Regioselective Air Oxidation of Sulfides to O,S-Acetals in a Bubble Column

Article abstract of DOI:10.1002/cssc.201402310

In this paper the use of a bubble column for a metal-free, selective oxidation of α-alkylthio-imines to O,S-acetals is presented. During the synthesis, which is straightforward to perform, the sulfides are oxidized to α-alkoxy- or, respectively, α-hydroxysulfide by adding activated carbon in the presence of atmospheric oxygen only. We show that the use of the bubble column, which is unusual on laboratory scale, improves the efficiency of the reaction in comparison to common laboratory techniques. As atmospheric oxygen alone is used for oxidation, this method is cost saving, environmentally friendly, and safe.

Full text of DOI:10.1002/cssc.201402310

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DOI: 10.1002/cssc.201402310
Regioselective Air Oxidation of Sulfides to O,S-Acetals in
a Bubble Column
Fabian Brockmeyer and Jꢀrgen Martens*
[
a]
In this paper the use of a bubble column for a metal-free, se-
lective oxidation of a-alkylthio-imines to O,S-acetals is present-
ed. During the synthesis, which is straightforward to perform,
the sulfides are oxidized to a-alkoxy- or, respectively, a-
hydroxysulfide by adding activated carbon in the presence of
atmospheric oxygen only. We show that the use of the bubble
column, which is unusual on laboratory scale, improves the ef-
ficiency of the reaction in comparison to common laboratory
techniques. As atmospheric oxygen alone is used for oxidation,
this method is cost saving, environmentally friendly, and safe.
Due to its unproblematic and environmentally friendly han-
dling, the use of air as well as the use of molecular oxygen as
oxidizing agents has steadily gained importance in preparative
[
1]
organic chemistry over the past years. Often metals serve as
[
1a–e]
catalysts during this process.
An alternative method is, for
example, the in situ generation of singlet oxygen from molecu-
lar oxygen by the addition of a photosensitizer (photo-oxida-
[
1i]
tion). The effectiveness of gas–fluid-reactions (or, respectively,
of a three-phase reaction, if a heterogeneous catalyst is used)
is usually highly dependent on the formation of the specific
phase boundary and thus on the reaction conditions. On labo-
ratory scale, the syntheses are usually performed under pres-
sure in appliances that enforce these conditions such as an au-
[
1a–g]
Figure 1. Heatable bubble column to perform heterogeneous catalyzed
gas–fluid-reactions.
toclave.
Alternatively, the gas can be passed into the reac-
tion solution in a reaction flask where the solution is blended
[
1h–j]
using a magnetic stirrer.
On the basis of these facts, an
easy and effective metal-free oxidation using atmospheric
oxygen was developed. The reaction was carried out in a heata-
ble bubble column (Figure 1). Even though bubble columns
strategy, sulfoxides, which are prepared from sulfides with the
aid of common oxidizing agents, are treated with acids to
obtain a-hydroxysulfides. Alternatively, the use of singlet
oxygen is possible. The peroxides formed during the oxidation
can be converted to the a-hydroxysulfides by using, for in-
[
2]
are common in industrial usage, they are rarely known on
laboratory scale. As we demonstrated through the results of
our work, the use of a bubble column, however, improves the
effectiveness of multi-phase reactions compared with conven-
tional methods considerably. As a model reaction for our analy-
ses we chose the oxidation of a-alkylthio-imines. The synthesis
of O,S-acetals starting from sulfides has been an important
part of research for many years. a-Hydroxysulfides are accessi-
[1i–j]
stance, triphenylphosphine.
Through electrolysis and by
[4]
also adding Et N·HF, a-alkoxylation is possible. However, a hal-
3
ogenation (for example a chlorination with NCS) followed by
[5]
a substitution is more common. The use of a bubble column
now provides an easy method for direct metal-free oxidation
of a-alkylthio-imines using atmospheric oxygen, where neither
the use of toxic or expensive oxidizing agents nor light expo-
sure requiring photosensitizers is needed.
[
3]
ble in a variation of the Pummerer reaction. Following this
[a] F. Brockmeyer, Prof. Dr. J. Martens
2,5-Dihydrothiazoles (3-thiazolines) (1) were used as sub-
Carl von Ossietzky Universitꢀt Oldenburg
Fakultꢀt fꢁr Mathematik und Naturwissenschaften
Institut fꢁr Chemie
Carl-von-Ossietzky-Str. 9–11, 26129 Oldenburg (Germany)
E-mail: juergen.martens@uni-oldenburg.de
Homepage: http://www.martens.chemie.uni-oldenburg.de
strates for the exploration of the oxidation reaction. The syn-
[6]
thesis of theses cyclic imines was first described by Asinger.
