Phase-vanishing method with gas evolution and its application to organic synthesis

Article abstract of DOI:10.1016/j.tetlet.2015.12.115

Using a phase-vanishing (PV) system, hydrogen, oxygen, and hydrogen sulfide generated in situ from CaH₂, KO₂, and P₂S₅, respectively, were directly reacted with substances in the organic phase to afford the desired products. The selective synthesis of sulfides and disulfides was achieved with the evolution of H₂S gas via tuning the bases used in the PV method. Using this PV system, reactions with hazardous gaseous reagents can be carried out easily and safely in a common test tube.

Full text of DOI:10.1016/j.tetlet.2015.12.115

Accepted Manuscript
Phase-vanishing method with gas evolution and its application to organic syn-
thesis
Ryosuke Matake, Yuki Niwa, Hiroshi Matsubara
PII:
S0040-4039(15)30530-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.115
TETL 47162
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Tetrahedron Letters
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Please cite this article as: Matake, R., Niwa, Y., Matsubara, H., Phase-vanishing method with gas evolution and its
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Tetrahedron Letters
Phase-vanishing method with gas evolution and its application to organic synthesis
Ryosuke Matake, Yuki Niwa and Hiroshi Matsubara*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Using a phase-vanishing (PV) system, hydrogen, oxygen, and hydrogen sulfide generated in situ
from CaH2, KO2, and P2S5, respectively, were directly reacted with substances in the organic
phase to afford the desired products. The selective synthesis of sulfides and disulfides was
achieved with the evolution of H2S gas via tuning the bases used in the PV method. Using this
PV system, reactions with hazardous gaseous reagents can be carried out easily and safely in a
common test tube.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Phase-vanishing method
Fluorous solvent
Gaseous reagents
Hydrogen sulfide
Disulfide
———
* Corresponding author. Tel.: +81-72-254-9698; fax: +81-72-254-9163; e-mail: matsu@c.s.osakafu-u.ac.jp

2
Tetrahedron Letters
exothermic reactions. Indeed, with the use of the PV method,
1. Introduction
such reactions can be carried out in a common test tube without
the need for cooling equipment and dropping funnels. In our first
study,2a we investigated the bromination of alkenes by using
molecular bromine as the reagent in the lower layer. Since our
first study, several reagents have been used in this method, e.g.
BBr3,2a SnCl4,2c and CH2I2.2e In addition to changing the reagents
in the lower layer, we have also substantially developed the PV
method. For instance, we demonstrated a Grignard-type reaction
using a quadraphasic PV system comprising a 1:1 mixture of
Galden HT135 and HT200,6 iodomethane, magnesium, ether, and
carbonyl compounds.4 In this method, alkyl magnesium iodide
reagents were successfully generated in situ and reacted with
carbonyl compounds, affording the desired products in good
yields.
Fluorous solvents (highly fluorinated compounds) have unique
features, for example, immiscibility with general organic solvents
and water and higher densities than those of typical organic
solvents. Several studies utilizing these features of fluorous
solvents to simplify post-reaction treatments (e.g. rapid
separation of products to efficiently recover reagents or catalysts)
have been reported over the past two decades.1 Meanwhile, we
developed a novel synthetic methodology using fluorous solvents
as a phase screen, known as the ‘phase-vanishing (PV) method’.2-
5
The PV method involves a triphasic reaction system, in which
fluorous media are used as a liquid membrane to steadily
transport reagents from the lower layer to the upper organic layer
that includes the substrate. In the PV method, the fluorous phase
regulates the transport of reagents by passive diffusion. The PV
system allows simple and easy control of heat evolution in
Scheme 1. Concept of the phase-vanishing method with gas evolution
Most recently, we reported an epoch-making PV method
(Scheme 1), in which acetylene gas evolved from calcium
carbide is simultaneously used in three organic reactions
The initial conditions used for hydrogen generation by the PV
method were similar to those used for the generation of
acetylene.5 For this purpose, CaH2 (8 mmol, ρ = 1.70 g cm−3)
was used as the source of hydrogen in the reagent phase (bottom
layer), and THF (ρ = 0.89 g cm−3) was used as the organic phase
(top layer). Galden HT135 (ρ = 1.72 g cm−3) was employed as
the fluorous phase, and water (22 mmol) was placed above it.
Dodecene (2 mmol) and the Wilkinson catalyst7 (5 mol%) were
added to the top layer, and then the air in the test tube was
removed using a syringe. The lower layer was gently stirred at
55 °C, ensuring that it did not mix the four layers. After a few
minutes, gentle gas evolution was observed, and after 20 h, the
reagent phase (CaH2) and aqueous phase had vanished. From the
organic layer, the hydrogenation product, dodecane, was
obtained in 90% yield (Scheme 3). Next, KO2 (ρ = 2.14 g cm−3)
was employed to generate oxygen. Using DMF as the organic
phase, the Wacker oxidation8 of the same substrate, dodecene,
was carried out at 80 °C for 20 h, affording 2-dodecanone in
47% yield (Scheme 4).9 Both results indicated that the PV
system evolving hydrogen or oxygen gas undergoes satisfactory
functionalization. As mentioned above, the PV system with gas
evolution has advantages, as reactions with gaseous reagents can
be conducted easily and safely without the use of any high-
pressure apparatus. Hence, we focused our attention on the
generation (and use) of more hazardous gases using the PV
method.
(Sonogashira
coupling,
Cu-catalysed
azide–alkyne
cycloaddition, and aldehyde–alkyne–amine coupling), affording
the desired products in good yields.5 This method also utilized
the passive diffusion of water into the fluorous solvent to obtain
gradual evolution of acetylene gas from calcium carbide.
Therefore, this method is advantageous for reactions requiring
acetylene gas as it avoids the use of high-pressure apparatus,
such as regulators and gas cylinders.
Herein, we report the evolution of gaseous reagents other than
acetylene (hydrogen, oxygen, and hydrogen sulfide) by the PV
method (Scheme 2) and the utilization of these gases in organic
synthesis. In addition, the selective synthesis of sulfides and
disulfides via the generation of hydrogen sulfide was achieved
by tuning the organic base used in the system.
Scheme 2. Generation of gaseous reagents from inorganic
compounds and water
2. Results and Discussion
2-1. Hydrogen (H2) & Oxygen (O2)

