzed Synthesis of Trifluoromethyl-
Cyclopropylboronates
Julia Altarejos, David Sucunza, Juan J. Vaquero, and Javier Carreras*
Cite This: Org. Lett. 2021, 23, 6174−6178
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ABSTRACT: A copper-catalyzed enantioselective cyclopropanation involving trifluorodiazoethane in the presence of alkenyl
boronates has been developed. This transformation enables the preparation of 2-substituted-3-(trifluoromethyl)-
cyclopropylboronates with high levels of stereocontrol. The products are valuable synthetic intermediates by transformation of
the boronate group. This methodology can be applied to the synthesis of novel trifluoromethylated analogues of trans-2-
arylcyclopropylamines, which are prevalent motifs in biologically active compounds.
penes,14 zinco-cyclopropanation of allylic alcohols15 and C−H
yclopropanes are widespread carbocycles in bioactive
borylation.16
1
Cnatural and synthetic compounds.
It is currently a
In this context, we focused our attention on the
enantioselective preparation of cyclopropanes that include
simultaneously a trifluoromethyl group and a pinacol boronate
as substituents. These versatile compounds would give access
to a wide range of trifluoromethyl−cyclopropane derivatives.
In the literature, there are only three examples of these types of
compounds, all of them have been obtained as racemates from
monosubstituted vinyl boron derivatives (see Scheme 1b).17
Herein, we report the enantioselective cyclopropanation of
trans-alkenyl boronates with trifluorodiazoethane catalyzed by
a copper(I)-bisoxazoline complex to obtain versatile 2-
substituted-3-(trifluoromethyl)cyclopropylboronates. It is
worth mentioning that the reactivity between alkenyl boroxines
and trifluorodiazoethane has been recently reported to prepare
α-trifluoromethyl allylboronic acids,18 by formation of highly
electrophilic BINOL boronate derivatives in a metal-free
procedure.
standard fragment in drug discovery, which allows one to
modulate properties such as lipophilicity, metabolic stability,
pKa or binding, among others.2 Nowadays, it is present in
numerous drugs, for example Ticagrelor,3 which is active
against cardiovascular diseases, or Tezacaftor,4 which is used to
treat cystic fibrosis.
Numerous methods have been described for the synthesis of
substituted cyclopropanes.5 Among all the different possibil-
ities, the preparation of cyclopropanes with fluorinated groups,
in particular trifluoromethyl, is of special interest.6 This
functional group is present in a vast number of therapeutic
compounds.7 However, the enantioselective procedures for the
preparation of trifluoromethylcyclopropanes are scarce in the
literature.8 All the existing protocols, which are summarized in
Scheme 1a, led to cyclopropanes with an unsubstituted carbon
on the three-membered ring. For this reason, there is still a
need to develop efficient enantioselective methodologies to
prepare all-carbon-substituted trifluoromethylcyclopropanes.
On the other hand, the synthesis of versatile cyclopropanes,
such as cyclopropylboronates, has also attracted the interest of
the synthetic community.9 A boronate group can be easily
transformed into a wide range of different functional groups.10
This allows the generation of compound libraries from a
common structure. In this area, several strategies have been
recently developed to prepare optically active cyclopropylbor-
onates, including cyclopropanation of alkenyl boronates with
diazo compounds,11 borylative cyclization of allylic carbonates,
phosphonates,12 or epoxides,13 hydroboration of cyclopro-
The cyclopropanation was initially studied with (E)-styryl
pinacolboronate (1a) as a model substrate. We commenced
using Cu(I)-tBuBOX (5 mol %) as a catalyst formed in situ in
DCE. Initial experiments showed that alkenyl boronate was not
fully consumed with 2 equiv of diazo added over the course of
Received: July 21, 2021
Published: July 28, 2021
https://doi.org/10.1021/acs.orglett.1c02420
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6174−6178
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configuration of cyclopropane 2a was determined by 1H NMR
experiments (see the Supporting Information).
