Formation of meta-arylsulfanyl- and meta-(alkylsulfanyl)phenols from cyclohexane-1,3-diones

Article abstract of DOI:10.1016/j.tet.2018.06.059

Reaction of cyclohexane-1,3-diones with TsCl/Et₃N and treatment of the resulting 3-(tosyloxy)cyclohex-2-en-1-ones with aryl- or alkyl thiols and K₂CO₃ in MeCN gives 3-(arylsulfanyl)cyclohex-2-en-1-ones or 3-(alkylsulfanyl)cyclohex-2-en-1-ones, respectively. These compounds are easily brominated at C-2 by using NBS in MeCN; exposure to DBU in MeCN at room temperature then causes aromatization to afford meta-arylsulfanyl- and meta-(alkylsulfanyl)phenols.

Full text of DOI:10.1016/j.tet.2018.06.059

Accepted Manuscript
Formation of meta-arylsulfanyl- and meta-(alkylsulfanyl)phenols from
cyclohexane-1,3-diones
Nhan Do Van Thanh, Subrata Patra, Derrick L.J. Clive
PII:
S0040-4020(18)30774-9
10.1016/j.tet.2018.06.059
TET 29655
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 May 2018
Revised Date: 21 June 2018
Accepted Date: 25 June 2018
Please cite this article as: Do Van Thanh N, Patra S, Clive DLJ, Formation of meta-arylsulfanyl-
and meta-(alkylsulfanyl)phenols from cyclohexane-1,3-diones, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.06.059.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Formation of meta-Arylsulfanyl- and meta-(Alkylsulfanyl)phenols from
Cyclohexane-1,3-diones
By Nhan Do Van Thanh, Subrata Patra and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
ABSTRACT: Reaction of cyclohexane-1,3-diones with TsCl/Et3N and treatment of the
resulting 3-(tosyloxy)cyclohex-2-en-1-ones with aryl- or alkyl thiols and K2CO3 in MeCN gives
3-(arylsulfanyl)cyclohex-2-en-1-ones or (alkylsulfanyl)cyclohex-2-en-1-ones, respectively.
These compounds are easily brominated at C-2 by using NBS in MeCN; exposure to DBU in
MeCN at room temperature then causes aromatization to afford meta-arylsulfanyl- and meta-
(alkylsulfanyl)phenols.
Keywords:
meta-(arylsulfanyl)phenols
meta-(alkylsulfanyl)phenols
aromatization
bromination
sulfides
*Corresponding author.
E-mail address: derrick.clive@ualberta.ca
1. Introduction
Three recent publications from this laboratory have described (Scheme 1) the conversion
of 2-bromocyclohex-2-en-1-one systems 2 into phenols1, 2 (2→3→4) as well as the introduction
of an alkyl or aryl substituent meta to the eventual phenolic hydroxyl (2→5→6).3 We have now
extended the aromatization of bromocyclohexenones to the preparation of meta-(arylsulfanyl)-

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Scheme 1. Our previous routes to phenols from bromocyclohexenones
and meta-(alkylsulfanyl)phenols.
The process involves preparation of a 2-bromo-3-
(arylsulfanyl)cyclohex-2-en-1-one 7 or the corresponding alkylsulfanyl compound, and then
aromatization (7→8) by treatment with DBU (Scheme 2). Some phenols of this type influence
intracellular mobilization of Ca+2 ions,4a inhibit the growth of HeLa cells4b,c or inhibit 17β-
hydroxysteroid dehydrogenase type 1,5a and several have been evaluated as potential
antidepressants.5b,c,d
Scheme 2. Extension of the aromatization method to 3-arylsulfanyl and 3-
(alkylsulfanyl)phenols
2. Results and discussion
Development of a route to compounds of type 7, required some exploration in order to
identify the best of several alternative approaches. In principle, the bromine can be introduced
either before or after the sulfur unit, and both possibilities were investigated.
Cyclohexane-1,3-dione (9) was easily brominated in near quantitative yield6 (9→10), but
conversion to the dibromide 11,7 with the intention of replacing the C-3 halogen by a sulfur unit,
was unsatisfactory as the dibromide seemed to be unstable. Therefore, we treated 10 with TsCl
and Et3N in order to prepare the bromo tosylate 12. However, the yield was poor (ca 40%) and
the product was accompanied by the known tosyloxy phenol8 13.

