Reduction cleavage of S-S bond by Zn/Cp2tiCl2: Application for the synthesis of β-arylthiocarbonyl compounds

Article abstract of DOI:10.3184/030823409X12592534682310

Diaryl disulfides were reduced efficiently by a Zn/Cp₂TiCl ₂ system at room temperature in dry THF to give the corresponding nucleophilic sulfur anion-titanocene complex, followed by reaction with α, β-unsaturated esters (ketones or nitriles) to afford the corresponding β-arylthioesters(ketone or nitrile) in good yields.

Full text of DOI:10.3184/030823409X12592534682310

750 RESEARCH PAPER
DECEMBER, 750–752
JOURNAL OF CHEMICAL RESEARCH 2009
Reduction cleavage of S–S bond by Zn/Cp2TiCl2: application for the
synthesis of β-arylthiocarbonyl compounds
Xiao Bo Xua, Xian Hong Yinb, Yu Yang Zhua, Xin Hua Xua,c*, Tao Luoa, Yin Hui Lia, Xiong Lua,
Ling Ling Shaoa, Jian Gao Pana and Rong Hua Yanga
aCentre of Medical Engineering, State Key Laboratory of Chem/Biosensing and Chemetrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, 410082, P.R. China
bCollege of Chemistry and Ecological Engineering, Guangxi University for Nationalities, Nanning, 530006, P.R. China
cNational Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
Diaryl disulfides were reduced efficiently by a Zn/Cp2TiCl2 system at room temperature in dry THF to give the
corresponding nucleophilic sulfur anion–titanocene complex, followed by reaction with a, b-unsaturated esters
(ketones or nitriles) to afford the corresponding b-arylthioesters(ketone or nitrile) in good yields.
Keywords: titanocene dichloride, zinc, reduction, diaryldisulfide, b-arylthioesters, b-arylthioketones, b-arylthionitriles
Recently, organic sulfur compounds have become of
increasing importance in organic synthesis. As important
difunctional compounds and attractive synthetic intermediates
in organic synthesis, b-thioesters have received considerable
attention.1,2 The general method for the their preparation is
the addition of thiols to acryl esters or acrylonitriles in the
presence of sodium ethoxide,3-5 but this requires strongly
basic conditions and the use of toxic and odorous thiols as
starting materials. It is well known that diaryl disufides, which
are air-stable, of low-toxicity and free of smell, have been in
great demand as intermediates to synthesise b-thiocarbonyl
compounds. Therefore, sulfur anions are generated in situ via
reductive cleavage of an S–S bond to avoid handling thiols.
Many approaches have been reported for reducing disulfides.
Previously, some of the more common reducing agents
such as sodium borohydride,6 lithium aluminum hydride,7
potassium trrisopropoxy borohydride,8,9 lithium tris(dialkyl
amino)aluminum hydrides,10 lithium tri-tert-butoxyaluminum
hydride,11 triphenyl phosphine,12 tributyl phosphine13,14 etc.
have been used to reductively cleave the S–S bond. Recently,
some metals such as In,15,16 Sn,17, Sm18 Cd,19 or some metal
halides such as SmI2,20 InI21 or a the combination of samarium
intolerance. The Cp2TiCl2 shows good stability in air and
has been widely applied in organic synthesis. The Cp2TiCl2/
Bui MgBr system could efficiently reductively cleave S–S
bonds,28 but this system was highly moisture-sensitive due
to the use of the Grignard reagent. It would be ideal if the
zinc and Cp2TiCl2 could be used together. We report here
the reduction of diaryl disulfides by a combined system of
Cp2TiCl2/Zn for the synthesis of b-arylthiocarbonyl and
nitrile compounds.
The experimental procedure is very simple. A mixture of
Cp2TiCl2 (1.0 mmol) with activated Zn dust (2.0 mmol) in dry
THF was stirred at room temperature for 1.0 h, the solution
turning to deep green from red-brown due to formation of
[Cp2TiCl]. When disulfide was added to the [Cp2TiCl]-
containing solution, a deep red colour immediately formed.
After addition of a, b-unsaturated carbonyl compounds or
nitriles to the reaction mixture, it gradually turned red-brown.
After hydrolysis and then separation, the target products of
b-arylthiocarbonyl compounds or the corresponding nitriles
were obtained in good yields (Scheme 1).
The results are shown in Table 1. One can see that the
reaction proceeded well for a variety of diaryldisulfides and
a,b-unsaturated carbonyl compounds or nitriles, all acrylic
esters and acrylonitriles and methyl ethenyl ketones gave the
corresponding products in satisfactory yields. The results also
revealed that the reaction is not sensitive to the electronic
nature of functional groups present in the aryl groups of
and a metal halide such as Sm/NiCl2 and Sm/CoCl2,23
22
were reported to cleave S–S bonds efficiently. However,
these methods involved using expensive or toxic metals.
