Organic Letters
Letter
thioesters employing easily accessible aryl C(sp2)−O electro-
philes has not been warranted yet.
groups other than OTf were also examined. It was found that
aryl iodide and bromide converted into 3aa in rather moderate
yields, respectively, with the formation of homocoupling
byproducts (entries 10 and 11), but aryl chloride and tosylate
were unreactive under the standard conditions (entries 12 and
13). Notably, in a gram-scale reaction, 3aa was afforded in
equally high yield (entry 14).
With the optimized reaction conditions in hand, we
examined the scope of aryl triflates (Scheme 2). Apart from
the model substrate 1a, aryl triflates that bear electron-
withdrawing groups, e.g., the carbonyl, cyano, trifluoromethyl,
sulfonyl and chloride group, at the para-position coupled with
2a, furnishing the corresponding thioesters 3ba−3fa in
moderate to good yields. Also, meta-substituted electron-
deficient aryl triflates were compatible coupling partners (as in
3ga); ortho-substituted aryl electrophiles converted into 3ha in
35% yield, likely due to the steric hindrance. Likewise, aryl
triflate derived from hymecromone participated in the coupling
reaction, affording 3ia in moderate yield.
However, when electron-rich and -neutral aryl triflates were
subjected to the standard setup (Scheme 2, method A), the
coupled products were only detected in low yields. We then
modified the reaction conditions, by using tetrabutylammo-
nium chloride (TBAC) as an additive and simultaneously
elevated the reaction temperature to 80 °C (Scheme 2, method
B).19 Under these conditions, thioesters 3ja−3sa were readily
accessed in good to excellent yields. Interestingly, 4-
fluorophenyl triflate, which was low-yielding under method A,
gave 3ta in 65% yield under method B. Heteroarenes such as
indole, carbazole, and thiophene were tolerated, as exemplified
by the formation of 3ua−3wa; structurally more complex 3xa
was also afforded in high yield. Of particular note is that
electron-donating groups at the ortho-position were not
detrimental to the coupling efficiency, which is in sharp
contrast to the formation of 3ha by method A. For instance,
3ya and 3za were formed in excellent yields, while more
sterically hindered 2,5-disubstituted aryl triflates coupled with
2a as well, thus providing 3a′a and 3b′a in 87% and 45% yield,
respectively. Overall, method A was capable of accommodating
activated electron-deficient aryl triflates, whereas less reactive
electron-rich and -neutral aryl electrophiles displayed a
preference for method B.
As part of our persistent interest in nickel-catalyzed cross-
electrophile coupling reactions,17 it was found that chlor-
oformates coupled with alkyl electrophiles under reductive
conditions, therefore furnishing carboxylate esters in high
yields.18 Inspired by these, we envisioned that readily
accessible O-tBu S-alkyl thiocarbonates were able to serve as
precursors to produce thioesters. Herein, we describe a mild
nickel-catalyzed reductive thiocarbonylations of aryl triflates
employing O-tBu S-alkyl thiocarbonates through C−O/C−O
bond cleavage, which provides a facile approach to the
preparation of aryl thioesters (Scheme 1d). The approach is
characterized by its broad substrate scope with respect to both
aryl electrophiles and thiocarbonates.
Our investigation commenced with the coupling of aryl
triflate 1a with O-tBu S-cyclohexyl thiocarbonate 2a to form
thioester 3aa. An extensive screening of nickel salts, ligands,
reductants, additives, and solvents eventually led to the high-
yielding combination of NiCl2(DME) with Phenanthroline
(Phen) in the presence of MgBr2 and Zn in N,N-
dimethylacetamide (DMA), wherein 3aa was produced in
95% yield (Table 1, entry 1). Blank experiments clearly
indicated that nickel salts, Phen, and Zn are essential (entries
2−4) and MgBr2 as an additive is important to secure a high
yield (entry 5). Phen L1 was generally superior to other
bidentate ligands such as L2 and L3 in the coupling event
(entries 6 and 7); monodentate ligand L4 and tridentate ligand
L5 gave no conversion (entries 8 and 9). Different leaving
a
Table 1. Selected Examples of Optimization Reactions
Next, we explored the generality of O-tBu S-alkyl
thiocarbonates in this nickel-catalyzed cross-coupling with
both electron-deficient (1a) and -rich (1j) aryl triflates
(Scheme 3), respectively. In general, a broad range of
thiocarbonates, which contain various primary, secondary,
and tertiary alkyl substituents onto the sulfur atom, coupled
effectively with 1a according to method A, as is evident from
the formation of 3ab−3ak. With respect to the coupling with
1j, the reactions proceeded smoothly with thiocarbonates that
bear nonsubstituted alkyl groups to furnish 3jb−3jd and 3jh−
3jk in moderate to good yields. In contrast, S-alkyl
thiocarbonates tethered with α- and β-ester motifs (as in
3je−3jg) were less effective acyl donors and accordingly
required higher catalyst and ligand loadings. This is due to the
rapid self-coupling of such activated thioesters.20 Similarly, the
competing disulfide bond formation significantly deteriorated
the yields of formation of 3al and 3jl, when O-tBu S-phenyl
thiocarbonate was utilized.
b
entry
variation of standard conditions
yield
c
1
2
3
4
5
6
7
8
None
w/o NiCl2(DME)
w/o Phen
w/o Zn
w/o MgBr2
L2 instead of Phen
L3 instead of Phen
L4 instead of Phen
L5 instead of Phen
I instead of OTf
Br instead of OTf
Cl instead of OTf
OTs instead of OTf
3.0 mmol of 1a
95% (91%)
trace
trace
trace
42%
72%
43%
trace
trace
34%
9
10
11
12
13
14
49%
trace
trace
c
89%
a
b
All reactions were performed on a 0.3 mmol scale. Determined by
1H NMR analysis using 2,5-dimethyl furan as the internal standard
c
As shown in Schemes 2 and 3, the methods displayed
excellent chemoselective cleavage of the C−O over the C−S
bond, although C−O bonds (≈ 100 kcal/mol) are known to
after quick flash column chromatography. Isolated yield. DME = 1,2-
dimethoxyethane. Tf = trifluoromethanesulfonate. Ts = toluene-
sulfonate.
2159
Org. Lett. 2021, 23, 2158−2163