Nickel-Catalyzed Decarbonylative Synthesis of Fluoroalkyl Thioethers

Article abstract of DOI:10.1021/acscatal.0c02950

This report describes the development of a nickel-catalyzed decarbonylative reaction for the synthesis of fluoroalkyl thioethers (RFSR) from the corresponding thioesters. Readily available, inexpensive, and stable fluoroalkyl carboxylic acids (RFCO2H) serve as the fluoroalkyl (RF) source in this transformation. Stoichiometric organometallic studies reveal that RF-S bond-forming reductive elimination is a challenging step in the catalytic cycle. This led to the identification of diphenylphosphinoferrocene as the optimal ligand for this transformation. Ultimately, this method was applied to the construction of diverse fluoroalkyl thioethers (RFSR), with R = both aryl and alkyl.

Full text of DOI:10.1021/acscatal.0c02950

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Letter
Nickel-Catalyzed Decarbonylative Synthesis of Fluoroalkyl
Thioethers
Conor E. Brigham, Christian A. Malapit, Naish Lalloo, and Melanie S. Sanford*
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ABSTRACT: This report describes the development of a nickel-
catalyzed decarbonylative reaction for the synthesis of fluoroalkyl
thioethers (RFSR) from the corresponding thioesters. Readily available,
inexpensive, and stable fluoroalkyl carboxylic acids (RFCO2H) serve as
the fluoroalkyl (RF) source in this transformation. Stoichiometric
organometallic studies reveal that RF−S bond-forming reductive
elimination is a challenging step in the catalytic cycle. This led to the
identification of diphenylphosphinoferrocene as the optimal ligand for
this transformation. Ultimately, this method was applied to the construction of diverse fluoroalkyl thioethers (RFSR), with R = both
aryl and alkyl.
KEYWORDS: nickel-catalysis, decarbonylation, fluoroalkyl carboxylic acids, thioether synthesis, fluoroalkylation
CFH2, and CH2CF3) appear in lead structures relevant to both
medicinal and agricultural chemistry.2,3 The most common
synthetic routes to RFSR involve either the electrophilic
fluoroalkylation of thiols (Figure 1B, i)3−5 or the coupling of
aryl/alkyl electrophiles with [M]−SRF nucleophiles (Figure
1B, ii).3,6−8 Both approaches have significant limitations with
respect to the breadth of RF substituents that can be
introduced, since very few of the necessary RF-containing
electrophiles/nucleophiles are commercially available.6,7 Fur-
thermore, many of these methods require other toxic, unstable,
or expensive reagents.3,4,6,7 Overall, more general synthetic
approaches to fluoroalkyl thioethers are of high interest, and
the use of readily available fluoroalkyl carboxylic acids as RF
precursors would be particularly enabling in this context.
This report describes the development of a Ni-catalyzed
reaction for constructing fluoroalkyl thioethers from the
corresponding thioesters (Figure 1B, iii). Our approach
leverages fluoroalkyl carboxylic acids as inexpensive, stable,
and commercially available RF precursors.9−12 As such, it
enables the construction of a variety of different fluoroalkyl
thioethers from a single thiol starting material.
luoroalkyl thioethers (RFSR) have emerged as increasingly
Fcommon motifs in bioactive molecules due to their unique
physiochemical properties.1 As shown in Figure 1A, thioethers
bearing diverse fluoroalkyl substituents (for example, CF2H,
Recent studies on Ni-catalyzed coupling reactions of
carboxylic acid derivatives13,14 led us to propose this
decarbonylative route to fluoroalkyl thioethers. Recent reports
from our group13c and others15−17 have demonstrated that
Received: July 6, 2020
Revised: July 13, 2020
Figure 1. (A) Representative examples of bioactive molecules
containing fluoroalkyl thioethers (RFSR). (B) Existing synthetic
approaches to RFSR (i, ii) and our approach (iii).
