A direct synthetic route to allyl sulfides from cyclic Morita–Baylis–Hillman alcohols

Article abstract of DOI:10.1080/17415993.2016.1255742

p-TsOH-mediated the direct α-substitution of cyclic Morita–Baylis–Hillman alcohols with aliphatic and aromatic thiols in refluxing THF. The reaction proceeded with complete α-regioselectivity and provided the corresponding allyl sulfides in moderate to good yields.

Full text of DOI:10.1080/17415993.2016.1255742

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
A direct synthetic route to allyl sulfides from cyclic
Morita–Baylis–Hillman alcohols
Yosra Oueslati, Ahlem Abidi, Hassen Mohamed Sbihi & Farhat Rezgui
To cite this article: Yosra Oueslati, Ahlem Abidi, Hassen Mohamed Sbihi & Farhat Rezgui
(2016): A direct synthetic route to allyl sulfides from cyclic Morita–Baylis–Hillman alcohols,
Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2016.1255742
To link to this article: http://dx.doi.org/10.1080/17415993.2016.1255742
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Date: 01 December 2016, At: 05:24

JOURNAL OF SULFUR CHEMISTRY, 2016
http://dx.doi.org/10.1080/17415993.2016.1255742
A direct synthetic route to allyl sulfides from cyclic
Morita–Baylis–Hillman alcohols
Yosra Oueslatia, Ahlem Abidia, Hassen Mohamed Sbihib and Farhat Rezguia
aLaboratoire de Chimie Organique Structurale et Macromoléculaire, Faculté des Sciences, Université de Tunis
El Manar, Tunis, Tunisie; bCollege of Science, Chemistry Department, King Saud University, Riyadh, Saudi
Arabia
ABSTRACT
ARTICLE HISTORY
Received 8 April 2016
Accepted 27 October 2016
p-TsOH-mediated the direct α-substitution of cyclic Morita–Baylis–
Hillman alcohols with aliphatic and aromatic thiols in refluxing THF.
The reaction proceeded with complete α-regioselectivity and pro-
vided the corresponding allyl sulfides in moderate to good yields.
KEYWORDS
Allyl sulfide; regioselectivity;
Morita–Baylis–Hillman;
Brønsted acid; allylic
substitution
1. Introduction
The exploration of allylic substitutions for the construction of carbon–sulfur bonds is of
widespread interest due to the growing need for versatile, mild, and selective methods in
the preparation of organosulfur compounds [1–10]. Allyl sulfide moiety is a structural
motif that is found in many natural and synthetic compounds with a broad spectrum of
biological activities, including antimicrobial [11], anticancer [12–14], and cardioprotective
effects [15]. A number of reports have disclosed the potential applications of allyl sulfides
in polymers chemistry [16,17], nanoparticles [18,19], and metathesis reactions for appli-
cation in protein modifications [20]. In view of their significance in organic synthesis, it is
still necessary to develop new and convenient synthetic routes to allyl sulfides.
The behavior of MBH adducts, as useful substrates [21–27], has been widely explored
for the nucleophilic displacement of common leaving groups with various nucleophiles
CONTACT Farhat Rezgu
rez_far@yahoo.fr
Laboratoire de Chimie Organique Structurale et Macromoléculaire,
Faculté des Sciences, Université de Tunis El Manar, Campus Universitaire, 2092 Tunis, Tunisie
Supplemental data for this article can be accessed here. http://dx.doi.org/10.1080/17415993.2016.1255742
© 2016 Informa UK Limited, trading as Taylor & Francis Group

