The direct synthesis of thioesters using an intermolecular radical reaction of aldehydes with dipentafluorophenyl disulfide in water

Article abstract of DOI:10.1039/b202129c

The combination of the water-soluble radical initiator, 2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044), and surfactant, cetyltrimethylammonium bromide (CTAB), was found to be the most suitable condition for the effective direct synthes

Full text of DOI:10.1039/b202129c

The direct synthesis of thioesters using an intermolecular radical
reaction of aldehydes with dipentafluorophenyl disulfide in water
Hisanori Nambu, Kayoko Hata, Masato Matsugi and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka 565-0871,
Japan. E-mail: kita@phs.osaka-u.ac.jp
Received (in Cambridge, UK) 28th February 2002, Accepted 3rd April 2002
First published as an Advance Article on the web 16th April 2002
The combination of the water-soluble radical initiator, 2,2A-
azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA–
044), and surfactant, cetyltrimethylammonium bromide
(CTAB), was found to be the most suitable condition for the
effective direct synthesis of useful active thioesters (penta-
fluorophenyl thioesters) in water.
absence of the surfactant, the reaction did not proceed at all
(entry 7).
The solvent effect on this reaction using 1a, 2a, VA–044 and
CTAB is shown in Table 2. From these results, water was found
to be the best solvent for the thioesterification. The thioester-
ification did not proceed in benzene or under neat conditions
(entries 1–3). In addition, when the radical initiators AIBN, V–
70L14 and Et3B were used in benzene, the yields of the
thioesters were lower than the former cases (entries 4–6).
We then investigated the generality of this pentafluorophenyl
thioesterification in water using VA–044 and CTAB, which was
the most effective condition. Under these conditions, alkyl and
aryl aldehydes (1b–g) were smoothly reacted with 2a to give the
corresponding thioesters (3b–g) in good yields (Table 3). The
yields of the thioesters might be affected by the stabilities of the
acyl radical intermediates.15
Thioesters are useful synthetic intermediates in organic synthe-
sis.1 For example, they have been employed as mild acyl
transfer reagents,2 building blocks of heterocyclic compounds3
for aldol reactions4 and for the synthesis of ketones5 and
amides.6 The synthesis of thioesters was achieved from thiols
(or equivalent thiol substrates) and activated carboxylic acid
derivatives, which were prepared from carboxylic acids using
activating reagents.7 Under these circumstances, the direct
synthesis of thioesters from aldehydes using thioanions or thiyl
radicals would be a useful method.8 Especially, no one has
reported the direct synthesis of thioesters from aldehydes using
thiyl radicals except for Takagi’s report.9 The method is the
shortest, but has some disadvantages from the viewpoint of
reagent efficiency. Namely, a large amount of the aldehyde is
required, since the aldehyde must be used not only as the
reagent but also as the solvent. Here we wish to report a highly
effective intermolecular radical reaction of C–S bond formation
in a micellar system using the combination of a water–soluble
initiator (Fig. 1)10 and surfactant11 in water. Our method
produces useful pentafluorophenyl thioesters, whose utility was
already clarified by Davis et al.,6 in high yields, and the reaction
is carried out under mild conditions in water.12 Therefore, much
attention is being devoted to this reaction from the viewpoint of
green chemistry.13
First, we examined the possibility of thioesterifications in
water with 3-phenylpropionaldehyde (1a) and dipentafluoro-
phenyl disulfide (2a) using various water-soluble azo-type
initiators and a catalytic amount of CTAB as the first chosen
surfactant (Table 1). As a result, we could confirm the formation
of thioesters in these systems. VA-044 was found to be the most
effective initiator among the initiators used in Table 1 (entry 1).