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Scheme 3. Formation of 3-bromo- and 3-(tosyloxy)enones
Several attempts were then made to introduce the sulfur unit directly using the
monobromide 10. To that end, treatment of 10 with PhSH, Ph3P and DEAD gave the desired
product (14), but only in ca 20% yield. Use of other coupling reagents such as DCC/DMAP9
or MeOCOCl/HOBT10 was equally unsatisfactory. We also treated cyclohexan-1,3-dione (9)
with PhSSPh and Ph3P, but again, the yield of the expected 3-(phenylsulfanyl)cyclohexenone
was very low (8%). All of these initial experiments were done with CH2Cl2 as solvent, except
for the experiment with PhSSPh, which was carried out in MeCN. We then examined the use of
MeOH and found that in this solvent simple treatment of the bromocyclohexanedione 10 with 1
equiv of PhSH for 24 h afforded 14 in 60% yield; however, attempts to raise the yield by varying
the number of equiv of PhSH or the nature of the solvent (MeOH, MeCN, CF3CH2OH, EtOH,
DMF, DMSO) were unsuccessful. We wondered if the observed formation of 14 was the result
of replacement of OH by OMe, followed by displacement of the methoxy group. To test this
possibility we added PhSH to a methanol solution of 15 (Scheme 4). However, overnight
storage of 15 in MeOH in the presence of PhSH did not provide any of the sulfide 14, as judged
by TLC analysis.

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Scheme 4. Attempted displacement of OMe by SPh
In related experiments (Scheme 5) cyclohexane-1,3-dione (9) was stored in MeOH for 1
week but very little ester 16 was formed (ca 10%). However, when PhSH (1 equiv) was added
the ester 16 was formed in ca 90% yield after an overnight reaction period. When the keto
sulfide 17 was kept overnight in MeOH, vinylogous ester 16 was again produced (ca 90%). This
observation cause us to store the brominated compound 14 in MeOH to see if incursion of
PhS/MeO exchange was responsible for the modest yield of 14, but in the event, 14 was found to
be stable to MeOH.
Scheme 5. Studies on MeO/PhS exchange
The outcome of these exploratory experiments forced us to turn to the alternative
approach in which the bromine is introduced after the sulfur unit.
The reaction between PhSH and cyclohexane-1,3-dione (9) in the presence of FeCl3, but
without solvent, afforded 17 in 72% yield,11 but this method is unsuitable for solid thiols as use
of a solvent is reported11 to greatly diminish the yield. At this point we decided to evaluate the
tosylate12 18. This compound is easily made in almost 90% yield, but it should be stored in a
freezer and used within a week. The best conditions for replacement of the tosyloxy group by
Scheme 6. Displacement of tosyloxy group by PhS
PhS involve use of MeCN as solvent with K2CO3 (5 equiv) as base and 1 equiv of PhSH. Under
these conditions, which are similar to those reported for the corresponding mesylate,13, 14 17 was
isolated in 71% yield. We have applied these conditions to a number of thiols (see Table 1) and
prefer it to the use of NaH in DMF, a procedure that also afforded 17 in similar yield.

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Table 1. Formation of meta-(arylsulfanyl)- and meta-(alkylsulfanyl)phenols