As it is well known that zinc is an abundant, inexpensive
and nontoxic metal in nature, the use of zinc seems to be an
attractive possibility to promote this reaction. Some system of
zinc/metal halide have been applied to reduce the S–S bond,
Zn/Cp2TiCl2,THF
such as Zn/TiCl4,24 Zn/ZrCl4,25 Zn/CoCl2 and Zn/AlCl3.27
X
26
ArSSAr
ArSCHYCH2X
+
Y
Unfortunately, most of these methods have one or more
disadvantages such as: (i) air- or moisture-sensitive reagents;
(ii) low yield; (iii) poor chemoselectivity or functional group
r.t N2
Scheme 1 The synthesis of b-arylthio compounds.
Table 1 The synthesis of b-arylthio compounds
Entry
Ar
Y
X
Time/h
M.p./°C
Yield/%
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
H
H
CO2CH3
CO2C2H5
CO2C4H9
CO2C8H17-n
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CN
4.0
4.5
4.0
8.0
5.0
3.5
4.0
4.5
4.0
4.5
5.0
1.0
Oil
92
90
73
68
61
85
90
87
92
86
81
98
Ph
Oil
Ph
H
Oil
Ph
H
Oil
Ph
CH3
H
Oil
p-ClC6H4
p-CH3 C6H4
p-CH3O C6H4
Ph
80–81[82]5
H
56–57[58]5
H
Oil
Oil
H
4j
4k
4l
p-Cl C6H4
p-CH3 C6H4
Ph
H
CN
52–53[54–55]30
H
CN
COCH3
Oil
Oil
H
* Correspondent. Xhx1581@yahoo.com.cn
PAPER: JC090762
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JOURNAL OF CHEMICAL RESEARCH 2009 751
2H, Ch2Co2), 1.20(t, J = 7.2 Hz, 3H, CH3); 13C NMR(100 MHz,
CDCl3): 14.1(CH3), 29.8 (CH2CO2), 31.4(SCH2), 61.3 (CO2CH2),
125.2(C6H5), 126.8(C6H5), 129.0(C6H5), 136.4(C6H5), 173.1(CO2).
PhSCH2CH2CO2CH2CH2CH2CH3:29 IR(film) nmax(cm-1): 1732; 1H
NMR (CDCl3, 400 MHz),7.20–7.39(m, 5H, C6H5), 4.10(q, J = 6.8 Hz,
2H, CO2CH2), 3.18(t, J = 7.4 Hz, 2H, SCH2), 2.64(t, J = 7.4 Hz,
2H, CH2CO2), 1.58–1.67(m, 2H, CH2CH2CH3), 1.33–1.43(m, 2H
CH2CH2CH3), 0.94(t, J = 7.0 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3): 13.7(CH2CH2CH3), 19.1(CH2CH2CH3), 29.1(CH2CH2CH3,
30.6(CH2CO2), 34.4(SCH2), 64.7(CO2CH2), 126.5(C6H5), 129.1
(C6H5), 130.1(C6H5), 135.2(C6H5), 171.9(CO2).
disulfides. Either electron-donating or electron-withdrawing
groups could be substituted leading to the desired products
in good yields. A detailed analysis of the results reveals that
the product yield of the methyl ethenyl ketones, in which the
carbonyl group has stronger electron withdrawing ability, is
higher than those of acrylic esters and acrylonitriles. Steric
hindrance an influence on the reaction. Compared with the
similar substrate unsubstituted at the b-position, the methyl
group substituted substrates required a little longer reaction
time to give a low yield. The size of the alkyl chain in the ester
group also had a significant influence, and as the alkyl chain
became longer, the products were obtained in lower yields.
Although further study is necessary to clarify the reaction
mechanism, thes results mentioned above suggest that this
reaction probably takes place through a reduction mechanism
as shown as following (Scheme 2).
The necessary use of zinc indicates the importance of
Cp2TiIIICl formation, which was actually observed in the
reaction mixture. Because the formation of Cp2TiCl(OH),
the Cp2TiCl2 cannot be regenerated at the final step. Two
equivalent of Cp2TiCl2 should be needed. Therefore, we tried
the reaction using a catalytic amount of Cp2TiCl2 and found
that the reaction actually proceeded inefficiently with only
10% yield of the desired product.
