Angewandte
Communications
Chemie
or Cl groups furnished the desired thiophosphates in high
tert-butyl peroxide,[5b] could not be realized by the previously
yields. Notably, a thiol with an electron-withdrawing CF3
group was smoothly coupled with 1a (69% yield, 5m)
whereas a NO2-substituted thiol afforded product 5n in
22% yield. Free amine and hydroxy groups, which hardly
survive in traditional approaches, were tolerated under these
conditions to afford the corresponding products 5o and 5p in
high yields.
Aside from dialkyl phosphonates, diphenyl phosphine
oxide (6) could also be coupled with octanethiol (2a) to
produce 7 in 78% yield (Scheme 4). Furthermore, this
Cs2CO3-catalyzed oxidative CDC reaction of phosphonates
(10 mmol) and thiols (12 mmol) could be performed on gram
scale.
reported oxidative CDC reaction of phosphonate and thiol.
Under the present Cs2CO3/O2 conditions, however, the ethyl-
thio-substituted thiol was phosphorylated smoothly to afford
demeton in 75% yield (Scheme 5b). The CDC reaction of
diethyl phosphonate (1a) with commercially available thiol
2q afforded thiophosphate 3q in 64% yield, which was easily
converted into echothiopate, a drug used for the treatment of
glaucoma[11] (Scheme 5c). Compound 11, a derivative of
zidovudine (AZT), which is used for the treatment of
AIDS,[12] exhibits attractive bioactivity, and could be coupled
with 4-chlorothiophenol to give 12 in 80% yield as amide,
double bond, azide, and ester groups are tolerated
(Scheme 5d). These experiments (Scheme 5) demonstrate
that the Cs2CO3/O2-based CDC reaction of thiols and
phosphonates is amenable to the late-stage synthesis and
modification of bioactive molecules.
À
À
Aside from P S bonds, sulfenylarenes bearing C S bonds
are widely used for the treatment of diseases because of their
therapeutic value.[13] Such compounds are usually synthesized
from prefunctionalized arenes such as aryl halides or aryl
boronic acids in transition-metal-catalyzed cross-coupling
reactions.[14] Methods for the direct sulfenylation of arenes
with sulfenylating agents,[15] such as sulfenyl halides,
N-thioimides, sulfonium salts, disulfides, quinone mono-O,S-
acetals, arylsulfonyl chlorides, and sulfonyl hydrazides, have
also been developed. Several reports have described oxida-
tive CDC reactions of arenes and thiols;[16] however, harsh
reaction conditions, narrow substrates scopes, or the employ-
ment of stoichiometric amounts of oxidant have strongly
restricted the widely application of these methods. Inspired by
À
À
Scheme 4. CDC reaction of P H/S H bonds on 10 mmol scale.
The present approach for the synthesis of S-alkyl thio-
phosphates features a broad substrate scope, and was also
applied in the concise synthesis of several bioactive molecules
(Scheme 5). Iprobenfos, a pesticide used against rice blast,
could be easily prepared by the CDC reaction of diisopropyl
phosphonate (1c) and benzyl thiol in 87% yield in the
presence of Cs2CO3 (Scheme 5a). The synthesis of demeton,
which bears a highly reactive ethylthio group that is easily
oxidized by oxidants such as tert-butyl hydroperoxide[5a] or
À
the above success in P S bond construction, we expanded the
À
Cs2CO3/O2 system to C S bond formation (Scheme 6). In the
presence of 20 mol% Cs2CO3, the coupling of indole deriv-
atives and thiols proceeded smoothly to afford sulfenylindoles
in good to high yields. Thiols bearing various functional
groups at the aryl ring, such as CF3 (14a), OMe (14d, 14e), Cl
(14c, 14 f, 14g), or Br (14b), furnished the desired products in
high yields. The substituents on the indole ring have little
influence on the sulfenylation. Other arenes, such as azain-
doles (14q, 14r), naphthalene (14s), and benzene (14t), could
also be sulfenylated. Importantly, both Cs2CO3 and air are
indispensable in the present coupling reaction of thiols and
arenes (see the Supporting Information).
We conducted detailed control experiments to understand
the roles of Cs2CO3 and O2 in this CDC reaction (Scheme 7).
Under the standard conditions without the addition of
phosphonate, octanethiol (2a) is converted into disulfide 15
in high yield (Scheme 7a). Cs2CO3 is indispensable in this
transformation (Scheme 7b). It is noteworthy that oxidative
couplings of thiols and disulfides with O2 as the oxidant are
usually catalyzed by flavoenzyme,[17a] laccase,[17b] heteroge-
neous gold catalysts,[17c] iron metal–organic frameworks,[17d]
eosin Y,[17e] or diaryl tellurides.[17f] Compared to these systems,
the present Cs2CO3/O2 system is much more economic,
practical, and environmentally friendly. As reported, aryl
disulfides can be easily converted into thiophosphates,[3j–l] but
AIBN is required for the reaction with aliphatic disulfides.[3m]
It is noteworthy that the efficiency of the reaction with
Scheme 5. Application of the Cs2CO3-catalyzed CDC reaction for the
synthesis of bioactive molecules.
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
These are not the final page numbers!