Scheme 3. Hydrogenation of 1-dodecene using the PV method with
hydrogen evolution
Fig. 1 PV method for the preparation of dibenzyl sulfide by the
evolution of hydrogen sulfide. The arrows indicate the interface of
each phase. (a) Quadraphasic system: P2S5, Galden HT135, water,
and THF solution of benzyl chloride and DBU (from the bottom).
(b) After the reaction was completed (55 °C, 20 h), the P2S5 layer
and aqueous layer disappeared, affording two phases: Galden HT135
and THF phase (from the bottom).
Scheme 4. Wacker oxidation using the PV method with oxygen
evolution
2-2. Hydrogen Sulfide (H2S)
Hydrogen sulfide10 is a useful gas to prepare thiols, sulfides,
and thiocarbonyl compounds; however, this malodorous gas is
very toxic.11 As a result, special apparatus, such as a well-vented
fume hood with a scrubber, is required when using this gas.
Hydrogen sulfide is also corrosive and flammable; additional
precautions are necessary to handle this gas. P2S5 (2 mmol, ρ =
2.09 g cm−3) was used as the source of hydrogen sulfide in the
reagent phase (bottom layer), and THF was used as the organic
phase (top layer). Galden HT135 was used as the fluorous phase,
and water (32 mmol) was placed above it. Notably, the order of
addition of the components is crucial for safely performing the
PV method. The careless addition of water to P2S5 results in the
intense evolution of hydrogen sulfide, resulting in a potentially
hazardous situation. Benzyl chloride (1 mmol) and DBU (10
mmol) were added to the organic layer (Fig. 1, left). After
removing the air in the test tube using a syringe, the lower layer
was gently stirred at 55 °C, ensuring that this layer did not mix
the four layers, similar to the procedure described in 2-1. Again,
after a few minutes, gentle gas evolution was observed, and after
20 h, the reagent phase (P2S5) and aqueous phase had vanished
(Fig. 1, right). From the organic layer, the desired product,
dibenzyl sulfide, was obtained in 50% yield (Table 1, entry 1).12
Using a series of benzyl chlorides, the substrate generality was
investigated, and Table 1 summarizes the results. Benzyl
chlorides
with
electron-withdrawing groups afforded
corresponding dibenzyl sulfides in moderate yields (entries 2 and
5), and similar reactivity was observed for methyl-substituted
benzyl chlorides (entries 3 and 4). Substitution with an ortho-
methyl group did not result in a lower yield of the product (entry
4). On the other hand, the use of methoxy-substituted benzyl
chloride resulted in a significantly lower yield of the product
(entry 6). Unfortunately, the product yields for preparation of
dibenzyl sulfides from benzyl chlorides by the PV method were
moderate, and lower than those obtained using traditional
methods.13 However, it should be emphasized that using the PV
method preparation of these products from the benzyl chlorides
using hydrogen sulfide gas can be conducted easily and safely.
In all cases, the substrates were completely consumed, while
in addition to the dibenzyl sulfides, low amounts of dibenzyl
disulfides were obtained (entries 1–6). As trace amounts of thiols
were detected in the reaction mixture by GC-MS, these
disulfides were probably formed by aerobic oxidation of the
thiols. Thus, we attempted to perform selective synthesis of
dibenzyl disulfides by tuning the reaction conditions.
Table 1. Preparation of Dibenzyl Sulfides and Disulfides Using the PV Method with Hydrogen Sulfide Generation
yield (%)a
entry
substrate
base
2
3

