Copper-catalyzed oxidative desulfurization-oxygenation of thiocarbonyl compounds using molecular oxygen: An efficient method for the preparation of oxygen isotopically labeled carbonyl compounds

Article abstract of DOI:10.1039/b701048f

A novel copper-catalyzed oxidative desulfurization reaction of thiocarbonyl compounds, using molecular oxygen as an oxidant and leading to formation of carbonyl compounds, has been developed, and the utility of the process is demonstrated by its application to the preparation of a carbonyl-¹⁸O labeled sialic acid derivative. The Royal Society of Chemistry.

Full text of DOI:10.1039/b701048f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Copper-catalyzed oxidative desulfurization–oxygenation of
thiocarbonyl compounds using molecular oxygen: an efficient method
for the preparation of oxygen isotopically labeled carbonyl compounds{
Fumitoshi Shibahara,* Aiko Suenami, Atsunori Yoshida and Toshiaki Murai*
Received (in Cambridge, UK) 23rd January 2007, Accepted 14th February 2007
First published as an Advance Article on the web 8th March 2007
DOI: 10.1039/b701048f
A novel copper-catalyzed oxidative desulfurization reaction of
thiocarbonyl compounds, using molecular oxygen as an
ð1Þ
oxidant and leading to formation of carbonyl compounds,
has been developed, and the utility of the process is demon-
strated by its application to the preparation of a carbonyl-18O
labeled sialic acid derivative.
In our initial studies, reactions of N-benzyl-benzenecarbothioa-
mide (4) and a catalytic amount of metal salts in DMSO under an
oxygen atmosphere at 80 uC were explored in order to assess the
catalytic activity of several metal salts (eqn (2), Table 1). We
observed that the reaction promoted by copper(I) chloride gave the
corresponding amide 5 quantitatively within a 15 min time period
(entry 1). In contrast, palladium(II) chloride was completely
inactive as a catalyst for this process (entry 2). Iron(III) chloride
and silver(I) acetate also promote the desulfurization reaction of 4
but these salts display low catalytic activities (entries 3, 4). No
reactions were observed to occur when nickel(II) or cobalt(II)
chloride are used or when metal salts are absent (entries 5–7).
Importantly, an oxygen atmosphere is necessary for the progress
of this reaction (entry 8). Studies of the CuCl promoted reaction of
4 demonstrated that the use of polar solvents, such as DMSO and
DMF (entry 9), are optimal. In contrast, only trace amounts of
product are formed when less polar solvents are employed
Stable and unstable isotopically labeled bioactive compounds have
served as key components in studies aimed at uncovering the in vivo
or in vitro behavior of biomolecules.1,2 Because most physiologi-
cally interesting substances contain carbonyl groups, methods for
the introduction of oxygen isotopes into this grouping are
particularly attractive and, as a result, are in high demand.2
However, no general procedures for accomplishing this task are
available. Consequently, the development of a versatile method for
direct oxygen isotope labeling that uses readily available water
and/or molecular oxygen as oxygen isotope sources, is highly
significant.
It is well known that thiocarbonyl compounds undergo
desulfurization to generate the corresponding carbonyl compounds
when treated with stoichiometric oxidants.3 As such, this reaction
has the potential of serving as a selective technique for introduction
of oxygen isotopes into carbonyl groups. However, a thiocarbonyl
desulfurization reaction involving molecular oxygen has not been
explored. One exception is the process described by Gano and Atik
that takes place under photo-irradiation conditions.3a
Table 1 Desulfurization–oxygenation of thioamide 4a
During our studies of transformations of thioamides,4 we
observed that an attempted metal-catalyzed Wacker-type cycliza-
tion5 reaction of allylated thioamide 1 failed to give the desired
thiazine 2. Instead, the amide 3, in which the sulfur atom of the
thioamide is replaced by oxygen, formed quantitatively (eqn (1)).
This observation led to an investigation in which we uncovered a
general copper-catalyzed thermal oxidative desulfurization-oxyge-
nation of thiocarbonyl compounds using molecular oxygen as an
oxidant. Below, we describe the results of this effort along with an
application of this process to the introduction of a carbonyl-18O
label into a biologically interesting sialic acid derivative by using
18O2 gas.
