ACS Catalysis
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
8316
ACS Catal. 2020, 10, 8315−8320
Brigham, Conor E.