2
Y. OUESLATI ET AL.
[28–38] including thiols. The most commonly used method for the preparation of allyl sul-
fides from MBH adducts makes use of allyl halides [11,39–42], carbonates [43,44], acetates
[12,45–51], thiocarbamates [52], and nitro derivatives [53,54].
The direct conversion of acyclic MBH alcohols into the corresponding allylic sulfones
using sodium phenyl sulfinate [55] or sulfinyl chloride [56] was previously reported. On
the other hand, the α-nucleophilic substitution of cyclic MBH alcohols with thiols using
Lewis acids has been previously described [57,58].
We envisioned herein to extend this allylation reaction to other linear, branched, or
aromatic thiols with six- and five-membered MBH alcohols 1a–c. This simple and efficient
synthetic procedure has been implemented for the synthesis of a wide range of γ -keto allyl
sulfides.
2. Results and discussion
The starting MBH alcohols 1a–c was prepared according to previously reported proce-
dures [59–61]. Initially, the alcohol 1a was selected as a model substrate and treated with
hexanethiol in THF using p-TsOH as a Bronsted acid catalyst to promote the nucleophilic
allylic substitution. The total conversion of the alcohol 1a into the corresponding product
2a in 55% yield within 2 h has been observed using at least 30 mol% of p-TsOH in refluxing
THF (Scheme 1, Table 1, entry 1). Significantly longer reaction times were necessary for
the completion of the reaction when less than 30 mol% of p-TsOH was used. On the other
hand, an increased amount of the title acid let to completion in shorter reaction times, but
with a lowered yield of 2a.
Under these optimized conditions, the allyl sulfides 2b–d, resulting from the direct
α-substitution of the hydroxyl moiety of the MBH alcohol 1a by branched or function-
alized thiols (Table 1, entries 2–4) as well as aromatic thiols (Table 1, entries 5 and 6), were
synthesized with a high regioselectivity, in 60–85% yields.
Next, in order to explore the scope of this synthetic protocol, we examined, under the
previous reaction conditions, the behavior of the MBH alcohol 1b, more hindered at the
α-position than alcohol 1a (Scheme 1), as well as the five-membered alcohol 1c. In all these
cases, we have observed that the nucleophilic allylic substitution of these alcohols worked
well with both aliphatic and aromatic thiols, affording the desired products 2g–l in good
yields (Table 1, entries 7–12).
It is noteworthy that when the cyclic MBH alcohol derived from benzaldehyde (Scheme
1, R = Ph) was tested in the title reaction, as a substrate, under the established conditions,
Scheme 1. Synthesis of γ -keto allyl sulfides 2a–l from the MBH alcohols 1a–c.

JOURNAL OF SULFUR CHEMISTRY
3
Table 1. Synthesis of γ -keto allyl sulfides 2a–l from the MBH alcohols 1a–ca [51,53,54,57,58,62]
Entry
1
Alcohol
Thiol
Allyl sulfideb
Time (h)
2
Yield (%)c
55
1a
2a:
2b:
2
1a
4
84
3
4
5
1a
1a
1a
2c:
2d:
2e:
6
5
4
62d
72
85
6
1a
2f:
24
60d
7
1b
1b
1b
1b
2g:
2h:
2i:
3
6
2
6
94e
88e
89e
97e
8
9
10
2j:
(continued).

4
Y. OUESLATI ET AL.
Table 1. Continued.
Entry
11
Alcohol
Thiol
Allyl sulfideb
Time (h)
2
Yield (%)c
84d
1c
2k:
2l:
12
1c
2
93
aReaction conditions: MBH alcohol 1a–c (2 mmol), thiol (4 mmol), p-TsOH (30 mol%), THF (2.0 mL), reflux.
bConsistent with published data [51,53,54,57,58,62].
cYield of isolated product after flash chromatography.
d90 mol% of p-TsOH was used.
e1.0 equiv of thiol was used.
Scheme 2. Synthesis of dithiane derivatives 3a and 3b from the MBH 1a and 1c.
a dehydration reaction exclusively occurred without the trace of the corresponding allyl
sulfide.
• Mechanistically, we believe that the dehydration of alcohol 1a is promoted by the
p-TsOH, generating an allyl carbocation that further undergoes a regioselective nucle-
ophilic attack by various thiols, affording the allyl sulfides 2 and regenerating the
p-TsOH [57].
On the other hand, 1,2-ethanedithiol, as a bidentate nucleophile, reacted with alcohols
1a and 1c, under the previous conditions, affording the intermediates 2-ketoallyl sulfides.
These latter, bearing a thiol moiety, subsequently reacted in an intramolecular 1,4-addition
on the cyclic enone subunit, to finally afford the bicyclic dithiane derivatives 3a and 3b in
70% and 67% overall yields, respectively (Scheme 2). 13C NMR spectra of each compound
revealed the doubling of almost all signals, suggesting the presence of two diastereomers
whose ring junctions may be cis and trans.1
3. Conclusion
In summary, we have provided a useful and efficient p-TsOH-mediated synthesis of func-
tionalized allyl sulfides 2a–l directly from the cyclic MBH alcohols. The reaction proceeded
in good yields with high regioselectivity for a variety of thiols. Moreover, the reaction of 1a
and 1c with 1,2-ethanedithiol led to bicyclic dithiane derivatives 3a and 3b, respectively.