(2)
Entry
Cat. (mol%)
Solvent
Time/h
Conv. (%)b
1
2
3
4
5
6
CuCl (20)
PdCl2 (20)
FeCl3 (20)
AgOAc (20)
NiCl2 (20)
CoCl2 (20)
—
CuCl (20)
CuCl (20)
CuCl (20)
CuCl (20)
CuCl (5)
CuCl (1)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Toluene
(CHCl2)2
DMSO
DMSO
1/4
16
25
20
6
6
16
1
3
6
6
7
16
100 (98)c
0
100
11
0
0
7
0
0
8d
9
100
Trace
Trace
34
10
11
12
13
a
0
Department of Chemistry, Faculty of Engineering, Gifu University,
Yanagido, Gifu, 501-1193, Japan. E-mail: fshiba@gifu-u.ac.jp;
mtoshi@gifu-u.ac.jp; Fax: +81 58 230 1893; Tel: +81 58 293 2616
{ Electronic supplementary information (ESI) available: Experimental
details, characterization of all new compounds, and mass spectrum charts
of co-product and elemental sulfur. See DOI: 10.1039/b701048f
Reactions were carried out with thioamide 4 in the presence of
catalytic amount of metal salt under an oxygen atmosphere at 80 uC.
Conversions were determined by 1H NMR. Isolated yields of 5
b
c
d
are given in the parenthesis. The reaction was carried out under Ar
atmosphere.
2354 | Chem. Commun., 2007, 2354–2356
This journal is ß The Royal Society of Chemistry 2007

View Article Online
by silica gel column chromatography (Table
2 and 3).
Furthermore, the 16O : 18O ratio does not change when partially
labeled amide 5 (16O : 18O = 15 : 85) is treated with 16O2 gas in the
presence of CuCl in DMSO.8 Therefore, carbonyl oxygen
exchange between 5 and H2O, DMSO or O2 gas does not occur
under the conditions used.
ð3Þ
To demonstrate the power of this novel oxygen isotope labeling
method, we explored its use in the preparation of the 18O-labeled
sialic acid derivative 16, which is a key building block of
glycoproteins and sugar chain (eqn (4)).9–11 The thioacylated sialic
acid 15, which serve as the substrate for this process, is formed
quantitatively by the reaction of 16 with Lawesson’s reagent.
Introduction of the 18O-label was performed by reacting 15 in
DMF at 80 uC for 24 h under an 18O2 atmosphere. This process
yields the 18O labeled sialic acid derivative 16 in quantitative yield
and a 16O : 18O ratio of 23 : 77.
Fig. 1 Scope of substrates.
(entries 10, 11). The amount of CuCl significantly influences the
reaction rate. When 5 mol% of CuCl is used, reaction takes place
slowly and only a 34% yield of amide 4 is obtained after a 7 h time
period (entry 12). In addition, no reaction occurs after 16 h when
1 mol% of CuCl is employed (entry 13).
Having developed optimized conditions for this process, we next
explored the substrate scope of the desulfurization process. Each
reaction was carried out in DMSO at 80 uC in the presence of
20 mol% of CuCl. The substrates and times required for their
complete conversion to the corresponding carbonyl compounds
are shown in Fig. 1.6 Although the rates of the catalytic reactions
were highly sensitive to the structures of the thioamide starting
materials, simple variations in reaction times enabled each process
to reach completion. The results of this effort show that
chalcogenocarbonyl compounds, such as N-thioacetyl protected
amino acid 9, thioester 10, dithioimide 11, thiourea 12, 13, and
selenoamide 14, serve as competent substrates for this reaction.