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Letter
Ni(0) phosphine complexes catalyze decarbonylative C−S
coupling reactions of (hetero)aryl thioesters to afford
(hetero)aryl thioether products (for example, see Figure 2A).
employed for the transformation in Figure 2A.13c15−17
However, only traces (<1%) of product 2a were detected
using PPh3, P(o-Tol)3, PCy3, or PBu3 (Figure 2C). In all of
these systems, the majority of the mass balance was the
unreacted starting material 1a.
We next conducted stoichiometric studies to identify the
problematic step(s) in this sequence. The treatment of a
toluene solution of Ni(cod)2/PnBu3 with 1 equiv of 1a resulted
in the formation of (PnBu3)2Ni(SPh)(CF2H) (II-PnBu3)
within 1 h at ambient temperature (Figure 2D). Complex II-
PnBu3 was characterized in situ via 19F and 31PNMR
spectroscopy, which show resonances indicative of a trans
configuration, with three-bond coupling between the CF2H
and PnBu3 ligands (JPF = 26.5 Hz). The formation of II-PnBu3
implicates the feasibility of two key steps of the catalytic cycle:
oxidative addition (step i) and carbonyl deinsertion (step ii).
However, when in situ-generated II-PnBu3 was heated at 130
°C for 2 h, none of the thioether product 2a was formed (step
iii). Instead, the resonances associated with II-PnBu3 slowly
decayed, without the observation of identifiable organic
products. This suggests that F2HC−S bond-forming reductive
elimination is challenging in this system and that alternative
ligands are required to enable this step.
Literature reports have shown that 1,1′-bis-
(diphenylphosphino)ferrocene (dppf) is particularly effective
for promoting challenging reductive elimination reactions.18 As
such, we next conducted an analogous stoichiometric experi-
ment with Ni(cod)2/dppf. As shown in Figure 3A, the
Figure 3. (A) Stoichiometric and (B) catalytic studies with dppf.
treatment of a toluene solution of Ni(cod)2/dppf with 1
equiv of 1a resulted in 70% consumption of 1a within 1 h at 50
°C. This was accompanied by the formation of 2a (in 12%
yield) along with broad signals in the 19F NMR spectrum.
Based on previous reports,18a these broad signals are indicative
of fluxional (dppf)NiII intermediates. Subsequent heating at
130 °C for 1 h resulted in S−CF2H bond formation to
generate 2a in 90% yield by 19F NMR spectroscopy (Figure
3A).19 Dppf was next examined as a ligand for the catalytic
transformation of 1a to 2a. As shown in Figure 3B, the
combination of 10 mol % Ni(cod)2 and 12 mol % dppf
afforded 2a in 58% yield over 20 h at 130 °C in toluene.
Further optimization of the reaction solvent and time resulted
in nearly quantitative yield over 4 h in THF (Figure 3B).20
The scope of this transformation was first explored with
respect to the substitution on sulfur (Figure 4). The
difluoromethyl thioester substrates 1a−1w were prepared via
the reaction of RSH with difluoroacetic anhydride. These were
typically obtained in quantitative yield without the need for
Figure 2. (A) Example of precedent for decarbonylative thioether-
ification. (B) Proposed catalytic cycle. (C) Initial catalysis studies.
(D) Stoichiometric studies with PnBu3 as ligand.
We hypothesized that an analogous pathway, using fluoroalkyl
thioesters as starting materials, could offer a route to RFSR
products. The proposed catalytic cycle (Figure 2B) involves
initial oxidative addition of the fluoroalkyl thioester at a Ni(0)
catalyst to form the acyl Ni(II)-intermediate, I (step i).
Carbonyl deinsertion then generates the Ni(II)(fluoroalkyl)-
(thiolate) intermediate II (step ii). Finally, II undergoes C−S
bond-forming reductive elimination (step iii) to yield the
target fluoroalkyl thioether product and regenerate the Ni(0)
catalyst.