[7]
[8]
Based on this common synthesis, a modified version was
established. Using this modified synthesis protocol a wider
range of products was accessible. Both, the Asinger reaction
itself and 3-thiazoline as the product of this reaction, form the
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201402310.
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[9]
basis for a large number of sequences of synthesis. They
the sulfoxides but rather the a-alkoxy- or, respectively, a-hy-
[
10]
[12]
have already found industrial application.
droxysulfides (3, 4). The proof of the structure was achieved
The 3-thiazolines used were synthesized following the classi-
cal (synthesis of 1a–c, Scheme 1) and the modified (synthesis
of 1d–h, Scheme 1) synthesis protocol.
by NMR, IR, and mass spectrometric analysis. In addition, we
were able to obtain single crystals of one a-alkoxy- and one a-
hydroxysulfide to verify the structure by X-ray crystal structure
[13]
Asinger already observed the oxidation of some of these 3-
analysis.
[
11]
thiazolines (1a–g) but mistakenly postulated the structure of
the corresponding sulfoxides 2 for the products of the oxida-
tion reaction. We successfully reproduced this oxidation. Fur-
thermore, we were able to verify that the products were not
As a first example, 3-thiazoline 1a was oxidized in MeOH
using atmospheric oxygen and a small amount of activated
carbon (Darco, 12–20 mesh, granular; Sigma Aldrich) to the
corresponding a-methoxysulfide 3a. Performing the oxidation
in a round bottom flask and blending the suspension with the
help of a conventional magnetic stirrer did not result in the
formation of a product (Table 1, entry 1). However, the oxida-
tion of 1a was realized using a KPG stirrer and product 3a was
formed with a moderate yield of 47% (Table 1, entry 3). With
a view to optimizing the reaction conditions, the model reac-
tion was carried out in a bubble column as shown in Figure 1.
In addition to a faster oxidation resulting in a shorter reaction
time the use of the bubble column led to an increased yield of
75% (Table 1, entry 5). In the case of the oxidation of 3-thiazo-
line 3b, the same observations were made (Table 1, entries 2,
4, and 6).
The bubble column used consisted of an inner column
(
20 mm inner diameter), including a gas tube with a frit as
a gas inlet, and an outer cladding filled with water to heat and
maintain the temperature of the reaction mixture at 558C
(
Figure 1). At this temperature, untreated compressed air was
passed into the reaction mixture. A frit was used to break up
the gas into tiny bubbles. The air pressure was adjusted with
the help of a flow controller to ensure that the activated
Scheme 1. Synthesis of the 3-thiazolines 1.
Table 1. Investigations on the practical conduction of the oxidation of the 3-thiazolines 1.
[
a]
1
2
3
4
5
[b]
Entry
1
Method
Solvent
Additive
Reaction time
h]
Product
R ÀR =R ÀR
R
Yield
[%]
[
1
2
3
4
5
6
7
1a
1b
1a
1b
1a
1b
1a
1a
1b
1b
1b
A
A
B
B
C
C
C
C
C
C
C
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
activated carbon
activated carbon
activated carbon
activated carbon
activated carbon
activated carbon
–
activated carbon
activated carbon
activated carbon
activated carbon
40
40
50
50
20
12
30
30
30
20
20
3a
3b
3a
3b
3a
3b
3a
3a
4a
4a
4a
ÀCH
À(CH
ÀCH
À(CH
ÀCH
2
C(CH
3
3
3
)
2
2
2
CH
CH
CH
2
2
2
C(CH
C(CH
C(CH
3
3
3
)
)
)
2
À
Me
Me
Me
Me
Me
Me
Me
Me
H
–
–
2
)
6
À
2
C(CH
)
)
2
À
47
29
75
76
15
74
–
2
)
6
À
2
C(CH
2
À
À(CH
2
)
6
À
ÀCH
ÀCH
2
C(CH
C(CH
3
)
)
2
CH
CH
2
C(CH
C(CH
3
)
)
2
À
[c]
8
9
0
2
3
2
2
3
2
À
H
2
O
À(CH
À(CH
À(CH
2
)
2
)
2
)
6
À
6
1
EtOAc (wet)
abs. EtOAc
À
H
H
60
–
11
6
À
[a] In all cases the substrate will be dissolved in the solvent and compressed air is passed into the heated (558C) reaction mixture. Method A: The reaction
mixture is blended using a magnetic stirrer (cylindrical, 25 mm, 900 rpm) in a 250 mL round bottom flask. Method B: The reaction mixture is blended
using a KPG stirrer (crescent„ 100 mm, 900 rpm) in a 1000 mL round bottom flask. Method C: Heated bubble column (20 mm inner diameter, volume
À1
1
70 mL, airflow 170–200 mL min ) (Figure 1). [b] All yields are isolated yields. [c] The reaction took place under complete exclusion of light.