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aYield from tosylate 18. bYield from 3-oxo-5-phenylcyclohex-1-en-1-yl 4-methylbenzene-1-
c
sulfonate. The material contains slight impurities.
We next dealt with introduction of the bromine. In the case of the simplest example (17)
bromination with NBS in CCl4 had been reported,15, 16 but we were uncertain of the generality of
the method because of the potential for reaction at the sulfur atom17 or at the benzene ring.18 In
our hands the action of NBS in MeCN on 3-(arylsulfanyl)cyclohex-2-enones was usually
satisfactory irrespective of whether an electron-donating or an electron-withdrawing group is
present in the arylsulfanyl unit. In the few examples where we made a comparison, use of CCl4
for the NBS bromination gave a lower yield than use of MeCN as the solvent. The thiol addition
and bromination steps worked equally well in the presence of an ortho methyl group (Table 1,
entry 6) or an ortho ester group (Table 1, entry 7), but in the case of a t-butylsulfanyl group the
yields were low (entry 10). The bromination was slow and so it was convenient to run the
reaction for an arbitrary period of 24 h. Our results are given in Table 1.
Finally, we studied the aromatization with DBU. This step proceeded smoothly but took
several hours; however, it was always complete after an overnight reaction period at room
temperature. The effect of changing the solvent for the aromatization was also examined; MeCN
generally gives a better result than THF, PhMe or CH2Cl2, and the reactions are best run at room
temperature; raising the temperature (50 °C), with the one example we studied (compound 14),
resulted in a significantly decreased yield (by 20%) in two successive runs. With the exception
of entry 10, the yields are in the range 63-90% with an average yield of 74%.
3. Other approaches
Other methods that have been used to prepare inter alia meta-(arylsulfanyl)- or meta-
(alkylsulfanyl)phenols include a number of procedures usually based on transition metals and
often run at an elevated temperature: Treatment of 3-(arylsulfanyl)cyclohexanones or the
corresponding cyclohex-2-enones with Pd/C in the presence of K2CO3 and H2 at 150 °C in
MeC(O)NMe2 effects dehydrogenation to the phenol (Eq. 1).19 Aryl thiols can be coupled with
aryl iodides at modest temperature (80 °C) in a process catalyzed by CuI (Eq. 2).20 Similarly,
both alkyl and aryl thiols undergo palladium-mediated coupling with aryl iodides and bromides
at 90–110 °C in the presence of a base (Eq. 3).21 Aryl and alkyl thiols have been coupled with

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arylboronic acids under the influence of ultrasound in the presence of Cu(OAc)2 (Eq. 4).22
Deprotonation of 3-bromophenol, followed by halogen/metal exchange and reaction with sulfur
generates a thiolate that can be alkylated by an alkyl halide (Eq. 5).23 Aryl thiolates made by
other methods can, of course, be alkylated with alkyl halides (Eq. 6).24 Aryl halides can also be
converted into thiolates by copper(II)-catalyzed reaction at 110 °C with 1,2-ethanedithiol in the
presence of KOH and, without isolation, the thiolates can be arylated on sulfur by addition of an
aryl iodide in DMF and heating at 120 °C (Eq. 7).25 A vinylogous thioester has been aromatized
by
dihalogenation and base treatment to afford a halogenated meta-(phenylsulfanyl) phenol (Eq.
8).26

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4. Conclusion
3-(Tosyloxy)cyclohex-2-en-1-ones, readily made from cyclohexan-1,3-diones, are
convertible into 3-(arylsulfanyl)- or 3-(alkylsulfanyl)cyclohex-2-en-1-ones by reaction at room
temperature with thiols in the presence of K2CO3. The products can be brominated at C-2 with
NBS in MeCN, and treatment with DBU in MeCN affords the corresponding 3-(arylsulfanyl)- or
3-(alkylsulfanyl)phenols. The reaction sequence occurs under mild conditions and avoids the
use of heavy metals.
5. Experimental section
5.1 General procedures.
Solvents used for chromatography were distilled before use. Commercial thin layer
chromatography plates (silica gel, Merck 60F-254) were used.
Silica gel for flash
chromatography was Merck type 60 (230−400 mesh). Dry solvents were prepared under an inert
13
atmosphere (N2) and transferred by syringe or cannula. The symbols s, d, t, and q used for C
NMR spectra indicate zero, one, two, or three attached hydrogens, respectively, the assignments
being made from APT spectra. Solutions were evaporated under water pump vacuum, and the
residue was then kept under oil pump vacuum. High resolution electrospray mass spectrometric
analyses were done with an orthogonal time-of-flight analyzer, and electron ionization mass
spectra were measured with a double-focusing sector mass spectrometer. Gradient flash
chromatography was done by stepwise small increases in the proportion of the more polar
solvent, as described for the individual experiments. NBS was recrystallized from water.27
5.1.1. 3-(Phenylsulfanyl)cyclohex-2-en-1-one (17)11
PhSH (0.055 mL, 0.50 mmol) was added to a stirred mixture of tosylate 18 (133 mg, 0.50
mmol), K2CO3 (413 mg, 2.50 mmol) and dry MeCN (1 mL) and stirring was continued overnight
(N2 atmosphere). Water (10 mL) was added and stirring was continued for 15 min. The mixture
was extracted with EtOAc (3 × 15 mL) and the combined organic extracts were washed with
brine, dried (MgSO4) and evaporated. Flash chromatography of the residue over silica gel (1 ×
1
25 cm), using 4:1 hexane-EtOAc, gave 17 (72 mg, 71%) as an oil: H NMR (CDCl3, 400 MHz)
δ 2.01–2.07 (m, 2 H), 2.34–2.38 (m, 2 H), 2.52 (td, J = 6.0, 0.8 Hz, 2 H), 5.47 (t, J = 1.2 Hz, 1

