ZrCl4 dispersed on dry silica gel provides a useful reagent for S-alkylation of thiols with alcohols under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2005.10.137

ZrCl₄ which is commercially available and not a costly compound, is a relatively safe chemical [LD₅₀ [ZrCl₄, oral rat] = 1688 mg Kg]. In this report we describe the use of ZrCl₄ dispersed on dry silica gel as an efficient reagent for the efficient preparation of thioethers from thiols with alcohols under solvent-free conditions.

Full text of DOI:10.1016/j.tetlet.2005.10.137

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 93–97
ZrCl4 dispersed on dry silica gel provides a useful reagent for
S-alkylation of thiols with alcohols under solvent-free conditions
Habib Firouzabadi,* Nasser Iranpoor* and Maasoumeh Jafarpour
Chemistry Department, College of Sciences, Shiraz University, Shiraz 71454, Iran
Received 5 August 2005; revised 18 October 2005; accepted 26 October 2005
Available online 22 November 2005
Abstract—ZrCl4 which is commercially available and not a costly compound, is a relatively safe chemical [LD50 [ZrCl4, oral
rat] = 1688 mg Kg]. In this report we describe the use of ZrCl4 dispersed on dry silica gel as an efficient reagent for the efficient prepa-
ration of thioethers from thiols with alcohols under solvent-free conditions.
ꢀ 2005 Published by Elsevier Ltd.
Versatile synthetic uses of thioethers in both bioorganic
and organic chemistry have ensured many studies of
their preparation by different methods. The thioether
linkage has been used to prepare cyclic analogues of
acyclic polypeptides to restrict their conformational
mobility and thus to increase their biological activity
and stability against biodegradation.1–4 They are also
useful heteroatomic functional groups in organic synthe-
sis, for example, by oxidation of thioethers, chiral
sulfoxides can be generated which can be used as auxilia-
ries in asymmetric synthesis.5–8 Moreover, sulfones
have been employed for stabilizing a-radicals9 and a-
anions,10 can act as cationic synthons,11 and also for
the formation of C–C bonds.12
However, in the majority of cases reported, the thio-
ethers have been prepared using expensive and commer-
cially unavailable materials,23,26 hazardous and
corrosive compounds such as, alkylating agents,24
strong reducing agents,17 harsh reaction conditions
and involve tedious work-up procedures.29,30 Addition-
ally, some of the reported methods cannot be used for
the preparation of different structurally and electroni-
cally diverse thioethers. For example, by applying
modified Mitsunobu conditions using liquid trimethyl-
phosphine combined with 1,10-(azodicarbonyl)dipiperi-
dine (a hazardous material) in the presence of
imidazole, aliphatic thiols react only with primary
alcohols to give thioethers. Other types of thiols and
alcohols did not react.20
A variety of methods is available for the preparation of
thioethers, such as, deoxygenation of sulfoxides,13,14 dis-
placement of leaving groups with sulfur nucleo-
philes,15,16 addition of thiols to carbonyl compounds
followed by in situ reduction of the generated intermedi-
ate thionium ion,17 anti-Markovnikov addition of
arene- and alkane–thiols to alkenes,18,19 Mitsunobu-
type reactions,20–24 metal-mediated cross-coupling
processes,25–27 and metal catalyzed hydrothiolation of
alkynes.28 These reported methods have been recently
reviewed.29,30
In continuation of our interest in exploring new applica-
tions of ZrCl4 in organic synthesis,31–34 we report that
ZrCl4 dispersed on dry silica gel allows the efficient prep-
aration of thioethers by the reaction of thiols with alco-
hols under solvent-free conditions (Scheme 1).
In order to optimize the reaction conditions, condensa-
tion of benzyl alcohol with 4-methylthiophenol was
studied as a model reaction in the presence of ZrCl4.
We observed that a sticky reaction mixture was obtained
ZrCl4
Keywords: Zirconium tetrachloride; Alcohols; Thiols; Silica gel; Thio-
ether; Solvent free.