JOURNAL OF SULFUR CHEMISTRY
5
4. Experimental section
4.1. General
IR spectra were recorded on an IFS 66v/S spectrometer. 1H NMR and 13C NMR spectra
1
were recorded on a 300 MHz spectrometer for H and 75 MHz for 13C in CDCl3, using
TMS as an internal standard (chemical shift in δ values, J in Hz). High-resolution mass
spectra (HRMS) were recorded on a micromass mass spectrometer. Mass spectra (EI) were
obtained at 70 eV. Analytical thin-layer chromatography (TLC) was performed on perco-
lated silica gel 60 F254 plates. Visualization was achieved by UV light (254 nm). Flash
chromatography was performed using Merck silica gel 60 and a gradient solvent system
(petroleum ether–ether).
4.2. General procedure for the synthesis of allylic sulfides 2a–l and dithiane
derivatives 3a–b promoted by p-TsOH
A 25 mL round-bottomed flask was charged with alcohol 1a–c (0.25 g, 2 mmol), p-TsOH
(0.6 mmol), and 4 mmol of thiol in 2 mL of THF. The resulting mixture was stirred in THF
at reflux for 2–24 h (Table 1). When the reaction, followed by TLC, was finished, the mix-
ture was treated with saturated aqueous NaHCO3. After the usual workup, the residue was
purified by chromatography on silica gel eluting with petroleum ether–ether. The results
are given in Table 1 and spectral data are in good agreement with those reported in the
literature [51,53,54,62].
4.2.1. (Hexylsulfanylmethyl)cyclohex-2-enone (2a) [51,62]
Yield = 55%; yellow oil; IR: 1673 cm−1; 1H NMR (300 MHz, CDCl3): 6.91 (t, J = 4.2 Hz,
1H), 3.29 (d, J = 3 Hz, 2H), 2.48–2.41 (m, 6H), 2.07–1.97 (m, 2H), 1.61–1.52 (m, 2H),
1.39–1.25 (m, 6H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): 198.1, 146.6,
136.5, 38.4, 32.3, 31.5, 30.3, 29.7, 28.6, 26.1, 23.0, 22.8, 14.0; HRMS (ESI): calcd for
C13H22OSNa [M + Na]+ 249.1289, found 249.1284.
4.2.2. 2-(Isopropylsulfanylmethyl)cyclohex-2-enone (2b) [62]
1
Yield = 84%; yellow oil; H NMR (300 MHz, CDCl3) δ 6.93 (t, J = 4.1 Hz, 1H), 3.34
(d, J = 1.3 Hz, 2H), 2.98–2.78 (m, 1H), 2.52–2.32 (m, 4H), 2.07–1.93 (m, 2H), 1.25 (d,
J = 6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 197.6, 146.1, 137.0, 38.3, 35.2, 28.5, 25.9,
23.2, 22.9; MS (m/z) (relative intensity): 184 (C10H16OS, M+, 58), 141 (96), 110 (100), 82
(86), 79 (69), 53 (46).
4.2.3. Ethyl 3-((6-oxocyclohex-1-enyl)methylsulfanyl)propanoate (2c) [62]
Yield = 62%; yellow oil; 1H NMR (300 MHz, CDCl3) δ 6.84 (t, J = 4.1 Hz, 1H), 4.04 (q,
J = 7.1 Hz, 2H), 3.20 (d, J = 1.0 Hz, 2H), 2.65–2.59 (m, 2H), 2.51–2.46 (m, 2H), 2.43–2.27
(m, 4H), 2.01–1.82 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 197.8,
171.6, 146.7, 135.6, 60.2, 38.0, 34.2, 29.7, 26.6, 25.7, 22.6, 13.8; MS (m/z) (relative intensity):
242 (C12H18O3S, M+, 14), 197 (24), 154 (72), 141 (100), 110 (78), 82 (74), 53 (61).