Scheme 1. Previous Synthesis of
Trifluoromethylcyclopropanes and Trifluoromethyl-
Cyclopropylboronates
Gratifyingly, good results of diastereo- and enantiocontrol
were obtained under these catalytic conditions (92:8 dr, 95:5
er). We examined different organic solvents such as THF or
toluene (see SI). Toluene significantly reduced reactivity and
diastereoselectivity, and THF led to no conversion of the
olefin. Subsequently we investigated different com-mercially
available BOX ligands. Whereas the iPrBOX (L2) ligand
decreased the conversion and stereocontrol of the reaction,
PhBOX (L3) slightly improved the diastereoselec-tivity
(entries 5-6). At this stage, concentration of trifluorodiazo-
ethane was increased from ca. 0.5 to 1 M, con-ducting to
complete conversion (entry 7). Furthermore, the amount of
diazo compound could be reduced to 2 equiva-lents (entry 8).
Under the optimized conditions, using 5 mol % of
[Cu(NCMe)4]PF6 and tBuBOX as the catalyst and 2 equiv
of trifluorodiazoethane added during 6 h, 69% of cyclo-
propylboronate 2a was isolated, with high level of stereo-
control (94:6 dr, 95:5 er).
With the optimized conditions in hand, the scope of the
cyclopropanation was examined (Scheme 2). The procedure
was successful with a variety of (E)-alkenyl boronates,
considering electron-withdrawing and electron-donating
groups (alkyl, halogens, trifluoromethyl, ether and ester
substituents) at different positions in the aromatic substituent
of the olefin. Moderate to good yields were obtained for the
entire series (40%−77%) and high stereoselectivity was also
achieved, in terms of diastereoselectivity (up to 95:5) and
enantioselectivity (up to 97:3). Notably, both parameters
increase as the electron density of the aromatic ring decreases.
A similar result was obtained with an electron-rich heterocycle
such as thiophene (2l), with moderate enantioselectivity
(90:10 er). Furthermore, an aliphatic-substituted cyclopropane
(2m) was also accessible with moderate yield and levels of
enantioinduction. In several substrates, an increase of the
equivalents of trifluorodiazoethane was necessary to achieve
complete conversion, whereas the reaction was suppressed in
the presence of functional groups such as nitrile or nitro. The
absolute configuration of the stereogenic centers of the
cyclopropane were determined by single-crystal X-ray
diffraction (XRD) analysis of p-bromo and p-methoxy
derivatives 2i and 2l (Scheme 2).19
2 h (Table 1, entry 1). This point was crucial from a practical
point of view, as cyclopropane 2a was not easily separable from
the starting material by column chromatography. Further
increases in the amount of the diazo compound (4 equiv)
combined with a longer reaction time (6 h) raised the
conversion to 90% (Table 1, entries 2−4). The relative
a
Table 1. Optimization of the Reaction Conditions
As mentioned above, cyclopropylboronates are versatile
intermediates in organic synthesis by the transformation of the
C−B bond. To highlight the synthetic utility of the new
compounds, we performed several transformations of the
pinacol boronate group, following reported methodologies
(Scheme 3). Boronic acid 3 was smoothly obtained by
treatment with methylboronic acid.20 Standard conditions of
Suzuki−Miyaura cross-coupling led to 3-trifluoromethyl-1,2-
diarylsubstituted cyclopropane 4 in good yield. Furthermore,
oxidation of the boronate group could be achieved under basic
conditions to get alcohol 5.10 Finally, amination of the
cyclopropylboronate was accomplished by using BCl3 and
BnN3 to get the benzylamine derivative in good yield (6).21
The latter transformations gave access to substituted trans-2-
trifluoromethylcyclopropan-1-amine and trans-2-trifluorome-
thylcyclopropanol, rarely described in the literature in an
enantioselective manner.22
entry ligand diazo (equiv) t (h)
conv (%)
dr
er
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L3
L3
L3
2
2
4
4
4
4
4
2
2
6
2
6
6
6
6
6
72
58
89
90
72
92:8
92:8
92:8
92:8
79:21
94:6
94:6
94:6
−
−
−
95:5
88:12
95:5
95:5
95:5
87
b
b
100
100 (69)
c
a
Reaction conditions: 1 (0.4 mmol), [Cu(NCMe)4]PF6 (0.02 mmol,
5 mol %), L (0.02 mmol, 5 mol %), DCE (1 mL), inert atmosphere,
trifluorodiazoethane (0.5 M DCE, 2−4 equiv) 6 h slow addition.