A side-reaction occurred when the typical radical initiator
AIBN was used (entry 5), while using Et3B, a known radical
initiator that acts at low temperature, the reaction hardly
proceeded at all (entry 6). Next, we examined the effect of
surfactants on the reaction using VA–044 in water. The cationic
surfactants (CTAC, CTAHSO4) gave the thioesters in good
yields (entries 8 and 9). However, the anionic surfactant (SDS),
the neutral surfactant (Triton X–100) and tetraethylammonium
bromide did not give a satisfactory result (entries 10–12). In the
The plausible mechanism of this reaction is shown in Scheme
1.† First, disulfide (2) dissociates with the initiator (VA–044) to
give the thiyl radical (A). Secondly, the hydrogen in the
aldehyde (1) is trapped by the thiyl radical (A), and then the acyl
Table 1 Effect of various initiators and additives
Entry Initiator
Additive
Temp./°C Time/h
Yield (%)
1
2
3
4
5
6
7
8
9
VA–044
VA–061
V–501
V–50
AIBN
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
None
50
80
70
60
80
rt–50
50
50
50
18
2
73
Decomp.
32
45
37
Trace
No reaction
67
63
18
16
Trace
24
24
12
24
24
24
24
24
24
24
Et3B
VA–044
VA–044
VA–044
VA–044
VA–044
VA–044
CTACa
CTAHSO4
SDSc
b
10
11
12
50
TritonX–100d 50
Et4N+Br2
50
a CTAC: cetyltrimethylammonium chloride. b CTAHSO4: cetyltrimethyl-
ammonium hydrogen sulfate. c SDS: sodium dodecyl sulfate. d Triton X-
100: polyoxyethylene(10)isooctylphenyl ether.
Table 2 Effect of various solvents and initiators
Entry Initiator Solvent Additive Temp./°C Time/h Yield (%)
1
2
3
4
5
6
VA–044 H2O
VA–044 Neat
VA–044 Benzene CTAB
CTAB
CTAB
50
50
50
80
50
rt
18
24
24
24
24
24
73
Trace
N.R.a
32
29
Trace
AIBN
V–70L
Et3B
Benzene None
Benzene None
Benzene None
a No reaction.
Fig. 1 Water-soluble radical initiators.
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CHEM. COMMUN., 2002, 1082–1083
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radical (B) is formed. The acyl radical reacts with the disulfide
(2) or thiyl radical (A), and the thioesterification (3) is achieved.
The thiol (2A) produced by the reaction of the thiyl radical (A)
and aldehyde (1) becomes the thiyl radical with the initiator, and
the thiyl radical (A) takes part in the reaction cycle again.
Whereas, Chatgilialoglu et al. have already reported that alkyl
radicals prepared by the initiator did not trap the hydrogen in the
aldehyde.15
which can be prepared by our method, has valuable utilities,
since they have already been shown to have a high activity
toward various nucleophiles.6 We believe that our system
would become the common method for the thioesterification
from the corresponding aldehydes.
We thank Wako Pure Chemical Industries, Ltd., for the
generous supply of several water-soluble azo-type initiators.
In summary, we have discovered that the combination of a
water-soluble radical initiator VA–044 and surfactant CTAB is
an ideal reaction system to accomplish C–S bond formation in
water. This method is effective for the synthesis of active
thioesters under mild conditions, and could be applied using
various aldehydes. Moreover, the pentafluorophenyl thioester,
Notes and references
† General procedure: VA–044 (48.5 mg, 0.15 mmol) was added to a
solution of aldehydes (1a–g) (0.30 mmol), dipentafluorophenyl disulfide
(2a) (119 mg, 0.30 mmol) and CTAB (21.9 mg, 0.060 mmol) in H2O (3 ml)
at rt. The reaction mixture was then stirred and heated to 50 °C. After 3 h,
an additional amount of the initiator VA–044 (48.5 mg, 0.15 mmol) was
added to the reaction mixture. The progress of the reaction was monitored
by TLC. The reaction mixture was then extracted with AcOEt, and the
organic layer was dried using Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel to give the
pure thioesters 3a–g.