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H), 7.40–7.48 (m, 5 H); 13C NMR (CDCl3, 100 MHz) δ 22.9, 30.2, 37.2, 120.9, 128.0, 129.8,
130.1, 135.5, 166.8, 196.0.
5.1.2. 2-Bromo-3-(phenylsulfanyl)cyclohex-2-en-1-one (14)15
Thio enone 17 (102 mg, 0.50 mmol) and then freshly crystallized NBS (98 mg, 0.55
mmol) were placed in a round-bottomed flask containing a magnetic stirrer. Dry MeCN (1.0
mL) was added and the mixture was stirred for 24 h (N2 atmosphere) with protection from light
(flask wrapped in aluminum foil). EtOAc (15 mL) was added and the mixture was washed
successively with aqueous Na2S2O3 (1 M), saturated aqueous NaHCO3, and brine. The organic
extract was dried (MgSO4) and evaporated. Flash chromatography of the residue over silica gel
1
(3 × 15 cm), using 4:1 hexane-EtOAc, gave 14 (102 mg, 72%) as a solid: mp 112–113 °C; H
NMR (CDCl3, 400 MHz) δ 1.93–1.97 (m, 2 H), 2.20 (t, J = 6.5 Hz, 2 H), 2.56 (t, J = 6.0 Hz, 2
H), 7.43–7.58 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ 22.5, 32.2, 37.1, 116.8, 129.1, 129.7,
130.4, 136.0, 164.3, 187.7.
5.1.3. 3-(Phenylsulfanyl)phenol (19)21
DBU (0.032 mL, 0.212 mmol) was injected into a stirred solution of 14 (30 mg, 0.11
mmol) in dry MeCN (1.0 mL) and stirring was continued overnight (N2 atmosphere). The
mixture was diluted with hydrochloric acid (5%, 10 mL) and stirring was continued for 15 min.
The mixture was extracted with EtOAc (3 × 15 mL) and the combined organic extracts were
washed with brine, dried (MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (1 × 15 cm), using successively hexane (ca 20 mL), 5% EtOAc-hexane (ca 50 mL),
1
10% EtOAc-hexane (ca 100 mL), gave 19 (19 mg, 89%) as an oil: H NMR (CDCl3, 400 MHz)
δ 4.98 (br s, 1 H), 6.70–6.80 (m, 1 H), 6.85–6.86 (m, 1 H), 6.98–7.00 (m, 1 H), 7.26 (t, J = 8.0
13
Hz, 1 H), 7.36–7.39 (m, 1 H), 7.41–7.44 (m, 2 H), 7.48–7.51 (m, 2 H); C NMR (CDCl3, 100
MHz) δ 113.9, 116.9, 122.7, 127.5, 129.3, 130.2, 131.9, 134.8, 137.89, 156.0.
5.1.4. 3-[(4-Fluorophenyl)sulfanyl]cyclohex-2-en-1-one (20)28
The procedure for making 17 was followed exactly, using 4-fluorobenzene-1-thiol (0.042
mL, 0.50 mmol), tosylate 18 (133 mg, 0.50 mmol), K2CO3 (413 mg, 2.50 mmol) and dry MeCN
(1 mL). Water (10 mL) was added and stirring was continued for 15 min. Flash
chromatography of the crude product over silica gel (3 × 15 cm), using 4:1 hexane-EtOAc, gave
20 (100 mg, 90%) as an oil: FTIR (CDCl3, cast) 2949, 1659, 1589, 1491, 1324, 1227, 1187 cm–
1; 1H NMR (CDCl3, 500 MHz) δ 2.03–2.06 (m, 2 H), 2.37 (t, J = 6.5 Hz, 2 H), 2.50–2.52 (m, 2
13
H), 5.41 (s, 1 H), 7.10–7.13 (m, 2 H), 7.44–7.47 (m, 2 H); C NMR (CDCl3, 125 MHz) δ 23.0
(t), 30.2 (t), 37.3 (t), 117.2 (d, 2JCF = 22.2 Hz), 120.9 (d, 4JCF = 3.6 Hz), 123.4 (d), 137.7 (d, 3JCF