Conversion measured by 1H NMR. Diastereomeric ratio (dr)
determined by 19F NMR analysis of the crude reaction mixture.
Enantiomeric ratio (er) determined by HPLC analysis of the isolated
Then, we focused our interest in amine derivative 6, as a
trifluoromethylated analogue of trans-2-arylcyclopropylamines.
This scaffold is common to numerous biological active
b
c
product. Trifluorodiazoethane (1.06 M DCE). Isolated yield.
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a
Scheme 2. Substrate Scope of Copper-Catalyzed Cyclopropanation of Alkenyl Boronates
a
Reaction conditions: 1 (0.61 mmol), [Cu(NCMe)4]PF6 (0.03 mmol, 5 mol %), (S,S)-L3 (0.03 mmol, 5 mol %), DCE (1.5 mL), inert atmosphere
b
c
trifluorodiazoethane in DCE (2 equiv), 6 h slow addition. Isolated yields. 76% at 1.25 mmol scale. Trifluorodiazoethane (6 equiv).
d
e
Trifluorodiazoethane (4 equiv). Thermal ellipsoids are drawn at the 50% probability level.
obtain the trifluoromethyl analogue 8 of LSD1 inhibitor in a
Scheme 3. Transformations of Cyclopropylboronate Ester
good yield.
Scheme 4. Preparation of a Trifluoromethyl Analogue of
LSD1 Inhibitor
a
Reaction conditions: (a) MeB(OH)2 (5 equiv), TFA (5%)/DCM, 8
h, 72%. (b) 4-iodoanisole (1.5 equiv), Pd2(dba)3·CHCl3 (10 mol %),
PPh3 (1 equiv), Ag2O (1.5 equiv), THF, 70 °C, 24 h, 45%. (c) 3 M
NaOH 30% H2O2 THF, 30 min, 68%. (d) BCl3 (5.0 equiv, CH2Cl2,
25 °C, 1.5 h), then BnN3 (3.0 equiv, CH2Cl2, from 0 to 25 °C, 2 h),
51%.
a
Reaction conditions: (a) BCl3 (5.0 equiv, CH2Cl2, 25 °C, 1.5 h),
then 7 (3.0 equiv, CH2Cl2, from 0 to 25 °C, 4 h), 55%.
In summary, we have developed a catalytic approach for the
preparation of enantiomerically enriched 2-substituted-3-
(trifluoromethyl)cyclopropylboronates by cyclopropanation
of (E)-alkenyl boronates with trifluorodiazoethane. This
methodology is general for a variety of substrates, using
commercially available copper catalyst and ligand. Valuable
synthetic intermediates can be obtained by the functionaliza-
tion of the C−B bond. This route provides straightforward
access to enantioenriched 2-aryl-3-(trifluoromethyl)-
cyclopropylamines, a relevant scaffold in medicinal chemistry.
compounds23 and is present in drugs such as Tranylcypromine
(an antidepressant), Ticagrelor (a platelet aggregation inhib-
itor), or candidates under clinical trials for the treatment of
cancer and neurodegenerative diseases.23,24 Because of the
implication of F atoms in the properties of bioactive
compounds,25 we targeted the enantioselective synthesis of a
CF3 analogue of a lysine-specific demethylase 1 (LSD1)
inhibitor (Scheme 4). The amination of cyclopropylboronate
2a with 3-(azidomethyl)-2-methoxypyridine (7) allowed us to
6176
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fruitful discussions and Pilar Franco (Chiral Technologies) for
HPLC advice. J.A. thanks MEFP for a predoctoral contract.
ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02420.
REFERENCES
■
(1) For selected reviews, see: (a) Ebner, C.; Carreira, E. M.
Cyclopropanation Strategies in Recent Total Syntheses. Chem. Rev.
2017, 117, 11651−11679. (b) Casar, Z. Synthetic Approaches to
Contemporary Drugs That Contain the Cyclopropyl Moiety. Synthesis
2020, 52, 1315−1345.
Experimental procedures; characterization data; 1H, 13C,
11B and 19F NMR spectral data; HPLC; mass
spectrometry data of new compounds and X-ray
crystallographic data for 2i and 2l (PDF)
̌
(2) (a) Talele, T. T. The “Cyclopropyl Fragment” Is a Versatile
Player That Frequently Appears in Preclinical/Clinical Drug
Molecules. J. Med. Chem. 2016, 59, 8712−8756. (b) Bauer, M. R.;
Di Fruscia, P.; Lucas, S. C. C.; Michaelides, I. N.; Nelson, J. E.; Storer,
R. I.; Whitehurst, B. C. Put a Ring on It: Application of Small
Aliphatic Rings in Medicinal Chemistry. RSC Med. Chem. 2021, 12,
448−471.
Accession Codes
CCDC 2079480 and 2079481 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
(3) Wijeyeratne, Y. D.; Joshi, R.; Heptinstall, S. Ticagrelor: A P2Y12
Antagonist for Use in Acute Coronary Syndromes. Expert Rev. Clin.
Pharmacol. 2012, 5, 257−269.
AUTHOR INFORMATION
(4) Hughes, D. L. Patent Review of Synthetic Routes and Crystalline
Forms of the CFTR-Modulator Drugs Ivacaftor, Lumacaftor,
Tezacaftor, and Elexacaftor. Org. Process Res. Dev. 2019, 23, 2302−
2322.
(5) Pellissier, H., Lattanzi, A.; Dalpozzo, R. Asymmetric Cyclo-
propanation. In Asymmetric Synthesis of Three-Membered Rings; John
Wiley & Sons, Ltd., 2017; pp 1−204.
■
Corresponding Author
Javier Carreras − Universidad de Alcalá, Departamento de
Química Orgánica y Química Inorgánica, and Instituto de
Investigación Química Andrés Manuel del Río (IQAR),
Alcalá de Henares 28805, Spain; Instituto Ramón y Cajal de
Investigación Sanitaria (IRYCIS), Madrid 28034, Spain;
orcid.org/0000-0002-1521-6758;
(6) For a selected reviews, see: (a) Decaens, J.; Couve-Bonnaire, S.;
Charette, A. B.; Poisson, T.; Jubault, P. Synthesis of Fluoro-,
Monofluoromethyl-, Difluoromethyl-, and Trifluoromethyl-Substi-
tuted Three-Membered Rings. Chem. - Eur. J. 2021, 27, 2935−
2962. For recent examples: (b) Cyr, P.; Flynn-Robitaille, J.; Boissarie,
P.; Marinier, A. Mild and Diazo-Free Synthesis of Trifluoromethyl-
Cyclopropanes Using Sulfonium Ylides. Org. Lett. 2019, 21, 2265−
2268. (c) Chen, G.-S.; Yan, X.-X.; Chen, S.-J.; Mao, X.-Y.; Li, Z.-D.;
Liu, Y.-L. Diastereoselective Synthesis of 1,3-Diyne-Tethered
Trifluoromethylcyclopropanes through a Sulfur Ylide Mediated
Cyclopropanation/DBU-Mediated Epimerization Sequence. J. Org.
Chem. 2020, 85, 6252−6260. (d) Chernykh, A. V.; Olifir, O. S.;
Kuchkovska, Y. O.; Volochnyuk, D. M.; Yarmolchuk, V. S.;
Grygorenko, O. O. Fluoroalkyl-Substituted Cyclopropane Derivatives:
Synthesis and Physicochemical Properties. J. Org. Chem. 2020, 85,
12692−12702.