Table 3 Application using various aldehydes
Entry
1
Aldehyde
Time/h
8
Product
Yield (%)
88
1 L. Field, Synthesis, 1972, 101 and references cited therein.
2 T. Mukaiyama, M. Araki and H. Takei, J. Am. Chem. Soc., 1973, 95,
4763.
CH3(CH2)9CHO 1b
3b
3 C. Alvarez-Ibarra, M. Mendoza, G. Orellana and M. L. Quiroga,
Synthesis, 1989, 560; R. Annunziata, M. Benaglia, M. Cinquini and F.
Cozzi, Tetrahedron Lett., 1995, 36, 613.
4 T. Mukaiyama, H. Uchiro, I. Shiina and S. Kobayashi, Chem. Lett.,
1990, 1019; S. Kobayashi, H. Uchiro, Y. Fujishita, I. Shiina and T.
Mukaiyama, J. Am. Chem. Soc., 1991, 113, 4247.
5 G. J. McGarvey, J. M. Williams, R. N. Hiner, Y. Matsubara and T. Oh,
J. Am. Chem. Soc., 1986, 108, 4943; L. S. Liebeskind and J. Srogl, J.
Am. Chem. Soc., 2000, 122, 11260.
2
3
4
1c
1d
1e
24
24
24
3c
3d
3e
47
56
72
6 A. P. Davis and J. J. Walsh, Tetrahedron Lett., 1994, 35, 4865; A. P.
Davis, S. Menzer, J. J. Walsh and D. J. Williams, J. Chem. Soc., Chem.
Commun., 1996, 453.
7 For example: (i) the coupling of carboxylic acids and thiols using some
activating reagents; S. Iimura, K. Manabe and S. Kobayashi, Chem.
Commun., 2002, 94 (ii) the coupling of heavy metal thiolates with acid
chlorides; G. Spessard, W. K. Chan and S. Masamune, Org. Synth.,
1982, 61, 134 (iii) the coupling of disulfides and carboxylic acids using
triphenylphosphine; T. Endo, S. Ikenaga and T. Mukaiyama, Bull.
Chem. Soc. Jpn., 1970, 43, 2632.
5
6
1f
8
3f
95
90
1g
24
3g
8 M. Kurauchi, T. Imamoto and M. Yokoyama, Tetrahedron Lett., 1981,
22, 4985; T. Inoue, T. Takeda, N. Kambe, A. Ogawa, I. Ryu and N.
Sonoda, J. Org. Chem., 1994, 59, 5824.
9 M. Takagi, S. Goto and T. Matsuda, J. Chem. Soc., Chem. Commun.,
1976, 92; M. Takagi, S. Goto, M. Tazaki and T. Matsuda, Bull. Chem.
Soc. Jpn., 1980, 53, 1982.
10 Y. Kita and M. Matsugi, Radical Initiators. In Radicals in Organic
Synthesis Volume 1 eds. P. Renaud and M. P. Sibi, Wiley-VCH,
Weinheim, 2001, p. 1–10; The water-soluble azo type radical initiators
used in our studies are available from Wako Pure Chemical Industries,
Ltd. Osaka, Japan.
11 Catalysis in Micellar and Macromolecular Systems, ed. J. H. Fendler,
Academic Press, New York, 1998.
12 cf. Radical reaction under micellar condition in water: Y. Kita, H.
Nambu, N. G. Ramesh, G. Anilkumar and M. Matsugi, Org. Lett., 2001,
3, 1157.
13 Organic Synthesis in Water, ed. P. A. Grieco, Blackie Academic,
London, 1998.
14 Y. Kita, K. Gotanda, C. Ohira, M. Suemura, A. Sano and M. Matsugi,
J. Org. Chem., 1999, 64, 6928 and references cited therein.
15 C. Chatgilialoglu, D. Crich, M. Komatsu and I. Ryu, Chem. Rev., 1999,
99, 1991 and references cited therein.
Scheme 1 A plausible mechanism of thioesterification.
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