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carbon was evenly dispersed
throughout the entire volume of
[
a,b]
Table 2. Oxidation of several 3-thiazolines using the bubble column (Figure 1).
the reaction solution by the air
À1
(
170–200 mL min ). Discharge
of the solvent was minimized by
the use of a reflux condenser.
The advantage of the bubble
column in comparison to stan-
dard laboratory methods (round
bottom flask combined with
a magnetic or KPG stirrer) is the
improved dispersion of the air
and the activated carbon within
the solution. As a consequence
thereof the specific reaction in-
terface is increased. Furthermore,
the flow of the air results in
a continuous thorough mixing
of the solution. Thus, depend-
ence of the reaction on the dif-
fusion of reactants is decreased
and the efficiency of the reaction
is increased.
Oxidation product
Method Yield Oxidation product
[%]
Method Yield
[%]
3
b, R=Me
A
B
76
60
3
a, R=Me
A
75
4a, R=H
[
c]
3
4
c, R=Me
b, R=H
A
B
59
53
3d , R=Me (dv=53:47)
4c , R=Me (dv=55:45)
A
B
73
69
[c]
3f, R=Me
3i, R=Et
3j, R=iPr
A
76
54
45
54
3
4
e, R=Me
d, R=H
71
48
A
A
4
e, R=H
B
3g, R=Me
4f, R=Me
68
55
3h, R=Me
A
72
[a] Solvent: Method A: Respective alcohol. Method B: Wet EtOAc. [b] All yields are isolated yields. [c] The given
yield shows the overall yield of both diastereomers.
A control experiment (oxida-
tion without activated carbon)
revealed the influence of the ac-
tivated carbon on the reaction, even if a slight formation of
the product 3a was observed (15%, Table 1, entry 7). After the
reaction, the used activated carbon can be filtered off and
used repeatedly in further oxidation reactions. Light is, howev-
er, not a relevant factor for the feasibility of the oxidation pro-
cess (Table 1, entry 8). This fact reveals that the reaction is not
a function of the formation of singlet oxygen.
and easy availability, its easy handling, and its environmental
friendliness.
A first step towards making this oxidation reaction a general
method for the synthesis of b,g-unsaturated sulfides was ac-
complished by the oxidation of a b-ketosulfide to the corre-
sponding O,S-acetal (12%; Scheme 2). We noticed that the for-
mation of the product 5 only occurred when the reaction was
performed in a bubble column and not in a solution blended
using a KPG-stirrer.
In addition to the methoxylation to products 3a and b, hy-
droxylation was targeted. Using water instead of MeOH did
not lead to the desired product 4a (Table 1, entry 9). However,
the hydroxylation occurred when using wet EtOAc as solvent
(Table 1, entry 10). Entry 11 shows that the presence of water is
essential for the formation of the product.
Under the optimized conditions (Table 1, entries 5, 6, and
10) the other previously synthesized 3-thiazolines 1c–h were
converted. Table 2 shows that the oxidation of 1c–h in the
bubble column to the corresponding a-alkoxysulfides (3a–h)
occurred with satisfactory or even good yields in all cases.
Accordingly, the synthesis of a-hydroxysulfides is also possible.
Here, aldiminic 3-thiazolines (1h) can be used alongside the
ketiminic 3-thiazolines (1a–g). We could not detect any signifi-
cant diastereoselectivity during the reaction process, for exam-
ple, the conversion of 3-thiazoline 1d led to a diastereomeric
mixture of 53:47 (3d) and 55:45 (4c), respectively.