S
R1
SH
+
R2
OH
R1
R2
silica gel
50 ºC
*
Corresponding authors. Tel.: +98 711 2284822; fax: +98 711 2280926
(H.F.); e-mail addresses: firouzabadi@chem.susc.ar.ir; iranpoor@
chem.susc.ac.ir
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.10.137

94
H. Firouzabadi et al. / Tetrahedron Letters 47 (2006) 93–97
Table 1. S-Alkylation of thiols with alcohols using ZrCl4 dispersed on dry silica gel under solvent-free conditionsa
Entry
1
Alcohol
Thiol
Productb
Time (min)
5
Conversion
100
Isolated yield (%)
94
SH
OH
OH
S
SH
S
2
3
15
40
95
60
90
53
OH
SH
S
S
OH
OH
4
5
25
20
80
93
75
87
SH
SH
S
SH
SH
SH
OH
6
7
8
2
25
60
100
100
56
94
94
50
S
MeO
Cl
MeO
Cl
OH
S
OH
S
O2N
O2N
SH
SH
SH
9
4
3
100
100
95
95
S
OH
10
OH
S
OH
11
12
5
100
96
95
92
S
SH
OH
15
S
S
OH
OH
13
14
10
8
93
96
88
90
SH
SH
S
S
SH
15
16
180
180
20
15
—
—
OH
S
SH
SH
OH
17
10
100
80
OH
S

H. Firouzabadi et al. / Tetrahedron Letters 47 (2006) 93–97
95
Table 1 (continued)
Entry
Alcohol
Thiol
Productb
Time (min)
Conversion
100
Isolated yield (%)
94
SH
18
7
OH
OH
S
SH
19
20
21
22
10
100
100
100
100
96
95
94
95
S
S
SH
30
15
15
OH
OH
OH
SH
S
SH
S
S
23c
20
100
95
HS
SH
S
OH
S
S
OH
OH
24c
25d
10
20
100
100
96
94
HS
HS
SH
SH
MeO
HO
MeO
HS
OMe
S
S
SH
a The reactions were run at 50 ꢁC and the molar ratio of alcohol/thiol/ZrCl4 was 1:1.1:0.5.
b All products were identified by their 1H NMR, 13C NMR and MS spectral data and elemental analysis.
c The molar ratio of alcohol/thiol/ZrCl4 was 2:1.1:1.
d The molar ratio of alcohol/thiol/ZrCl4 was 1:2.1:1.
with the formation of the corresponding thioether in
around 50–60% yield. Increasing the reaction time did
not affect the yield of the product. We found that, using
benzyl alcohol (1 mmol), 4-methylthiophenol (1.1
mmol) and ZrCl4 (0.5 mmol) dispersed on 0.3 g of
molecular sieves, alumina, or silica gel, in the absence
of solvent, the reaction proceeded very cleanly at
50 ꢁC and the corresponding thioether was isolated in
94% yield. We also tried a similar reaction in the pres-
ence of molecular sieves, alumina or silica gel without
using ZrCl4. The reaction was not successful and the
starting materials remained intact. ZrCl4 dispersed on
dry silica gel was used for the remainder of this study
for the preparation of other thioethers.
preparation of macrocyclic or polymeric sulfur-contain-
ing compounds.
Primary and secondary aliphatic alcohols do not react
with thiols in the presence of this reagent and remain
mostly intact after the typical reaction times (Table 1,
entries 15 and 16).
Generation of a classical carbocation is improbable in
these reactions. Adamantanol, because of its structure,
does not allow the generation of a classical carbocation
(Table 1, entry 18). In addition, the reaction of 2-(4-
biphenyl-4-yl)-2-propanol (Table 1, entry 9) was not
accompanied by the production of its corresponding ole-
fin as an elimination by-product. The low yield and the
rather slow rate of the reaction involving 4-nitrobenzyl
alcohol is an indication of the generation of an unstable
partially positively charged intermediate (Table 1, entry
8). By considering these facts, we may suggest the fol-
lowing mechanism for the reaction (Scheme 2).