4
Tetrahedron Letters
1
2
R = H (1a)
DBU
50 (46)b (2a)
5
2
R = 4-Cl (1b)
R = 4-CH3 (1c)
R = 2-CH3 (1d)
R = 4-CF3 (1e)
R = 4-OCH3(1f)
R = H (1a)
DBU
DBU
DBU
DBU
DBU
DIPEA
TEA
61 (2b)
3
47 (2c)
2
4
48 (2d)
3
5
55 (2e)
2
6
31 (2f)
6
7
-
-
-
-
-
-
-
36 (3a)
32 (3a)
59 (3c)
68 (3c)
34 (3d)
55 (3e)
30 (3f)
8
R = H (1a)
9
R = 4-CH3 (1c)
R = 4-CH3 (1c)
R = 2-CH3 (1d)
R = 4-CF3 (1e)
R = 4-OCH3 (1f)
DIPEA
TEA
10
11
12
13
TEA
TEA
TEA
aYields were determined by 1H-NMR using 1,1,2,2-tetrachloroethane as an internal standard. bIsolated yield.
Scheme 5 shows a plausible reaction mechanism: Weaker bases are used to furnish disulfides, as they slow the reaction rate for
the dehydrogenation of the generated thiols, thereby increasing the amount of thiols in situ; as a result, disulfides are generated by
the oxidative coupling of thiols. Namely, in the reaction, the base was changed from DBU to N,N-diisopropylethylamine (DIPEA).
As a result, disulfides were exclusively obtained, albeit in moderate yields (Table 1, entries 7 and 9). With the use of trimethylamine
as the base, dibenzyl disulfides were also obtained as the sole product (Table 1, entries 8, 10–13) with similar yields.14 In all cases,
the substrates were completely consumed.
Scheme 5. Plausible reaction mechanism for the preparation of dibenzyl sulfide and dibenzyl disulfide
3. Conclusions
In summary, we generated hydrogen, oxygen, and hydrogen sulfide from CaH2, KO2, and P2S5, respectively, in a test tube by the
PV method and used these gases in several organic reactions. The hydrogenation and oxidation of alkenes were found to proceed by
the PV method with gas evolution. Furthermore, in the case of hydrogen sulfide, the selective synthesis of dibenzyl sulfides and
dibenzyl disulfides was achieved by adjusting the base used in the organic phase. Importantly, reactions using hydrogen sulfide,
which is a very toxic gas, could be carried out safely and easily by the PV method. This method is advantageous, as it avoids the use
of high-pressure apparatus, such as regulators and gas cylinders. Notably, with the use of the PV method, several reactions using
gaseous reagents can be carried out in a simple and safe manner, as the method uses a simple test tube, which is commercially
available all over the world.
4. Typical procedure for the synthesis of dibenzyl sulfides using the PV method with hydrogen sulfide evolution
Phosphorus pentasulfide (444 mg, 2.0 mmol) and a magnetic stirring bar (oval, 10 mm × 5 mm) were placed in a Pyrex test tube
(15 mm φ × 130 mm), and into this test tube, Galden HT135 (2 mL) was slowly added using a syringe. Subsequently, water (572
mg, 31.7 mmol), a solution of benzyl chloride (128 mg, 1.0 mmol) in THF (4 mL), and DBU (1.54 g, 10.1 mmol) were slowly