We initiated these investigations by targeting the conversion
of difluoromethyl thioester 1a to thioether 2a (Figure 2C). We
focused on catalysts based on a combination of Ni(cod)2 and
monodentate phosphine ligands (PR3), which were previously
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Letter
substrates containing either one or two electron-donating
ortho-substituents afforded 2m−2o in moderate to good
yields.
Primary, secondary, and tertiary alkyl thiols were also
effective substrates for this transformation (for example 2p, 2s,
and 2t in Figure 4B). Thiol-containing biologically active
compounds such as captopril (2v) and thioglucose (2w)
underwent conversion to the corresponding difluoromethyl
thioethers in good yields. In these systems, unreacted starting
material accounted for the remaining mass balance when the
yields were modest. Importantly, the catalytic cycle does not
require an exogenous base. This limits racemization of
substrates like 2v during catalysis.
Finally, we used this approach to synthesize a series of
different fluoroalkyl thioethers. As shown in Figure 5, the
Figure 4. Scope of (A) aryl and (B) alkyl thioethers. a% conversion of
1 to 2 as determined by 19F NMR spectroscopy. bYield determined by
19F NMR spectroscopy with 4-fluorotoluene as internal standard.
cCatalyst loading was increased to 15 mol % Ni(cod)2, 18 mol % dppf.
Figure 5. Scope of fluoroalkyl groups derived from commercial
RFCO2H. Isolated yields. See the SI for details. Catalyst loading was
increased to 20 mol % Ni(cod)2, and Xantphos was used as the ligand
at 24 mol %.
a
purification by column chromatography. Aryl thioesters
bearing electron-donating and -neutral substituents (1b−1f)
afforded good yields of the difluoromethyl thioether products
(Figure 4A). Substituents such as ethers, amines, and amides
were compatible. Aryl thioesters bearing electron-withdrawing
groups resulted in lower yields (see products 2h−2l), with the
exception of 4-fluorothiophenol derivative, 2g. In these
systems, the major side products were diarylthioethers, which
are likely formed via competing activation of the aryl−S bond
of the product by the Ni(0) catalyst.21 This transformation
showed modest sensitivity to sterics on the aryl ring, and
substrates for this transformation were synthesized from
commercially available RFCO2H and thiols. Catalytic decar-
bonylation then provided the partially fluorinated thioether
products 2x−2ab in good to excellent yields. Importantly,
these products are challenging to access using most existing
approaches (Figure 1B), because of the inaccessibility of the
required fluoroalkylating reagents. One current limitation of
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Examining the “Lipophilic Hydrogen Bond Donor” Concept. J. Med.
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this approach is that fluorinated derivatives (e.g., SCF3,
SCF2CF3) afford none of the desired fluoroalkyl thioether
product.22 A stoichiometric study of the CF3 system showed
the formation of Ni−CF3 intermediates; however, no thioether
product was detected upon heating these species. This result
suggests that the S−RF reductive elimination step remains a
challenge in these systems.23
̈
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Insecticidal Active Mixtures Comprising Arylquinazolinone Com-
pounds. WO 2013/030262, August 13, 2012.
In summary, a nickel-catalyzed decarbonylative coupling
reaction was developed to convert fluoroalkyl thioesters to the
analogous thioethers. This method leverages readily available
fluorocarboxylic acids as commercial and stable fluoroalkyl
sources to install these functional groups, which are
increasingly prevalent in biologically active molecules.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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Experimental details, characterization data, and NMR
spectra of compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Melanie S. Sanford − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0001-9342-9436; Email: mssanfor@
umich.edu
Authors
Conor E. Brigham − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States
Christian A. Malapit − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0002-8471-4208
Naish Lalloo − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States
̈
N. J. W.; Tegelbeckers, B. J. P.; Hessel, V.; Wang, X.; Noel, T. A Mild
and Fast Photocatalyic Trifluoromethylation of Thiols in Batch and
Continuous-Flow. Chem. Sci. 2014, 5, 4768−4773. (h) Bottecchia, C.;
̈
Wei, X.-J.; Kuijpers, K. P. L.; Hessel, V.; Noel, T. Visible Light-
Induced Trifluoromethylation and Pefluoroalkylation of Cysteine
Residues in Batch and Continuous Flow. J. Org. Chem. 2016, 81,
7301−7307.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c02950
(6) (a) Arimori, S.; Matsubara, O.; Takada, M.; Shiro, M.; Shibata,
N. Difluoromethylsulfonyl Hypervalent Iodonium Ylides for Electro-
philic Difluoromethylthiolation Reactions Under Copper Catalysis. R.