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1
= 8.5 Hz), 164.0 (d, JCF = 252.0 Hz), 165.0 (s), 166.7 (s), 196.0 (s); exact mass (EI) m/z calcd
for C12H14FOS (M+) 222.0515, found 222.0515.
5.1.5. 2-Bromo-3-[(4-fluorophenyl)sulfanyl]cyclohex-2-en-1-one (20a)
The procedure for making 14 was followed exactly, using thio enone 20 (60 mg, 0.27
mmol), freshly crystallized NBS (53 mg, 0.30 mmol) and dry MeCN (1.0 mL). Flash
chromatography of the crude product over silica gel (3 × 15 cm), using 4:1 hexane-EtOAc, gave
20a (60 mg, 73%) as a solid: mp 135–136 °C; FTIR (CDCl3, cast) 3097, 3070, 2956, 2935,
1
1665, 1588, 1543, 1491, 1266, 1222, 1185 cm–1; H NMR (CDCl3, 500 MHz) δ 1.95 (quintet, J
= 6.5 Hz, 2 H), 2.16–2.19 (m, 2 H), 2.55 (t, J = 6.5 Hz, 2 H), 7.12–7.15 (m, 2 H), 7.54–7.56 (m,
2
2 H); 13C NMR (CDCl3, 125 MHz) δ 22.5 (t), 32.2 (t), 37.1 (t), 117.02 (d, JCF = 22.1 Hz),
4
3
1
117.03 (s), 124.6 (d, JCF = 3.6 Hz), 138.2 (d, JCF = 8.7 Hz), 163.8 (s), 164.1 (d, JCF = 252.6
Hz), 187.6 (s); exact mass (EI) m/z calcd for C12H1081BrFOS (M+) 301.9599, found 301.9597.
5.1.6. 3-[(4-Fluorophenyl)sulfanyl]phenol (20b)
The procedure for making 19 was followed exactly, using DBU (0.088 mL, 0.590 mmol)
and 20a (88.4 mg, 0.294 mmol) in dry MeCN (1.0 mL). Flash chromatography of the crude
product over silica gel (1 × 15 cm), using 3:7 hexane-CH2Cl2, gave 20b (39 mg, 60%) as an oil:
1
FTIR (CDCl3, cast) 3380, 3092, 1589, 1489, 1474, 1439, 1225, 1156 cm–1; H NMR (CDCl3,
500 MHz) δ 4.81 (s, 1 H), 6.65–6.67 (m, 2 H), 6.80–6.82 (m, 1 H), 7.02–7.06 (m, 2 H), 7.14 (td,
13
J = 8.0, 1.0 Hz, 1 H), 7.40–7.43 (m, 2 H); C NMR (CDCl3, 125 MHz) δ 113.7 (d), 115.9 (d),
116.5 (d), 116.6 (d, 2JCF = 22.4 Hz), 121.7 (d), 129.3 (d, 4JCF = 3.4 Hz), 130.2 (d), 134.9 (d, 3JCF
1
= 8.5 Hz), 138.7 (d), 156.0 (s), 162.7 (d, JCF = 248.5 Hz); exact mass (EI) m/z calcd for
C12H9OFS (M+) 220.0358, found 220.0355.
5.1.7. 3-[(4-Methoxyphenyl)sulfanyl]cyclohex-2-en-1-one (21)11
The procedure for making 17 was followed exactly, using 4-methoxybenzene-1-thiol
(0.12 mL, 1.00 mmol), tosylate 18 (266 mg, 1.00 mmol), K2CO3 (826 mg, 5.00 mmol) and dry
MeCN (2 mL) Flash chromatography of the crude product over silica gel (3 × 15 cm), using 4:1
hexane-EtOAc, gave 21 (210 mg, 90%) as an oil: FTIR (CDCl3, cast) 3004, 2962, 1654, 1587,
1
1578, 1494, 1325, 1290, 1250 cm–1; H NMR (CDCl3, 500 MHz) δ 2.04 (quintet, J = 6.5 Hz, 2
H), 2.36 (t, J = 6.5 Hz, 2 H), 2.49–2.51 (m, 2 H), 3.82 (s, 3 H), 5.42 (s, 1 H), 6.90–6.93 (m, 2 H),
7.36–7.38 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 22.9 (t), 30.1 (t), 37.3 (t), 55.4 (q), 115.5 (d),
118.5 (s), 120.6 (d), 137.0 (d), 161.2 (s), 168.0 (s), 196.1 (s); exact mass (EI) m/z calcd for
C13H14O2S (M+) 234.0715, found 234.0718.