Email: javier.carreras@uah.es
Authors
Julia Altarejos − Universidad de Alcalá, Departamento de
Química Orgánica y Química Inorgánica, and Instituto de
Investigación Química Andrés Manuel del Río (IQAR),
Alcalá de Henares 28805, Spain; Instituto Ramón y Cajal de
Investigación Sanitaria (IRYCIS), Madrid 28034, Spain
David Sucunza − Universidad de Alcalá, Departamento de
Química Orgánica y Química Inorgánica, and Instituto de
Investigación Química Andrés Manuel del Río (IQAR),
Alcalá de Henares 28805, Spain; Instituto Ramón y Cajal de
Investigación Sanitaria (IRYCIS), Madrid 28034, Spain;
orcid.org/0000-0002-3307-4204
Juan J. Vaquero − Universidad de Alcalá, Departamento de
Química Orgánica y Química Inorgánica, and Instituto de
Investigación Química Andrés Manuel del Río (IQAR),
Alcalá de Henares 28805, Spain; Instituto Ramón y Cajal de
Investigación Sanitaria (IRYCIS), Madrid 28034, Spain;
orcid.org/0000-0002-3820-9673
(7) Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design
and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018,
61, 5822−5880.
(8) (a) Le Maux, P.; Juillard, S.; Simonneaux, G. Asymmetric
Synthesis of Trifluoromethylphenyl Cyclopropanes Catalyzed by
Chiral Metalloporphyrins. Synthesis 2006, 2006, 1701−1704.
(b) Denton, J. R.; Sukumaran, D.; Davies, H. M. L. Enantioselective
Synthesis of Trifluoromethyl-Substituted Cyclopropanes. Org. Lett.
2007, 9, 2625−2628. (c) Morandi, B.; Mariampillai, B.; Carreira, E.
M. Enantioselective Cobalt-Catalyzed Preparation of Trifluoromethyl-
Substituted Cyclopropanes. Angew. Chem., Int. Ed. 2011, 50, 1101−
1104. (d) Tinoco, A.; Steck, V.; Tyagi, V.; Fasan, R. Highly Diastereo-
and Enantioselective Synthesis of Trifluoromethyl-Substituted Cyclo-
propanes via Myoglobin-Catalyzed Transfer of Trifluoromethylcar-
bene. J. Am. Chem. Soc. 2017, 139, 5293−5296. (e) Kotozaki, M.;
Chanthamath, S.; Fujii, T.; Shibatomi, K.; Iwasa, S. Highly
Enantioselective Synthesis of Trifluoromethyl Cyclopropanes by
Using Ru(II)−Pheox Catalysts. Chem. Commun. 2018, 54, 5110−
5113. (f) Huang, W.-S.; Schlinquer, C.; Poisson, T.; Pannecoucke, X.;
Charette, A. B.; Jubault, P. General Catalytic Enantioselective Access
to Monohalomethyl and Trifluoromethyl Cyclopropanes. Chem. - Eur.
J. 2018, 24, 10339−10343. (g) Carminati, D. M.; Decaens, J.; Couve-
Bonnaire, S.; Jubault, P.; Fasan, R. Biocatalytic Strategy for the Highly
Stereoselective Synthesis of CHF2-Containing Trisubstituted Cyclo-
propanes. Angew. Chem., Int. Ed. 2021, 60, 7072−7076.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02420
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge MICINN (PID2019-105007GA-
I00, CTQ2017-85263-R), Instituto de Salud Carlos III
(FEDER funds, ISCIII RETIC REDINREN RD16/0009/
0015), Comunidad de Madrid and Universidad de Alcalá
(CM/JIN/2019-025, CCG19/CC-038) for financial support.
We thank Dr. C. Golz, University of Göttingen, for the X-ray
analyses of compounds 2i and 2l. We also thank Dr. Pedro
Pérez and Dr. Ana Caballero, Universidad de Huelva, for
6177
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Org. Lett. 2021, 23, 6174−6178