Phosphovanadomolybdic acid catalyzed desulfurization-oxygenation of secondary and tertiary thioamides into amides using molecular oxygen as the terminal oxidant

Article abstract of DOI:10.1039/c5nj03579a

In the presence of phosphovanadomolybdic acids, e.g., H₆PV₃Mo₉O₄₀, desulfurization-oxygenation of various kinds of structurally diverse secondary and tertiary thioamides proceeded efficiently using molecular oxygen as the terminal oxidant, affording the corresponding amides in moderate to excellent yields. In addition, ¹⁸O-labeled amides could readily be synthesized using H₂¹⁸O as the oxygen source.

Full text of DOI:10.1039/c5nj03579a

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Phosphovanadomolybdic acid catalyzed
desulfurization–oxygenation of secondary and
tertiary thioamides into amides using molecular
oxygen as the terminal oxidant†
Cite this:DOI: 10.1039/c5nj03579a
Received (in Montpellier, France)
16th December 2015,
Accepted 21st March 2016
Ning Xu, Xiongjie Jin, Kosuke Suzuki, Kazuya Yamaguchi and Noritaka Mizuno*
DOI: 10.1039/c5nj03579a
www.rsc.org/njc
In the presence of phosphovanadomolybdic acids, e.g., H6PV3Mo9O40
,
desulfurization–oxygenation of various kinds of structurally diverse
secondary and tertiary thioamides proceeded efficiently using
molecular oxygen as the terminal oxidant, affording the corre-
sponding amides in moderate to excellent yields. In addition,
18O-labeled amides could readily be synthesized using H218O as
the oxygen source.
Thioamides have attracted considerable attention in a wide
range of fields.1–6 In the fields of pharmaceuticals and bio-
chemistry, they have been utilized as an important class of
drugs, e.g., for thyrotoxicosis control, and for incorporation
into peptides as isosteres for the amide linkages.2 In the field of
organic synthesis, they have often been utilized as versatile
synthons due to their unique reactivities and wide availability; for
Scheme 1 Transformations of thioamides using O2 as the terminal oxidant
(R, R0 = alkyl, aryl; R00 = H, alkyl, aryl).
example, a variety of important chemicals, such as amides,3,4 crucial that O2 could be utilized for the re-oxidation of the
nitriles,5 and sulfur-containing heterocycles,1a,6 have been reduced catalysts.5a,6a
synthesized through oxidative transformations of thioamides in
During the course of our investigations on aerobic oxidative
the presence of various kinds of oxidants. The choice of oxidant thioamide transformations, we found that phosphovanado-
determines the efficiency and practicability of the systems, and molybdic acids efficiently catalyzed desulfurization–oxygenation
molecular oxygen (O2) is regarded as the ‘‘greenest’’ oxidant. With of various kinds of structurally diverse secondary and tertiary
a strong awareness of that, we have recently developed catalytic thioamides using O2 as the terminal oxidant, giving the corres-
aerobic oxidative transformations of thioamides (Scheme 1, ponding amides (Scheme 1, lower). In addition, 18O-labeled
upper): (i) manganese oxide-catalyzed oxidative dehydrosulfuriza- amides could readily be synthesized by this catalytic system
tion of primary thioamides to nitriles5a and (ii) phosphovanado- using H218O as the oxygen source. Despite the numerous efforts
molybdic acid-catalyzed oxidative dimerization of primary towards the development of desulfurization–oxygenation of
thioamides to 3,5-disubstituted 1,2,4-thiadiazoles.6a The key thioamides, challenges still remain because previously reported
to realizing these transformations as the efficient catalytic ones systems frequently employ metal-, halogen-, or organic-based
was that the catalysts possessed both acidic and oxidation oxidants or hydrogen peroxide,3 and there have been only a few
properties to promote the de(hydro)sulfurization and the oxida- catalytic systems utilizing O2 as the terminal oxidant.4 Although
tion of S2ꢀ species to elemental sulfur (S0 species).5a,6a It was also phosphovanadomolybdic acids have been reported to be cata-
lytically active for various kinds of oxidation reactions,7,8 their
use for this kind of transformation has never been reported so
far, to the best of our knowledge.