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5.1.8. 2-Bromo-3-[(4-methoxyphenyl)sulfanyl]cyclohex-2-en-1-one (21a)
The procedure for making 14 was followed exactly, using thio enone 20 (86.2 mg, 0.353
mmol), freshly crystallized NBS (69.2 mg, 0.389 mmol) and dry MeCN (1.0 mL). Flash
chromatography of the crude product over silica gel (3 × 15 cm), using 4:1 hexane-EtOAc, gave
21a (81.9 mg, 74%) as a solid: mp 115–117 °C; FTIR (CDCl3, cast) 2971, 2947, 1662, 1590,
1454, 1438, 1253, 1187 cm–1; 1H NMR (CDCl3, 400 MHz) δ 1.93 (quintet, J = 6.4 Hz, 2 H), 2.18
(t, J = 6.4 Hz, 2 H), 2.53 (t, J = 6.4 Hz, 2 H), 3.84 (s, 3 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.46 (d, J =
8.8 Hz, 2 H); 13C NMR (CDCl3, 100 MHz) δ 22.5 (d), 32.1 (d), 37.2 (d), 55.5 (q), 115.2 (d),
116.2 (s), 119.7 (s), 137.6 (d), 161.4 (s), 165.6 (s), 187.7 (s); exact mass (EI) m/z calcd for
C13H1381BrO2S (M+) 313.9799, found 313.9796.
5.1.9. 3-[(4-Methoxyphenyl)sulfanyl]phenol (21b)
The procedure for making 19 was followed exactly, using DBU (0.035 mL, 0.240 mmol)
and 21a (37.5 mg, 0.120 mmol) in dry MeCN (1.0 mL). Flash chromatography of the crude
product over silica gel (1 × 15 cm), using successively hexane (ca 20 mL), 5% EtOAc-hexane
(ca 50 mL), 10% EtOAc-hexane (ca 100 mL), gave 21b (24 mg, 86%) as an oil: FTIR (CDCl3,
1
cast) 3396, 1591, 1493, 1439, 1289, 1248, 1173 cm–1; H NMR (CDCl3, 500 MHz) δ 3.85 (s, 3
H), 4.92 (br s, 1 H), 6.57–6.60 (m, 2 H), 6.74 (ddd, J = 5.0, 1.5, 1.0 Hz, 1 H), 6.90 (dd, J = 9.0,
13
3.0 Hz, 2 H); 7.10 (t, J = 8.0 Hz, 1 H), 7.43 (dd, J = 9.0, 3.0 Hz, 2 H); C NMR (CDCl3, 125
MHz) δ 55.4 (q), 112.8 (d), 114.4 (d), 115.1 (d), 120.2 (d), 123.6 (s), 130.0 (d), 135.9 (d), 140.6
(s), 156.0 (s), 160.1 (s); exact mass (EI) m/z calcd for C13H12O2S (M+) 232.0558, found
232.0561.
5.1.10. 3-[(4-Bromophenyl)sulfanyl]cyclohex-2-en-1-one (22)
The procedure for making 17 was followed exactly, using 4-bromobenzene-1-thiol (378
mg, 2.00 mmol), tosylate 18 (532 mg, 2.00 mmol), K2CO3 (1.652 g, 10 mmol) and dry MeCN (4
mL). Flash chromatography of the crude product over silica gel (2 × 25 cm), using 4:1 hexane-
EtOAc, gave 22 (443 mg, 78%) as an oil: FTIR (CDCl3, cast) 3076, 2950, 2889, 1649, 1579 cm–
1; 1H NMR (CDCl3, 500 MHz) δ 2.03–2.08 (m, 2 H), 2.38 (dd, J = 7.5, 1.0 Hz, 2 H), 2.51 (ddd, J
= 7.5, 6.0, 1.0 Hz, 2 H), 5.45 (apparent t, J = 1.5 Hz, 1 H), 7.33–7.35 (m, 2 H), 7.54–7.57 (m, 2
H); 13C NMR (CDCl3, 125 MHz) δ 22.9 (t), 30.2 (t), 37.2 (t), 121.1 (d), 125.0 (s), 127.1 (s),
133.1 (d), 137.0 (d), 165.9 (s), 195.9 (s); exact mass (EI) m/z calcd for C12H1181BrOS (M+)
283.9694, found 283.9691.
5.1.11. 2-Bromo-3-[(4-bromophenyl)sulfanyl]cyclohex-2-en-1-one (22a)