6
Y. OUESLATI ET AL.
4.2.4. Methyl 2-((6-oxocyclohex-1-enyl)methylsulfanyl)acetate (2d) [51,62]
1
Yield = 72%; colorless oil; H NMR (300 MHz, CDCl3) δ 6.96 (t, J = 4.1 Hz, 1H), 3.74
(s, 3H), 3.40 (d, J = 0.9 Hz, 2H), 3.19 (s, 2H), 2.49–2.42 (m, 4H), 2.08–1.95 (m, 2H); 13
C
NMR (75 MHz, CDCl3) δ 198.0, 170.8, 147.7, 135.1, 52.3, 38.2, 32.9, 30.4, 25.9, 22.9; MS
(m/z) (relative intensity): 214 (C10H14O3S, M+, 15), 182 (29), 155 (17), 141 (100), 109 (13),
79 (38), 53 (24).
4.2.5. 2-((4-Chlorophenylsulfanyl)methyl)cyclohex-2-enone (2e) [51,62]
1
Yield = 85%; yellow oil; H NMR (300 MHz, CDCl3) δ 7.34–7.13 (m, 4H), 6.76 (t,
J = 3.5 Hz, 1H), 3.66 (d, J = 1.0 Hz, 2H), 2.49–2.39 (m, 2H), 2.36–2.25 (m, 2H), 2.05–1.88
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 197.9, 147.7, 134.9, 134.7, 132.3, 131.5, 128.8, 38.2,
32.8, 25.9, 22.8; MS (m/z) (relative intensity): 252 (C13H13ClOS, M+, 94), 144 (82), 109
(41), 108 (44), 81 (100), 79 (76), 53 (73).
4.2.6. 2-((Pyrimidin-2-ylsulfanyl)methyl)cyclohex-2-enone (2f)
Yield = 60%; yellow solid; mp = 90–92°C; 1H NMR (300 MHz, CDCl3) δ 8.33 (d,
J = 4.9 Hz, 2H), 7.01 (t, J = 4.0 Hz, 1H), 6.83 (t, J = 4.9 Hz, 1H), 3.80 (d, J = 1.1 Hz, 2H),
2.38–2.12 (m, 4H), 1.84–1.78 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 197.9, 171.9, 157.0,
147.8, 135.4, 116.4, 38.0, 28.7, 25.9, 22.7; MS (m/z) (relative intensity): 220 (C11H12N2OS,
M+, 79), 192 (22), 187 (100), 163 (51), 131 (33), 112 (32), 79 (46), 53 (61); HRMS (ESI):
calcd for C11H13N2OS [M + H]+ 221.07486, found 221.07594.
4.2.7. 2-(1-(Propylsulfanyl)ethyl)cyclohex-2-enone (2g) [51,62]
Yield = 94%; yellow oil; IR: 1670 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.03 (t, J = 4.2 Hz,
1H), 4.04 (qd, J = 7.0, 0.6 Hz, 1H), 2.54–2.33 (m, 6H), 2.08–1.92 (m, 2H), 1.67–1.48 (m,
2H), 1.35 (d, J = 7.1 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
197.8, 145.2, 141.7, 38.5, 35.7, 33.6, 26.0, 22.8, 22.7, 21.4, 13.6; HRMS (ESI): calcd for
C11H18OSNa [M + Na]+ 221.0976, found 221.0971.
4.2.8. 2-(1-(Isopropylsulfanyl)ethyl)cyclohex-2-enone (2h)
1
Yield = 88%; colorless oil; H NMR (300 MHz, CDCl3) δ 7.03 (t, J = 4.1 Hz, 1H), 4.10
(q, J = 7.0 Hz, 1H), 2.89–2.81 (m, 1H), 2.50–2.35 (m, 4H), 2.04–1.92 (m, 2H), 1.33 (d,
J = 7.0 Hz, 3H), 1.25–1.21 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 197.4, 145.0, 142.8,
38.6, 35.2, 35.10, 26.2, 23.8, 23.5, 22.9, 22.2; MS (m/z) (relative intensity): 198 (C11H18OS,
M+, 37), 155 (99), 124 (100), 96 (30), 79 (25), 67 (39), 55 (25); HRMS (ESI): calcd for
C11H19OS [M + H]+ 199.11566, found 199.11642.
4.2.9. 2-(1-(Benzylsulfanyl)ethyl)cyclohex-2-enone (2i)
1
Yield = 89%; yellow oil; H NMR (300 MHz, CDCl3) δ 7.28–7.16 (m, 5H), 6.92 (t,
J = 4.2 Hz, 1H), 3.98 (q, J = 7.0 Hz, 1H), 3.66 (s, 2H), 2.38–2.27 (m, 4H), 1.94–1.84 (m,
2H), 1.29 (d, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 197.3, 145.0, 141.7, 138.6,
128.9, 128.4, 126.8, 38.6, 36.8, 36.6, 26.0, 22.7, 21.3; MS (m/z) (relative intensity): 246
(C15H18OS, M+, 6), 155 (100), 123 (45), 91 (58), 77 (19), 65 (23), 55 (18); HRMS (ESI):
calcd for C15H19OS [M + H]+ 247.11566, found 247.12180.