Department of Applied Chemistry, School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp;
Our initial experiments focused on the transformation of
Fax: +81-3-5841-7220; Tel: +81-3-5841-7272
N-phenylthiobenzamide (1a) to N-phenylbenzamide (2a) under
† Electronic supplementary information (ESI) available: Compound data. See
DOI: 10.1039/c5nj03579a
various reaction conditions. The reaction did not proceed at all
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Table 1 Effect of solvents on the desulfurization–oxygenation of 1a to
the vanadium content, i.e., H4PVMo11O40 o H5PV2Mo10O40
H6PV3Mo9O40 E H7PV4Mo8O40 for phosphomolybdic acids
(Table 2, entries 2, 4, 5, and 8); H4PVW11O40 o H5PV2W10O40
o
2aa
o
Entry
Solvent
Conv. of 1a (%)
Yield of 2a (%)
H6PV3W9O40 for phosphotungstic acids (Table 2, entries 12–14).
With regard to the polyatoms of vanadium-containing HPAs,
molybdenum was better than tungsten (Table 2, entries 2, 4,
and 5 vs. entries 12–14). It is well known that molybdic acids
possess higher oxidation potentials in comparison with tungstic
acids.10 Air could be utilized for the transformation, while the
reaction was somewhat slower than that in O2 (Table 2, entry 6 vs.
entry 5). Under Ar atmosphere, an almost stoichiometric amount
of 2a with respect to the vanadium species employed (6 mol%)
was produced (Table 2, entry 7), thus indicating that O2 can act as
the terminal oxidant for the present desulfurization–oxygenation.
When using vanadium-free HPAs, such as H3PMo12O40,
H4SiMo12O40, H3PW12O40, and H4SiW12O40, the reaction hardly
proceeded and gave 2a in only 5–8% yields (Table 2, entries 1, 9, 11,
and 15). Although these results and the above-mentioned reaction
in Ar suggest that vanadium is an indispensable component for the
present desulfurization–oxygenation, simple vanadium compounds,
such as V2O5, NaVO3, and VO(acac)2 (acac = acetylacetonate), hardly
catalyzed the desulfurization–oxygenation (Table 2, entries 17–19).
Furthermore, the catalytic activities of phosphovanadomolybdic
acids were much superior to those of simple mixtures of
vanadium compounds and H3PMo12O40 (Table 2, entries 20–22).
Therefore, the substitution of vanadium into HPA frameworks is
important to obtain a high catalytic performance.6a,7,8 It has been
reported that vanadium-containing HPAs can efficiently catalyze
single-electron oxidation of various kinds of substrates (including
S2ꢀ species) and that the vanadium sites play important roles.6a,7,8
Moreover, the reduced HPAs can readily be re-oxidized by O2.6a,7,8
The acid function of the catalysts was also very important for the
present desulfurization–oxygenation; acid-type H4PVMo11O40
efficiently catalyzed the desulfurization–oxygenation (Table 2,
entry 2), whereas no production of the desired 2a was observed
when the reaction was carried out using the corresponding
tetra-n-butylammonium (TBA) salt (Table 2, entry 3).
Next, the scope of the present phosphovanadomolybdic acid-
catalyzed desulfurization–oxygenation was investigated. As shown
in Fig. 1, various kinds of structurally diverse secondary and
tertiary thioamides could be converted into the corresponding
amides in the presence of H6PV3Mo9O40. The amide products
could readily be isolated by simple column chromatography on
silica gel, and the isolated yields of several products are reported
in Fig. 1. N-Substituted thiobenzamides were quantitatively con-
verted into the desired amides. The larger scale reaction was also
effective; when the H6PV3Mo9O40-catalyzed 2.5 mmol-scale reac-
tion (twenty-fold scale-up) of 1a was carried out, the desired amide
2a was obtained in 99% yield at 60 1C for 0.5 h. The transforma-
tions of N-aryl thioacetamides, which contain electron-donating
as well as electron-withdrawing substituents on the phenyl rings,
proceeded efficiently. The chloro- and bromo-substituted sub-
1
2
3
4
5
6
7
8
9
Acetonitrile
1,4-Dioxane
Chloroform
Tetrahydrofuran
2-Propanol
Ethanol
Methanol
N,N-Dimethylformamide
Dimethyl sulfoxide
Water
499
44
29
19
8
98
40
29
17
8
6
3
2
1
1
6
3
3
2
10
1
a
Reaction conditions: 1a (0.125 mmol), H6PV3Mo9O40 (2 mol% with
respect to 1a), solvent (2 mL), 60 1C, O2 (1 atm), 0.5 h. Yields were
determined by HPLC using naphthalene as the internal standard.
in the absence of catalysts. The results of solvent screening are
summarized in Table 1.9 Among the solvents examined, aceto-
nitrile was the best solvent for the transformation and gave
98% yield of 2a (Table 1, entry 1). 1,4-Dioxane, chloroform,
and tetrahydrofuran gave moderate yields of 2a (Table 1,
entries 2–4). In contrast, highly polar solvents, such as water,
alcohols, N,N-dimethylformamide, and dimethyl sulfoxide,
were not suitable for the present transformation likely because
of their strong coordination to the catalyst (Table 1, entries 5–10).