The results demonstrate that the bubble column is a suitable
device also on laboratory scale for performing reactions that
utilize both a liquid and a gaseous phase. Thus, the use of
a bubble column allowed the efficient and environmentally
friendly oxidation of the sulfides 1. Air as a means for oxidation
is an enormous advantage of this synthesis method. The main
advantageous aspects of air in this context are its low price
Scheme 2. Oxidation of a b-keto sulfide.
In conclusion, we synthesized new O,S-acetals starting from
3-thiazolines by introducing a hydroxyl or an alkoxy group. To
achieve this, a synthesis protocol was used that made it possi-
ble to oxidize the substrates without using expensive metals,
toxic oxidizing agents, or photosensitizer. With the aid of acti-
vated carbon the sulfides were oxidized to the O,S-acetals by
atmospheric oxygen. Most noteworthy is the fact that the reac-
tions were carried out in a bubble column, which is an uncon-
ventional apparatus for laboratory syntheses. The benefits of
the bubble column in the reaction process lead to higher
yields at decreased reaction times in comparison to the com-
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monly used laboratory techniques. Due to the large number of
known syntheses in which gaseous reactants are involved and
the easy handling of the bubble column, this apparatus has
the potential to play a major role in laboratory organic synthe-
ses in the immediate future.
4648–4651; Angew. Chem. 2006, 118, 4764–4767; d) S. Mukhopadhyay,
G. Rothenberg, G. Lando, K. Agbaria, M. Kazanci, Y. Sasson, Adv. Synth.
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Experimental Section
General: All reactions were performed in standard glassware with
no special precautions taken for the exclusion of moisture or air or
in a heated bubble column (Figure 1). MeOH was refluxed with Mg
and freshly distilled prior to use. Activated carbon was purchased
from Sigma Aldrich (Darco, 12–20 mesh, granular). Preparative
[2] N. Kantarci, F. Borak, K. O. Ulgen, Process Biochem. 2005, 40, 2263–2283.
[
3] K. Griesbaum, A. A. Oswald, B. E. Hudson, J. Am. Chem. Soc. 1963, 85,
969–1974.
1
[
[
[
[
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Offermanns, Angew. Chem. Int. Ed. Engl. 1967, 6, 907–919; Angew.
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8] a) J. Martens, H. Offermanns, P. Scherberich, Angew. Chem. Int. Ed. Engl.
column chromatography was carried out using Grace SiO (0.035–
2
0
.070 mm, type KG 60). Yields refer to analytically pure samples.
1
Isomer ratios were determined by means of H NMR integrals of
cleanly separated signals.
Characterization: TLC was performed on Machery-Nagel SiO F254
2
[
plates on aluminum sheets. Melting points were obtained on
a melting point apparatus (Laboratory Devices) and were uncor-
1
981, 20, 668; Angew. Chem. 1981, 93, 680; b) F. Brockmeyer, D. Krçger,
T. Stalling, P. Ullrich, J. Martens, Helv. Chim. Acta 2012, 95, 1857–1870.
1
13
rected. H and C NMR spectra were recorded using a Bruker AM
[9] a) W. Schwarze, K. Drauz, J. Martens, Chem.-Ztg. 1987, 111, 149–153;
b) K. Johannes, M. Watzke, J. Martens, J. Heterocycl. Chem. 2010, 47,
697–702; c) F. Brockmeyer, T. Stalling, J. Martens, Synthesis 2012, 44,
1
3
00 (measuring frequency: H NMR—300.1 MHz), a Bruker AMX R
1
13
5
00 (measuring frequency: H NMR—500.1 MHz,
C NMR—
2947–2958; d) A. Dçmling, I. Ugi, Angew. Chem. Int. Ed. Engl. 1993, 32,
1
25.8 MHz) or a Bruker Avance III 500 (measuring frequency:
1
13
563–564; Angew. Chem. 1993, 105, 634–635; e) A. Dçmling, I. Ugi,
Angew. Chem. Int. Ed. 2000, 39, 3168–3210; Angew. Chem. 2000, 112,
H NMR—499.9 MHz, C NMR—125.7 MHz) spectrometer in CDCl3
or C D solution. All chemical shifts are quoted on the d scale in
6
6
3300–3344.
ppm. As an internal standard, the signal of residual non-deuterated
[
10] a) F. Asinger, W. Schꢂfer, W.-C. Witte, Angew. Chem. Int. Ed. Engl. 1964, 3,
313–314; Angew. Chem. 1964, 76, 273–273; b) W. M. Weigert, H. Offer-
manns, P. Scherberich, Angew. Chem. Int. Ed. Engl. 1975, 14, 330–336;
Angew. Chem. 1975, 87, 372–378; c) I. Hoppe, U. Schçllkopf, M. Nieger,
E. Egert, Angew. Chem. Int. Ed. Engl. 1985, 24, 1067–1068; Angew.
Chem. 1985, 97, 1066–1067.