Carbonyl oxygen isotope labeling of thioamide 4 by using 18O2
gas was examined next (eqn (3)). The extent of 18O introduction
into the amide product 5 was determined by using mass
spectrometric analysis (Table 2 and 3). When DMSO is used as
the solvent, 16O atom is preferentially introduced into the amide at
initial stages of the reaction (2–5 min) and the 16O : 18O ratio after
complete reaction is ca. 48 : 52. In contrast, the reaction of 4
carried out in DMF, although taking place slowly, gives 5 with a
16O : 18O ratio of ca. 16 : 84. These observations suggest that
DMSO can serve as a competitive oxidant for the catalytic
process7 and that oxygen gas is an efficient oxygen source for the
reaction in DMF. In addition, the 16O : 18O ratio in 5 remains
unchanged after aqueous work up and purification of the product
ð4Þ
A pale yellow, low polarity solid byproduct is generated in each
desulfurization reaction. The mass spectrum of this substance
contains a molecular ion peak at m/z 256 and fragment peaks that
are separated by 32 mass units. This fragmentation pattern is
exactly the same as that of elemental sulfur.12 This result clearly
suggests that elemental sulfur (S8) is the co-product. In addition,
the amount of elemental sulfur produced in each case is nearly
stoichiometrically equivalent to the amount of amide formed.
These observations suggest that the thiocarbonyl sulfur (oxidation
number = 22) is formally oxidized and eliminated from starting
thiocarbonyl compound as elemental sulfur (oxidation number =
0). Importantly, the generated elemental sulfur does not poison the
copper catalyst. Further, co-products of sulfur compounds bearing
oxygen atoms, such as sulfur dioxide, were not observed, and it is
suggested that the thiocarbonyl sulfur did not directly contact the
oxygen under the reaction pathway.
Although the intermediates involved in the desulfurization
reaction have not yet been identified, it is possible to envisage a
plausible mechanism for this process (Fig. 2). The initial event in
the proposed pathway involves stepwise two-electron oxidation of
the thiocarbonyl sulfur in I by in situ generated copper(II) to give
intermediate II. The reduced copper(I) species is then re-oxidized to
copper(II) by molecular oxygen. A reduced nucleophilic O(2II)
Table 2 The labeling reaction in DMSO
Time
2 min
5 min 45 min (completion) After work up
16O : 18O 100 : 0 93 : 7 51 : 49
48 : 52
Table 3 The labeling reaction in DMF
Time
5 min
Trace
4 h (completion)
16 : 84
After work up
15 : 85
16O : 18O
Fig. 2 Tentative reaction pathway.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 2354–2356 | 2355

View Article Online
2 For examples of using isotope-oxygen labeled compounds and
species (probably water and/or copper complexes) is formed in this
step in a manner similar to that observed in the catalytic cycle of
the Wacker oxidation.13 The generated nucleophilic oxygen species
adds to II and elemental sulfur is eliminated to give the
corresponding amide IV.
observation of nucleic acid base pairing by solid-state 17O NMR,
see: (a) G. Wu, S. Dong and R. Ida, Chem. Commun., 2001, 891; (b)
G. Wu, S. Dong, R. Ida and N. Reen, J. Am. Chem. Soc., 2002, 124,
1768.
3 (a) J. E. Gano and S. Atik, Tetrahedron Lett., 1979, 48, 4635; (b)
A. Corsaro and V. Pistara´, Tetrahedron, 1998, 54, 15027; (c)
I. Mohammadpoor-Baltork, M. M. Khodaei and K. Nikoofar,
Tetrahedron Lett., 2003, 44, 591 and references cited therein.
4 For examples of our recent studies on transformation of thioamides, see:
(a) T. Murai, H. Niwa, T. Kimura and F. Shibahara, Chem. Lett., 2004,
33, 508; (b) T. Murai, Y. Mutoh, Y. Ohta and M. Murakami, J. Am.
Chem. Soc., 2004, 126, 5968; (c) T. Murai, H. Sano, H. Kawai, H. Aso
and F. Shibahara, J. Org. Chem., 2005, 70, 8148; (d) T. Murai, R. Toshio
and Y. Mutoh, Tetrahedron, 2006, 62, 6312; (e) F. Shibahara,
A. Kitagawa, E. Yamaguchi and T. Murai, Org. Lett., 2006, 8, 5621;
(f) T. Murai and F. Asai, J. Am. Chem. Soc., 2007, 129, 780.
5 For a recent example of Wacker-type cyclization, see: R. M. Trend,
Y. K. Ramtohul, E. M. Ferreira and B. M. Stoltz, Angew. Chem., Int.
Ed., 2003, 42, 2892 and references cited therein.