3
added in order, forming four layers. A rubber septum was fitted to the test tube, and the septum was pierced using a needle equipped
with a balloon, which acted as a reservoir of hydrogen sulfide gas during the reaction. The air in the test tube was removed using a
syringe until the balloon was completely deflated. The test tube was heated in an oil bath at 55 °C for 20 h with slow stirring,
ensuring not to mix the layers, and then it was allowed to cool to ambient temperature. After removing Galden HT135 using a glass
pipette, the organic layer was transferred to a separatory funnel using diethyl ether and water. The organic layer was separated, and
the aqueous layer was extracted with diethyl ether. The combined organic layers were then dried over sodium sulfate, filtered, and
concentrated. The residue was purified by column chromatography on silica gel using hexane/chloroform (4:1) as the eluent,
affording desired product 2a (49 mg, 46%) as a light brown oil.
Acknowledgement
This work was partially supported by a Grant-in-Aid for Scientific Research (C) (no. 24550213) from the Japan Society for the
Promotion of Science (JSPS).
Supplementary data
Products 2aS1, 2bS1, 2cS1, 2dS1, 2eS2, 3aS3, 3bS4, 3cS3, 3dS3, and 3fS5 are known compounds and showed the identical spectra
according to the literature shown in the Supplementary data. New compounds, 2f and 3e, were characterized by 1H & 13C NMR, IR
spectra, LR-MS (EI), and HRMS (EI). These data are available in the Supplementary data associated with this article can be found
in the online version.
References and notes
1.
2.
For a general review of fl m th, I. T. In Handbook of Fluorous Chemistry; Wiley-VCH:
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Ryu, I.; Matsubara, H.; Yasuda, S.; Curran, D. P. Org. Lett. 2003, 5, 1167. (c) Matsubara, H.; Yasuda, S.; Ryu, I. Synlett 2003, 247. (d) Rahman,
Md. T.; Kamata, N.; Matsubara, H.; Ryu, I. Synlett 2005, 2664. (e) Matsubara, H.; Tsukida, M.; Yasuda, S.; Ryu, I. J. Fluorine Chem. 2008, 129,
951. (f) Matsubara, H.; Tsukida, M.; Ishihara, D.; Kuniyoshi, K.; Ryu, I. Synlett 2010, 2014; (g) Jana, N. K.; Verkade, J. G. Org. Lett. 2003, 5,
3787; (h) Iskra, J.; Stavber, S.; Zupan, M. Chem. Commun. 2003, 2496; (i) Curran, D. P.; Werner, S. Org. Lett. 2004, 6 1 1 ( ek, A.;
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Lett. 2013, 54, 7124.
3.
For reviews on the phase-vanishing method, see: (a) Ryu, I.; Matsubara, H.; Nakamura, H.; Curran, D. P. Chem. Rec. 2008, 8, 351; (b) Iskra, J. Lett.
Org. Chem. 2006, 3, 170; (c) Van Zee, N. J.; Dragojlovic, V. Chem. Eur. J. 2010, 16, 7950.
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Matsubara, H.; Niwa, Y.; Matake, R. Synlett 2015, 26, 1276.
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Galden HT135 and HT200 are polyether-type perfluorinated solvents, which are commercially available from Solvay Solexis Inc. The kinetic
viscosities of Galden HT135 and HT200 at 25 °C are 1.0 and 2.4 cSt, respectively.
Fig. 2 General structure of Galden
7.
8.
9.
Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J. Chem. Soc. A,1966, 1711.
Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80.
We carried out the Wacker oxidation of 1-dodecene several times using the PV method with oxygen evolution. However, the yields of 2-
dodecanone were moderate, up to 47%.
10. For a review of hydrogen sulfide as a reagent, see: Dittmer, D. C. In Encyclopedia of Reagents for Organic Synthesis, 2nd ed.; Paquette, L. A.;
Crich, D.; Fuchs, P. L.; Molander, G. A., Ed.; John Wiley & Sons: Chichester, UK, 2009; Vol. 7, pp 5452.
11. For example; Beauchamp, R. O.; Bus, J. S.; Popp, J. A.; Boreiko, C. J.; Andjelkoviche, D. A. CRC Critical Reviews in Toxicology, 1984, 13, 25.
12. Dibenzyl sulfide prepared using hydrogen sulfide gas generated separately afforded the product in 65% yield, indicating that the reactivity of the
reaction is very similar to that of the PV method. For experimental details, see the supplementary data.
13. (a) Pradhan, N. C.; Sharma, M. N. Ind. Eng. Chem. Res. 1990, 29, 1103; (b) Ido, T.; Susaki, T.; Jin, G.; Goto, S. Appl. Catal. A:Gen. 2000, 201,
139; (c) Maity, S. K.; Pradhan, N. C.; Patwardhan, A. V. J. Mol. Catal. A: Chem. 2006, 250, 114; (d) Sen, S.; Pradhan, N. C.; Patwardhan, A. V.
Asia-Pac. J. Chem. Eng. 2011, 6, 257; (e) Sidiq, N.; Bhat, M. A.; Khan, K. Z.; Khuroo, M. A. Heteroatom Chem. 2012, 23, 373; (f) Hajipour, A. R.;
Pourkaveh, R.; Karimi, H. Appl. Organometal. Chem. 2014, 28, 879; (g) Firouzabadi, H.; Iranpoor, N.; Gorginpour, F.; Samadi, A. Eur. J. Org.
Chem. 2015, 2914; (h) Lu, G. P.; Cai, C. Green Chem. Lett. Rev. 2012, 5, 481.
14. Dibenzyl disulfide prepared using hydrogen sulfide gas generated separately afforded the product in 22% yield, indicating that the reactivity of the
reaction is inferior to that of the PV method. For experimental details, see the supplementary data.

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R. Matake, Y. Niwa, H. Matsubara*