JOURNAL OF SULFUR CHEMISTRY
7
4.2.10. 2-(1-(4-Chlorophenylsulfanyl)ethyl)cyclohex-2-enone (2j)
1
Yield = 97%; yellow oil; H NMR (300 MHz, CDCl3) δ 7.30–7.20 (m, 4H), 6.86 (t,
J = 4.2 Hz, 1H), 4.44 (q, J = 7.0 Hz, 1H), 2.44 (t, J = 6.7, 2H), 2.34 (q, J = 5.6 Hz, 2H),
2.00–1.88 (m, 2H), 1.35 (d, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 197.3, 145.8,
140.1, 133.5, 133.4, 133.03, 128.7, 39.1, 38.3, 25.9, 22.6, 20.6; MS (m/z) (relative inten-
sity): 266 (C14H15ClOS, M+, 15), 144 (14), 123 (100), 108 (14), 95 (20), 67 (24), 55 (14);
HRMS (ESI): calcd for C14H1635ClOS [M + H]+ 267.06104, found 267.06390; calcd for
C14H1637ClOS [M + H]+ 269.05809, found 269.06106.
4.2.11. 2-(Propylsulfanylmethyl)cyclopent-2-enone (2k)
1
Yield = 84%; yellow oil; H NMR (300 MHz, CDCl3) δ 7.55–7.38 (m, 1H), 3.25 (d,
J = 0.7 Hz, 2H), 2.67–2.37 (m, 6H), 1.67–1.55 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 207.6, 158.7, 143.6, 34.7, 34.6, 26.4, 25.5, 22.7, 13.3; MS (m/z) (relative
intensity): 170 (C9H14OS, M+, 29), 127 (38), 96 (100), 67 (26), 53 (10); HRMS (ESI): calcd
for C9H15OS [M + H]+ 171.08436, found 171.08152.
4.2.12. 2-((4-Chlorophenylsulfanyl)methyl)cyclopent-2-enone (2l)
Yield = 93%; white solid; mp = 76–78°C; 1H NMR (300 MHz, CDCl3) δ 7.42–7.35 (m,
1H), 7.27–7.22 (m, 4H), 3.64 (d, J = 1.2 Hz, 2H), 2.60–2.50 (m, 2H), 2.46–2.37 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 207.0, 159.3, 142.0, 134.5, 132.6, 131.1, 128.9, 34.4, 28.0,
26.3; MS (m/z) (relative intensity): 238 (C12H11ClOS, M+, 100), 205 (27), 144 (56), 108
(43), 95 (33), 67 (93), 53 (28); HRMS (ESI): calcd for C12H1235ClOS [M + H]+ 239.02974,
found 239.02574; calcd for C12H1237ClOS [M + H]+ 241.02679, found 241.02360.
4.2.13. 2,5-Dithia-bicyclo[5.4.0]undecan-8-one (3a) [51,54,62]
1
Yield = 70%; white solid; mp = 150–152°C; IR (CHCl3): 1710, 1410 cm−1; H NMR
(300 MHz, CDCl3) δ 4.32–2.66 (m, 8H), 2.53–1.64 (m, 6H); 13C NMR (75 MHz, CDCl3)
δ 209.1, 207.9, 60.4, 55.4, 50.2, 50.0, 42.0, 40.6, 39.4, 39.3, 37.5, 37.0, 33.4, 33.3, 33.0, 31.3,
25.4, 23.0; MS (m/z) (relative intensity): 202 (C9H14OS2, M+, 100), 174 (16.9),110 (54.1),97
(22.3).
4.2.14. Hexahydrocyclopenta[e][1,4]dithiepin-6(7H)-one (3b)
Yield = 67%; white solid; mp = 64–66°C; 1H NMR (300 MHz, CDCl3) δ 4.10–4.04 (m,
1H), 3.25–2.80 (m, 7H), 2.46–2.20 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 216.8, 214.5,
63.4, 59.6, 50.1, 45.5, 38.4, 38.2, 37.7, 37.0, 34.5, 32.5, 30.7, 28.4, 27.1; MS (m/z) (relative
intensity): 188 (C8H12OS2, M+, 100), 154 (35), 127 (32), 95 (51), 85 (27), 67 (51); HRMS
(ESI): calcd for C8H13OS2 [M + H]+ 189.04078, found 189.03743.
Note
1. The separation of diastereomers could not be achieved by column chromatography, and on the
basis of their 1H NMR spectrum, the diastereomeric ratio could not be determined.
Disclosure statement
No potential conflict of interest was reported by the authors.

8
Y. OUESLATI ET AL.
Funding
We gratefully acknowledge financial support of this work by the Ministry of Higher Education of
Tunisia. The authors would like to extend their sincere appreciation to the Deanship of Scientific
Research at King Saud University for its funding of this research through the Research Group Project
No RGP-243.
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