1
13
solvent was used [CDCl ]: 7.26 ( H NMR) and 77.16 ppm ( C NMR);
3
1
13
[14]
C D : 7.16 ( H NMR) and 128.06 ppm ( C NMR)]. Assignments of
6
6
the signals were supported by measurements applying DEPT and
COSY techniques. Mass spectra were obtained on a Waters Q-TOF
Premier (electrospray ionization) and a Finnigan-MAT 212 mass
spectrometer with isobutane as reagent gas (chemical ionization).
The IR spectra were recorded using a Bruker Tensor 27 spectrome-
ter equipped with a “Golden Gate” diamond-ATR (attenuated total
reflection) unit.
[
11] F. Asinger, W. Schꢂfer, M. Baumann, H. Rçmgens, Liebigs Ann. Chem.
1
964, 672, 103–133.
[
12] Comparison of IR spectra and melting points reveals that Asinger and
co-workers also synthesized the a-alkoxy- and a-hydroxysulfide (3 and
[11]
4
). Melting points [8C] (F. Asinger /this work): 3a 124.5/123; 4a 145–
[
15]
146/139; 4b 180–181/174; 4c (diastereomeric mixture) 133–135/135;
4d 112–115/117; 4e 165/160; 4 f 165–170/167. A targeted synthesis of
a sulfoxide was realized by oxidation with mCPBA starting from 2,2,5,5-
Synthesis: (RS)-2-Chlorocyclooctanone,
2-chloro-2-phenylacetal-
[16]
[17]
dehyde,
1,2-diphenyl-2-(p-tolylthio)ethan-1-one,
tetramethyl-2,5-dihydro-thiazol were prepared according to pub-
and 2,2,5,5-
[18]
[
19]
tetramethyl-3-thiazoline
(product: 2,2,5,5-tetramethyl-2,5-dihydro-
[11]
[19]
lished procedures. 3-Thiazolines 1a, 1b, 1d–1g and 1c were
prepared analogous to reported syntheses. Due to the hitherto in-
complete characterization, all these 3-thiazolines were fully charac-
terized (see the Supporting Information for further details). Com-
pounds 3a and 4a–4 f were previously reported by Asinger and
thiazol-1-oxid 6). The IR spectrum of this product exhibits a characteris-
tic IR band at 1034 cm . The oxidation of the 3-thiazolines 1 used in
this work to the sulfoxides 2 is not possible with the aid of the
common methods.
À1
[13] CCDC 986968 (3a) and CCDC 986969 (4c) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[11]
co-workers, but an incorrect structure was assigned by them.
[
14] G. R. Fulmer, A. J. M. Miller, N. H. Sherden, H. E. Gottlieb, A. Nudelman,
Acknowledgements
B. M. Stoltz, J. E. Bercaw, K. I. Goldberg, Organometallics 2010, 29, 2176–
2
179.
The authors gratefully acknowledge Wolfgang Saak and Marc
Schmidtmann for X-ray crystallography.
[
15] K. M. Brummond, K. D. Gesenberg, Tetrahedron Lett. 1999, 40, 2231–
2234.
[
16] K. G. R. Masschelein, C. V. Stevens, Tetrahedron Lett. 2008, 49, 4336–
4338.
Keywords: green chemistry
oxidation · synthesis
· acetals · o,s-hemiacetals ·
[17] F. Effenberger, W. Russ, Chem. Ber. 1982, 115, 3719–3736.
[
18] S. Kçpper, K. Lindner, J. Martens, Tetrahedron 1992, 48, 10277.
19] F. Asinger, M. Thiel, H. Usbeck, K.-H. Grçbe, H. Grundmann, S. Trꢂnker,
Liebigs Ann. Chem. 1960, 634, 144–156.
[
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Hansen, H. C. Andersen, A. Riisager, Angew. Chem. Int. Ed. 2006, 45,
Received: April 14, 2014
Revised: June 3, 2014
Published online on July 30, 2014
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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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