We found that this method was applicable for the prepa-
ration of thioethers from the reaction of cinnamyl alco-
hol, adamantanol and structurally and electronically
diverse benzyl alcohols with aromatic or aliphatic thiols
and also with dithiols.35,36 We noted that electronic fac-
tors play a role in these reactions. Aromatic alcohols
substituted with electron-donating groups reacted faster
than those substituted with electron-withdrawing groups
and also provided the thioethers in higher yields (Table
1, entries 6–9). This method is also useful for the high
yielding preparation of dithioethers using dithiols (Table
1, entries 23 and 24). We have also used this method for
the efficient preparation of dithioethers,37 (Table 1,
entry 25) which could be used as precursors for the
In conclusion, we have described a new application of
ZrCl4 dispersed on dry silica gel for the easy and efficient
synthesis of different thioethers by the reaction of
aliphatic and aromatic thiols with cinnamyl alcohol,
adamantanol and structurally and electronically diverse
benzyl alcohols under solvent-free conditions. The
method is not suitable for the preparation of thioethers
from saturated primary and secondary alcohols.

96
H. Firouzabadi et al. / Tetrahedron Letters 47 (2006) 93–97
R1
H
Acknowledgments
S
Cl
δ−
δ+
Support for this work by Iran TWAS Chapter at ISMO
and Shiraz University Research Council is highly appre-
ciated. We are also grateful to Dr. A. A. Esmaeili from
Birjand University and Dr. S. Rayati from Zanjan
University for the mass and NMR spectral data,
respectively.
δ+
O
R1SH + R2OH + ZrCl4-SiO2
R1 = alkyl, aryl
ZrCl2-SiO2
R2
H
Cl
R2 = benzyl, cinnamyl, adamantyl, t-butyl
R1SR2 + ZrOCl2-SiO2 +2HCl
References and notes
Scheme 2.
1. Moberg, H. I.; Omnaas, J. R. J. Am. Chem. Soc. 1985,
107, 2986–2987.
2. Hurby, V. J.; Al-Obeidi, F.; Kazmierski, W. Biochem. J.
1990, 268, 249–262.
3. Kataoka, T.; Beusen, D. D.; Clark, J. D.; Yodo, M.;
Marshall, G. R. Biopolymers 1992, 32, 1519–1533.
4. Hurby, V. J.; Bonner, G. G. Methods Mol. Biol. 1994, 35,
201–240.
Dithiols have also been used successfully for the prepa-
ration of their corresponding dithioethers using struc-
turally different alcohols in excellent yields. We believe
that this procedure provides a valuable addition to cur-
rent methodologies.
5. Solladie, G. Synthesis 1981, 185–196.
6. Posner, G. H. In The Chemistry of Sulfones and Sulfoxides;
Patai, S., Rappoport, Z., Sterling, C. J. M., Eds.; Wiley:
Chichester, 1988, Chapter 16.
7. Mata, E. G. Phosphorus, Sulfur Silicon 1996, 117, 231–
286.
8. Carreno, M. C. Chem. Rev. 1995, 95, 1717–1760.
9. Paquette, L. A. Synlett 2001, 1–12.
10. Najera, C.; Sansano, J. M. Recent Res. Develop. Org.
Chem. 1998, 2, 637–683.
Selected spectral data of thioethers: (Table 1, entry 1): 1H
NMR (CDCl3, 250 MHz): d (ppm) = 2.28 (s, 3H), 4.05 (s,
2H), 7.10–7.68 (m, 9H); 13C NMR (CDCl3, 63 MHz): d
(ppm) = 21.08, 39.23, 128.55, 129.71, 130.15, 131.79,
132.822, 136.49, 136.94; MS (m/e) = 214 [M]+. Anal.
Calcd for (C14H14S): C, 78.46; H, 6.58. Found: C,
1
78.48; H, 6.61. (Table 1, entry 5): H NMR (CDCl3,
300 MHz): d (ppm) = 0.82 (m, 6H), 1.33 (m, 4H), 1.55
(m, 1H), 4.19 (s, 2H); 13C NMR (CDCl3, 63 MHz): d
(ppm) = 24.9, 27.6, 33.7, 36.5, 38.9, 127.9, 128.8, 129.1,
139.4; MS (m/e) = 206 [M]+. Anal. Calcd for
(C13H18S): C, 75.67; H, 8.79. Found: C, 75.63; H, 8.82.