PhSCH2CH2CO2CH2(CH2)6CH3:30 IR(film)
n
max(cm-1): 1734;
1H NMR (CDCl3, 400 MHz), 7.37–7.20(m, 5H, C6H5), 3.98(t,
J = 6.8 Hz, 2H, CO2CH2), 3.15(t, J = 7.0 Hz, 2H, SCH2), 2.65(d,
J = 7.0 Hz, 2H, CH2CO2), 1.59–1.54(m, 2H, CO2CH2CH2), 1.37–1.26
(m, 10H, CO2CH2CH2 (CH2)5CH3), 0.91(t, J = 7.0 Hz, 3H, CH3);
13C NMR (100 MHz, CDCl3): 11.3(CH3), 14.3(CH2CH3), 23.6
(CH2CH2CH3), 23.9 (CH2CH2CH2CH3), 28.6(CO2CH2CH2CH2CH2),
29.6(CO2CH2CH2CH2), 31.2 (CO2CH2CH2), 34.6(CH2CO2), 38.9
(SCH2), 67.3(CO2CH2), 126.8(C6H5), 128.9(C6H5), 130.5(C6H5),
135.6(C6H5), 172.3(CO2).
PhS(CH3)CHCH2CO2CH2CH3:30 IR(film)
n
max(cm-1): 1735;
1H NMR (CDCl3, 400 MHz), 7.42–7.45(m, 2H, C6H5), 7.23–7.32(m,
3H, C6H5), 4.12(q, J = 7.0 Hz, 2H, CO2CH2), 3.58–3.64(m, 1H, CH),
2.62(dd, J = 6.0 Hz, 15.4 Hz, 1H, 1/2CH2CO2, 2.43(dd, J = 6.0 Hz,
15.4 Hz, 1H, 1/2CH2CO2), 1.32(d, J = 6.4 Hz, 3H, PhS(CH3)
CH), 1.25(t, J = 7.0 Hz, 3H, CO2CH2CH3); 13C NMR (100 MHz,
CDCl3): 14.2(CO2CH2CH3), 20.9(PhS(CH3)CH), 39.5(CH2CO2),
41.9(CH), 60.6(CO2CH2), 127.4(C6H5), 128.9(C6H5), 132.9(C6H5),
133.9(C6H5), 171.4(CO2).
In summary, we have developed a highly efficient method
for the reductive cleavage of S–S bond and applied it to
the synthesis of b-arylthiocarbonyl and b-thio compounds.
It has various merits such as air-stable starting materials, mild
and neutral reaction conditions, convenient manipulation and
good yields.
p-ClC6H4SCH2CH2CO2CH2CH3:5 IR(KBr)
n
max(cm-1): 1731;
1H NMR (CDCl3, 400 MHz), 7.26–7.32(m, 4H, p-ClC6H4), 4.15(q,
J = 7.0 Hz, 2H, CO2CH2), 3.14(t, J = 7.2 Hz, 2H, SCH2CH2), 2.60(t,
J = 7.2 Hz, 2H, SCH2CH2), 1.26(t, J = 7.0 Hz, 3H, CH3); 13C NMR
(100 MHz,CDCl3): 14.2(CH3), 29.3 (SCH2CH2), 34.3(SCH2),
60.8(CO2CH2), 129.1(C6H4), 131.5(C6H4), 132.6(C6H4), 133.8
(C6H4), 171.6(CO2).
Experimental
1H NMR were recorded on INOVA-400 spectrometer, using CDCl3
as the solvent with TMS as an internal standard; IR spectra were
determined on Perkin-Elmer 683 spectrophotometer; tetrahydrofuran
was distilled from sodium benzophenone. Zinc was activated by
dilute acid followed by washing with water and drying.
p-CH3C6H4SCH2CH2CO2CH2CH3:5 IR(film) nmax(cm-1): 1732;
1H NMR (CDCl3, 400 MHz), 7.32(d, J = 8.0 Hz, 2H, C6H4), 7.19(d,
J = 8.0 Hz, 2H, C6H4), 4.15(q, J = 7.2 Hz, 2H, CO2CH2), 3.13(t,
J = 7.6 Hz, 2H, SCH2CH2), 2.62(t, J = 7.6 Hz, 2H, SCH2CH2), 2.35(s,
3H, p-CH3C6H4), 1.26(t, J = 7.2 Hz, 3H, CH2CH3); 13C NMR (100
MHz, CDCl3): 14.2(CH2CH3), 21.1(p-CH3C6H4), 29.8(SCH2CH2),
34.5(SCH2), 60.7(CO2CH2), 129.8(C6H4), 131.0(C6H4), 131.1(C6H4),
136.8(C6H4), 171.8(CO2).