Earlier, Portella et al. described a photo-induced single-electron-
transfer oxidation–activation of thiocarbonyl compounds by
oxygen gas.14 In contrast to the photochemical counterpart, the
present catalytic reaction proceeds without loss of efficiency under
dark conditions. In addition, the reaction does not take place in
the absence of the copper catalyst or oxygen gas (Table 1, entries 7
and 8). Although demonstrating its unique features, these
observations do not rule out a possible mechanism for the
copper-catalyzed reaction involving electron transfer from thio-
carbonyl sulfur to activated molecular oxygen promoted by an
active copper species (eg., oxo-complex).14,15
6 The completion of the reactions was monitored by TLC and 1H NMR
analyses.
In conclusion, we have uncovered a new transition-metal-
catalyzed oxidative desulfurization–oxygenation reaction of
thiocarbonyl compounds that uses molecular oxygen as a
stoichiometric oxidant. In addition, we have shown how this
process can be used to introduce oxygen isotope labels into
biologically important substances.
7 The activation pathway of DMSO with oxygen gas and a copper
catalyst is not clear. However, in this context, Mikolajczyk and
coworker reported a similar desulfurization–oxygenation reaction,
which is promoted by a catalytic amount of an electrophile such as
sulfuric acid, boron trifluoride or iodine in DMSO. This reaction gives
the corresponding carbonyl compound, and dimethyl sulfide and
elemental sulfur as side products, see: (a) M. Mikolajczyk and J. Luczak,
Synthesis, 1974, 491; (b) M. Mikolajczyk and J. Luczak, Synthesis, 1975,
114.
We thank Prof. S. Itoh (Osaka City University, Japan) for
helpful discussions, and Dr H. Ando (Gifu University, Japan) for
a kind personal lecture about the biology and transformations of
sialic acids and for the donation of the sialic acid derivative 16.
This work was supported by Grant-in-Aids for Young Scientists
(No. 17750084) and for Scientific Research on Priority Area (No.
18037024, ‘‘Advanced Molecular Transformations of Carbon
Resources’’) from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
8 See ESI{.
9 For syntheses of sialic acid-containing oligo saccharides, see review:
G.-J. Boons and A. V. Demchenko, Chem. Rev., 2000, 100, 4539.
10 For biology of sialic acid derivatives, see: (a) A. Varki, Glucobiology,
1993, 3, 97; (b) Biology of Sialic Acids, ed. A. Rosenberg, Plenum Press,
New York, London, 1995.
11 Sialic acids-containing glycoproteins play important roles as biological
recognition of viruses. For example, N-acetyl sialic acids (Neu5Ac) are
key units of receptor for the attachment of influenza A and B viruses.
12 See Supplementary Information (Figure S1){.
13 R. Jira, in Applied Homogeneous Catalysis with Organometallic
Compounds, ed. B. Cornils and W. A. Herrmann, Wiley-VCH,
Weinheim, 2nd edn, 2002, vol. 1, ch. 2, pp 386–405.
14 V. M. Timoshenko, J.-P. Bouillon, A. N. Chernega, Y. G. Shermolovich
and C. Portella, Eur. J. Org. Chem., 2003, 2471.
Notes and references
1 For selected reviews and examples, see: (a) K. M. Brindle and
I. D. Campbell, Q. Rev. BioPhys., 1987, 19, 159; (b) J. S. Fowle and
A. P. Wolf, Acc. Chem. Res., 1997, 30, 181; (c) A. R. Coggan, Proc.
Nutr. Soc., 1999, 58, 953; (d) M. Suzuki, R. Noyori, B. La˚ngstro¨m and
Y. Watanabe, Bull. Chem. Soc. Jpn., 2000, 73, 1053; (e) H. Yorimitsu,
Y. Murakami, H. Takamatsu, S. Nishimura and E. Nakamura, Angew.
Chem., Int. Ed., 2005, 44, 2708.
15 For a selected review on molecular oxygen activation by copper
complexes, see: S. Itoh and S. Fukuzumi, Bull. Chem. Soc. Jpn., 2002,
75, 2081.
2356 | Chem. Commun., 2007, 2354–2356
This journal is ß The Royal Society of Chemistry 2007