As shown in Table 2, the desired amide product 2a was signi-
ficantly obtained when the reaction was performed using
vanadium-containing heteropoly acids (HPAs). In these cases,
2a was selectively obtained without the formation of any by-
products. The catalytic activities increased with an increase in
Table 2 Effect of catalysts on the desulfurization–oxygenation of 1a to
2aa
Entry
Catalyst
Conv. of 1a (%)
Yield of 2a (%)
1
2
3
4
H3PMo12O40
H4PVMo11O40
TBA4PVMo11O40
H5PV2Mo10O40
H6PV3Mo9O40
H6PV3Mo9O40
H6PV3Mo9O40
H7PV4Mo8O40
H4SiMo12O40
H5SiVMo11O40
H3PW12O40
H4PVW11O40
H5PV2W10O40
H6PV3W9O40
H4SiW12O40
H5SiVW11O40
V2O5
9
64
4
88
499
84
11
99
8
65
5
11
45
81
7
6
59
o1
84
98
80
8
94
8
63
5
5
6b
7c
8
9
10
11
12
13
14
15
16
17d
18d
19d
20e
21e
22e
23
8
45
74
7
6
5
o1
o1
o1
15
21
6
o1
o1
o1
15
20
6
NaVO3
VO(acac)2
V2O5 + H3PMo12O40
NaVO3 + H3PMo12O40
VO(acac)2 + H3PMo12O40
w/o
o1
o1
a
Reaction conditions: 1a (0.125 mmol), catalyst (2 mol% with respect strates selectively afforded the corresponding amides without
to 1a), acetonitrile (2 mL), 60 1C, O2 (1 atm), 0.5 h. Yields were
determined by HPLC using naphthalene as the internal standard. Air
(1 atm). Ar (1 atm). Vanadium (10 mol%). Vanadium (10 mol%) +
H3PMo12O40 (1 mol%). w/o = without.
occurrence of dehalogenation. It should be noted that linear
and cyclic aliphatic thioamides could also be converted into the
corresponding aliphatic amides.
b
c
d
e
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Scheme 3 A tentatively proposed possible reaction mechanism for the
present desulfurization–oxygenation of thioamides into amides (R, R0 = alkyl,
aryl; R00 = H, alkyl, aryl).
reaction will be one of the most useful procedures for the
synthesis of 18O-labeled amides.
Based on the above-mentioned experimental results, we
here proposed a possible reaction mechanism for the present
desulfurization–oxygenation (Scheme 3). The present trans-
formation is possibly composed of the following four elementary
steps. Steps 1 and 2 are equilibrium reactions to generate the
intermediate A. When the reaction is carried out in the presence
of H218O, the 18O atom is incorporated into the substrate in step
2 (Scheme 2).12 If catalysts do not possess acidic properties, the
intermediate A is hardly generated, thus resulting in no produc-
tion of the desired amide product, as mentioned above (Table 2,
entry 3). In step 3, the oxidative desulfurization takes place
through the HPA-catalyzed oxidation of the S2ꢀ species in the
intermediate A,6a,11 and then the reduced HPA is re-oxidized by
O2.6a,7,8 The oxidation ability should be required to effectively
promote this step, and thus phosphovanadomolybdic acids
which possess relatively high oxidation potentials in comparison
with other HPAs are suitable catalysts for the present transfor-
mation. Finally in step 4, the deprotonation proceeds to afford
the corresponding amide.
In conclusion, we have successfully developed for the first
time the efficient catalytic desulfurization–oxygenation of
secondary and tertiary thioamides into amides using O2 as
the terminal oxidant and water as the oxygen source. Various
kinds of structurally diverse thioamides could be applied to this
catalytic system. Moreover, it should be noted that 18O-labeled
amides could readily be synthesized by utilizing H218O. The key
to realizing this transformation as the efficient catalytic one was
the use of phosphovanadomolybdic acids which possess both
acidic and oxidation properties.