Typical procedure: To a solution of Cp2TiCl2 (0.25 g, 1.0 mmol) in
dry THF (6.0 mL) was added Zn dust (0.13 g, 2.0 mmol). The resulted
mixture was stirred at room temperature under a N2 atmosphere
for 1.0 h. Then the disulfide (0.5 mmol) was added to the reaction
mixture and the solution became a deep red colour. After that, acrylic
esters or acrylnitriles or methyl ethenyl ketone (1.0 mmol) was
added and resulting mixture was stirred at room temperature under
a N2 atmosphere for a period of time listed in Table 1. Then dilute
hydrochloric acid (20 mL. 1.2 M) was added, after usual work-up,
the products were purified by preparative TLC on silica gel using
light petroleum-ether as eluent (30:1).
p-CH3OC6H4SCH2CH2CO2CH2CH3:5 IR(film) nmax(cm-1) 1736.
1H NMR (CDCl3, 400 MHz), 7.36(d, J = 8.0 Hz, 2H, C6H4), 6.86(d,
J = 8.0 Hz, 2H, C6H4), 4.20(q, J = 6.8 Hz, 2H, CO2CH2), 3.80(s, 3H,
OCH3), 3.12(t, J = 7.0 Hz, 2H, SCH2CH2), 2.61(t, J = 7.0 Hz, 2H,
SCH2CH2), 1.21(t, J = 6.8 Hz 3H, CH2CH3); 13C NMR(100 MHz,
CDCl3): 14.3(CH3), 31.6(SCH2CH2), 34.8(SCH2CH2), 55.8(OCH3),
61.6(CO2CH2), 114.6(C6H4), 125.8(C6H4), 134.6(C6H4), 159.8
(C6H4), 171.3(CO2).
1
PhSCH2CH2CO2CH3:25 IR(film)nmax(cm-1) 1735; H NMR (CDCl3,
PhSCH2CH2CN:4 IR(film) nmax(cm-1): 2250; 1H NMR (CDCl3,
400 MHz), 7.25–7.45(m, 5H, C6H5), 3.15(t, J = 7.0 Hz, 2H, SCH2),
2.55(t, J = 7.0 Hz, 2H, CH2CN) 13C NMR (100 MHz, CDCl3):
18.3(CH2CN), 30.2(SCH2), 118.1(CN), 127.8(C6H5), 129.4(C6H5),
131.4(C6H5), 133.2(C6H5).
400 MHz) 7.20–7.35(m, 5H, C6H5), 3.70(s, 3H, CH3), 3.10(t, J = 7.3 Hz,
2H, PhCH2), 2.70(t, J = 7.3 Hz, 2H, CH2CO); 13C NMR(100 MHz,
CDCl3) 28.7 (SCH2CH2), 33.4(SCH2), 63.2(CO2CH3), 126.8(C6H5),
128.3(C6H5), 132.4(C6H5), 134.2(C6H5), 173.2(CO2).
PhSCH2CH2CO2CH2CH3:3 IR(film) nmax(cm-1) 1732; 1H NMR
(CDCl3, 400 MHz), 7.20–7.45(m, 5H, C6H5), 4.20(q, J = 7.2 Hz,
2H, CO2CH2), 3.13(t, J = 7.0 Hz, 2H, SCH2), 2.63(t, J = 7.0 Hz,
p-ClC6H4SCH2CH2CN:4 IR(film) nmax(cm-1): 2244; 1H NMR
(CDCl3, 400 MHz), 7.27–7.37(m, 4H, C6H4), 3.11(t, J = 6.8 Hz,
2H, SCH2), 2.59(t, J = 6.8 Hz, 2H, CH2CN); 13C NMR (100 MHz,
2 Cp2TiIIICl
ZnCl2
2 Cp2TiIVCl2
+
+
Zn
2 Cp2TiIIICl
2 Cp2TiClSAr
+ ArSSAr
X
Y
ArS
Y
Cp2TiClSR1
X
+
+
Y
Cp2TiCl
X
Y
H2O
+
Cp2TiCl(OH)
X
ArS
ArS
Cp2TiCl
Scheme 2 Proposed mechanism for the synthesis of b-arylthio compounds promoted by the Cp2TiCl2/Zn system.
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752 JOURNAL OF CHEMICAL RESEARCH 2009
6
7
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CDCl3): 29.1(CH3), 31.2(CH2CO), 34.6(SCH2), 125.3(C6H5),
126.8(C6H5), 129.1(C6H5), 136.2(C6H5), 207.1(CO).
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Received 15 August 2009; accepted 23 November 2009
Paper 09/0762 doi: 10.3184/030823409X12592534682310
Published online: 8 December 2009
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