(Table 1, entry 9): 1H NMR (CDCl3, 250 MHz): d
(ppm) = 1.69 (s, 6H), 2.29 (s, 3H) 6.97–7.69 (m, 13H);
13C NMR (CDCl3, 63 MHz): d (ppm) = 21.08, 30.8,
48.6, 127.5, 127.7, 128.1, 128.3, 130.2, 130.4, 133.02,
134.8, 135.2, 148.6; MS (m/e) = 318 [M]+. Anal. Calcd
for (C22H22S): C, 82.97; H, 6.96. Found: C, 82.95; H,
11. Chinchila, R.; Najera, C. Recent Res. Develop. Org. Chem.
1997, 1, 437–467.
12. Yao, Q. Org. Lett. 2002, 4, 427–430.
13. Madesclaire, M. Tetrahedron 1988, 44, 6537–6580.
14. Nicolaou, K. C.; Koumbis, A. E.; Snyder, S. A.; Simon-
sen, K. B. Angew. Chem., Int. Ed. 2000, 39, 2529–2533.
15. Zaragoza, F.; Stephensen, H. Angew. Chem., Int. Ed. 2000,
39, 554–556.
16. Dowsland, J.; McKerlie, F.; Procter, D. J. Tetrahedron
Lett. 2000, 41, 4923–4927.
17. Procter, D. J.; Archer, N. J.; Needham, R. A.; Bell, D.;
Marchington, A. P.; Rayner, C. M. Tetrahedron 1999, 55,
9611–9622.
18. Kumar, P.; Pandey, P. K.; Hegde, V. R. Synlett 1999,
1921–1922.
19. Chelucci, G.; Culeddu, N.; Saba, A.; Valenti, R. Tetra-
hedron: Asymmetry 1999, 10, 3537–3546.
20. Falck, J. R.; Lai, J.-Y.; Cho, S.-D.; Yu, J. Tetrahedron
Lett. 1999, 40, 2903–2906.
21. Garofalo, A.; Campiani, G.; Fiorini, I.; Nacci, V. Tetra-
hedron 1999, 55, 1479–1490.
22. Shibata, K.; Yamaga, H.; Mitsunobu, O. Heterocycles
1999, 50, 947–968.
1
6.99. (Table 1, entry 10): H NMR (CDCl3, 250 MHz):
d (ppm) = 2.23 (s, 3H), 5.46 (s, 1H), 7.10–7.46 (m,
14H); 13C NMR (CDCl3, 63 MHz): d (ppm) = 21.1,
52.2, 127, 127.6, 129.4, 130.1, 131.1, 133.3, 135.4, 145.3;
MS (m/e) = 290 [M]+. Anal. Calcd for (C20H18S): C,
82.71; H, 6.25. Found: C, 82.74; H, 6.27. (Table 1, entry
1
18): H NMR (CDCl3, 250 MHz): d (ppm) = 1.47–1.99
(m, 15H), 2.35 (s, 3H), 7.06 (d, J = 8 Hz, 2H), 7.36 (d,
J = 8 Hz, 2H); 13C NMR (CDCl3, 63 MHz): d
(ppm) = 21.0, 26.2, 28.3, 37.4, 37.9, 44.2, 128.5, 129.78,
129.88, 132.85, 137.7; MS (m/e) = 258 [M]+. Anal. Calcd
for (C17H22S): C, 79.01; H, 8.58. Found: C, 79.04; H,
23. Palomo, C.; Oiarbide, M.; Lopez, R.; Gomez-Bengoa, E.
Tetrahedron Lett. 2000, 41, 1283–1286.
1
8.60. (Table 1, entry 24): H NMR (CDCl3, 250 MHz):
d (ppm) = 1.71 (m, 2H), 2.45 (t, J = 7.3 Hz, 4H), 3.57
(s, 4H), 3.79 (s, 6H), 6.85 (d, J = 6.65 Hz, 4H), 7.17(d,
J = 6.65 Hz, 4H); 13C NMR (CDCl3, 63 MHz): d
(ppm) = 29.7, 32.2, 36.9, 55.5, 113.3, 127.9, 131.6,
158.7; MS (m/e) = 348 [M]+; Anal. Calcd for
(C19H24O2S2): C, 65.48; H, 6.94. Found: C, 65.50; H,
24. Zaragoza, F. Tetrahedron 2001, 57, 5451–5454.
25. Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett.
2000, 2, 2019–2022.