Fig. 1 Scope of the present desulfurization–oxygenation of secondary and
tertiary thioamides. Reaction conditions: 1 (0.125 mmol), H6PV3Mo9O40
(2 mol% with respect to 1), acetonitrile (2 mL), O2 (1 atm). a Isolated yields.
b Yields were determined by HPLC or GC using naphthalene as the internal
standard. cH6PV3Mo9O40 (4 mol%).
As mentioned above, the acid function of the catalysts was
very crucial for the present desulfurization–oxygenation, and
no formation of the amide product was observed when using
the TBA salt (Table 2, entry 3). We have previously reported
that phosphovanadomolybdic acids can catalyze the aerobic
oxidation of the S2ꢀ species in primary thioamides to elemental
sulfur.6a In the present system, elemental sulfur was isolated
after the reaction (ESI†).11 Notably, when the transformation of
thioamides was performed in a mixed solvent of acetonitrile/
H218O, the corresponding 18O-labeled amides were significantly
produced (Scheme 2),12 suggesting that the oxygen atoms in
these amides mostly come from water. We emphasize that this
Experimental
General
Scheme 2 Synthesis of 18O-labeled amides. Reaction conditions:
1
(0.125 mmol), catalyst (2 mol% with respect to 1), acetonitrile/H218O
(1.9 mL/0.1 mL), 60 1C, O2 (1 atm), 4 h for 1a, and 1 h for 1b. Yields were
determined by HPLC using naphthalene as the internal standard. The
18O contents were determined by GC-MS analysis.
HPLC analyses were performed on a Shimadzu Prominence
system using a UV detector (Shimadzu SPD-20A, 220 nm or
254 nm) equipped with a Shiseido CAPCELL PAK UG80 column
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(4.6 mm ID ꢁ 250 mm length) using a mixed solvent of
acetonitrile/water as an eluent (3/1 or 4/1 v/v). GC analyses were
performed on a Shimadzu GC-2014 with a FID equipped with
an InertCap 1 capillary column. GC-MS spectra were recorded
on a Shimadzu GCMS-QP2010 at an ionization voltage of 70 eV
equipped with an InertCap 5MS/Sil capillary column. NMR
spectra were recorded on a JEOL ECA-500 (1H, 500.0 MHz;
13C, 125.0 MHz) by using 5 mm tubes. Chemical shifts (d) were
reported in ppm downfield from tetramethylsilane (TMS).
H3PMo12O40, H3PW12O40, and H4SiW12O40 were obtained from
Wako, and other heteropoly acids were obtained from Nippon
Inorganic Colour & Chemical. The number of water of crystallization
in HPAs was 20–30 per polyanion, and the molecular weights of
HPAs were calculated as triacontahydrates. TBA4PVMo11O40 was
prepared using the cation-exchange method. H218O was obtained
from Aldrich (18O content: 497%). Solvents, amides, several
thioamides (1a, 1b, 1k, and 1o), and Lawesson’s reagent were
obtained from Kanto Chemical, TCI, Wako, Aldrich, or Acros
(reagent grade), and used as received. The other thioamides
were synthesized starting from the corresponding amides using
Lawesson’s reagent.13
Catalytic reaction
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internal standard), and acetonitrile (2 mL) were placed in a
Pyrex-glass tube reactor with a magnetic stir bar, and the
reaction solution was vigorously stirred at 60 1C or 90 1C in
1 atm of O2. The reaction system was homogeneous. The
operations under anaerobic conditions (Ar atmosphere) were
carried out in a glove box. During the reaction, a small volume
of the reaction solution was periodically sampled, and then the
conversion of 1 and the yields of amide products 2 were
determined by HPLC or GC analysis. As for product isola-
tion, naphthalene was not used. After the reaction was com-
pleted, the reaction mixture was directly subjected to column
chromatography on silica gel using a mixed solvent of
n-hexane/diethyl ether as an eluent (typically 1/1 or 1/2 v/v),
giving the analytically pure amide products. The products were
confirmed by comparison of their GC retention times, GC-MS
patterns, and/or 1H and 13C NMR spectra with those of the
authentic samples (ESI†).
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Acknowledgements
This work was supported in part by JSPS KAKENHI grant
numbers 15H05797 and 25289283. We thank Mr Li Chifeng
(the University of Tokyo) for his help with the preparation of
TBA4PVMo11O40
.
Notes and references
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(ESI†).
9 When the reaction of 1a was carried out under the condi- 12 We confirmed that 18O-labeled amides were not produced
tions described in Table 1 using 1 mol% H6PV3Mo9O40, the
yield of 2a reached up to 80% for 1.5 h, and then no further
by the reaction of 16O-amides and H218O in the presence of
HPAs.
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