Soc. Open Sci. 2016, 3, 160102. (b) Ran, Y.; Lin, Q.-Y.; Xu, X.-H.;
Qing, F.-L. Radical Difluoromethylation of Thiols with Difluorome-
thylphosphonium Triflate Under Photoredox Catalysis. J. Org. Chem.
2017, 82, 7373−7378. (c) Yang, J.; Jiang, M.; Jin, Y.; Yang, H.; Fu, H.
Visible-light Photoredox Difluoromethylation of Phenols and
Thiophenols with Commercially Available Difluorobromoacetic
Acid. Org. Lett. 2017, 19, 2758−2761.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
(7) (a) Wu, J.; Gu, Y.; Leng, X.; Shen, Q. Copper-Promoted
Sandmeyer Difluoromethylthiolation of Aryl and Heteroaryl Diazo-
nium Salts. Angew. Chem., Int. Ed. 2015, 54, 7648−7652. (b) Zhu, D.;
Gu, Y.; Lu, L.; Shen, Q. N-Difluoromethylthiophthalimide: A Shelf-
Stable, Electrophilic Reagent for Difluoromethylthiolation. J. Am.
Chem. Soc. 2015, 137, 10547−10553.
(8) Chen, S.; Zhang, M.; Liao, X.; Weng, Z. Copper-Catalyzed 2,2,2-
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(9) Fluorinated carboxylic derivatives have been used for some
decarboxylative trifluoromethylation and difluoromethylation reac-
tions; however, these systems are typically limited to explorations of
Ar-CF3 and Ar-CF2H coupling (see refs 10,11). To our knowledge,
fluoroalkyl carboxylic acid derivatives have not been utilized to access
fluoroalkyl thioethers.
(10) For examples of the use of RFCO2H and its derivatives as RF
sources, see: (a) Beatty, J. W.; Douglas, J. J.; Cole, K. P.; Stephenson,
C. R. J. A Scalable and Operationally Simple Radical Trifluorome-
ACKNOWLEDGMENTS
■
We acknowledge financial support from NIH NIGMS
(GM073836 and GM136332) and the Danish National
Research Foundation (Carbon Dioxide Activation Center;
CADIAC) for support.
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(18) (a) Ferguson, D. M.; Bour, J. R.; Canty, A. J.; Kampf, J. W.;
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Palladium(II) Complexes. Organometallics 2019, 38, 519−526.
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Mikami, K. Palladium Catalyzed Negishi Cross-Coupling of Aryl
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(19) Decarbonylative conversion of 1a to 2a could be carried out in
high yields with both stoichiometric and catalytic loadings of
Ni(cod)2 and dppf. Attempts to characterize the organometallic
intermediate(s) in situ by NMR spectroscopy were impeded by their
fluxionality (see SI for details).
(20) Several other large bite angle bidentate phosphines, including
Xantphos and DPEphos, afforded significant yields in this trans-
formation. See SI for more details on reaction optimization.
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Letter
(22) See SI for catalyst screening of the decarbonylative
trifluoromethylation of thiophenol.
(23) Stoichiometric studies of the reaction between Ni(cod)2/dppf
and (trifluoromethyl)thioesters showed the formation of Ni-CF3
intermediates by 19F NMR spectroscopy (see SI), suggesting that
oxidative addition and carbonyl deinsertion are taking place.
However, no S-CF3 coupling was observed by 19F NMR spectroscopy
or GCMS when these intermediates were heated.
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