26. Wendeborn, S.; De Mesmaeker, A.; Brill, W. K.-D.;
Berteina, S. Acc. Chem. Res. 2000, 33, 215–224.
27. Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4,
4309–4312.
28. Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am. Chem.
Soc. 1999, 121, 5108–5114.
29. Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2000, 835–
871.
1
6.97. (Table 1, entry 25): H NMR (CDCl3, 250 MHz):
d (ppm) = 1.30 (t, J = 6.2 Hz, 2H), 1.86 (m, 4H), 2.40–
2.63 (m, 8H), 3.68 (s, 4H), 7.26 (s, 4H); 13C NMR
(CDCl3, 63 MHz): d (ppm) = 24.7, 32.4, 36.7, 39.2,
128.6, 137.4; MS (m/e) = 318 [M]+. Anal. Calcd for
(C14H22S4): C, 52.78; H, 6.96. Found: C, 52.80; H, 6.95.
30. Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2001, 335–
354.

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97
31. Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synlett 1999,
319–320.
32. Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synlett 1999,
321–323.
33. Firouzabadi, H.; Iranpoor, N.; Jafarpour, M. Tetrahedron
Lett. 2004, 45, 7451–7454.
34. Firouzabadi, H.; Iranpoor, N.; Jafarpour, M. Tetrahedron
Lett. 2005, 46, 4107–4110.
added and the mixture stirred for a few minutes. Then,
alcohol (2 mmol) was added and the mixture was stirred at
50 ꢁC for the appropriate reaction time (monitored by
TLC and GC), (Table 1, entries 23 and 24). Then, the
reaction mixture was washed with an aqueous solution of
NaOH (10%, 10 ml) and extracted with Et2O (2 · 10 ml).
The organic layer was separated and dried over anhydrous
CaCl2 and filtered. Evaporation of the solvent afforded the
desired product. Further purification was achieved
by preparative plate silica chromatography eluting
with n-hexane. Structural assignments of the products
35. General procedure for the S-alkylation of thiols by alcohols:
To a mixture of ZrCl4 (0.116 g, 0.5 mmol) and dry silica
gel [0.3 g (60, 70–230 mesh) dried at 100 ꢁC under vacuum
for 24 h] at 50 ꢁC, thiol (1.1 mmol) was added and the
resulting mixture was stirred for a few minutes. Then, the
alcohol (1 mmol) was added and the mixture was stirred at
50 ꢁC for the appropriate reaction time (monitored by
TLC and GC) (Table 1). Then, the reaction mixture was
washed with an aqueous solution of NaOH (10%, 10 ml)
and extracted with Et2O (2 · 10 ml). The organic layer was
separated and dried over anhydrous CaCl2 and filtered.
Evaporation of the solvent afforded the desired product.
Further purification was achieved by preparative plate
silica chromatography eluting with n-hexane. Structural
1
are based on their H NMR, 13C NMR and MS spectra
and elemental analysis.
37. Typical procedure for the double S-alkylation of 1,3-
propanedithiol using 1,4-benzenedimethanol (entry 24):
To a mixture of ZrCl4 (0.233 g, 1 mmol) and dry silica
gel [0.3 g (60, 70–230 mesh) dried at 100 ꢁC under vacuum
for 24 h] at 50 ꢁC, 1,3-propanedithiol (2.1 mmol) was
added and the mixture stirred for a few minutes. Then,
1,4-benzenedimethanol (1 mmol) was added and the
resulting mixture was stirred at 50 ꢁC for 20 min (moni-
tored by TLC). The product was extracted by the addition
of acetone followed by filtration. The filtrate was evapo-
rated under vacuum to afford the desired product. Further
purification was achieved by preparative plate silica
chromatography eluting with n-hexane. Structural assign-
ment of the product was based on its 1H NMR, 13C NMR
and MS spectra and elemental analysis.
1
assignments of the products are based on their H NMR,
13C NMR and MS spectra and elemental analysis.
36. General procedure for the double S-alkylation of dithiols
using alcohols: To a mixture of ZrCl4 (0.233 g, 1 mmol)
and dry silica gel [0.3 g (60, 70–230 mesh) dried at 100 ꢁC
under vacuum for 24 h] at 50 ꢁC, dithiol (1.1 mmol) was