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The procedure for making 14 was followed exactly, using thio enone 22 (200 mg, 0.710
mmol), freshly crystallized NBS (151 mg, 0.840 mmol) and dry MeCN (1.5 mL). Flash
chromatography of the crude product over silica gel (1.2 × 25 cm), using 4:1 hexane-EtOAc,
gave 22b (100 mg, 78%) as a solid: mp 118–120 °C; FTIR (CDCl3, cast) 3079, 3060, 2957,
2931, 1666, 1538 cm–1; 1H NMR (CDCl3, 500 MHz) δ 1.94–1.99 (m, 2 H), 2.20 (dd, J = 6.0, 6.0
13
Hz, 2 H), 2.55–2.58 (m, 2 H), 7.41–7.44 (m, 2 H), 7.57–7.60 (m, 2 H); C NMR (CDCl3, 125
MHz) δ 22.5 (t), 32.3 (t), 37.1 (t), 117.4 (s), 125.4 (s), 128.2 (s), 132.9 (d), 137.4 (d), 163.0 (s),
187.6 (s); exact mass (EI) m/z calcd for C12H1079BrOS (M + H)+ 360.8892, found 360.8894.
5.1.12. 3-[(4-Bromophenyl)sulfanyl]phenol (22b)
The procedure for making 19 was followed exactly, using DBU (0.08 mL, 0.53 mmol)
and 22a (97 mg, 0.26 mmol) in dry MeCN (1.5 mL). Flash chromatography of the crude product
over silica gel (1 × 30 cm), using successively hexane (ca 20 mL), 5% EtOAc-hexane (ca 50
mL), 10% EtOAc-hexane (ca 100 mL), gave 22b (60 mg, 79%) as an oil: FTIR (CDCl3, cast)
3375, 3059, 2954, 2925, 1583, 1472 cm–1; 1H NMR (CDCl3, 500 MHz) δ 4.84 (br s, 1 H), 6.72
(ddd, J = 8.0, 2.5, 0.5 Hz, 1 H), 6.77 (m, 1 H), 6.90 (ddd, J = 8.0, 1.5, 0.5 Hz, 1 H), 7.16–7.26
(m, 3 H), 7.43 (dt, J = 9.0, 2.0 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ 114.5 (d), 117.4 (d),
121.4 (s), 123.2 (d), 130.4 (d), 132.4 (d), 132.9 (d), 134.5 (s), 136.8 (s), 156.0 (s); exact mass
79
(EI) m/z calcd for C12H8 BrOS (M – H)– 278.9485, found 278.9477.
5.1.13. 3-[(4-Methylphenyl)sulfanyl]cyclohex-2-en-1-one (23)11
The procedure for making 17 was followed exactly, using 4-methylbenzene-1-thiol (248
mg, 2.00 mmol), tosylate 18 (532 mg, 2.00 mmol), K2CO3 (1.652 g, 10.00 mmol) and dry MeCN
(4 mL). Flash chromatography of the crude product over silica gel (2 × 25 cm), using 4:1
hexane-EtOAc, gave 23 (401 mg, 93%) as a solid: mp 45–48 °C; FTIR (CDCl3, cast) 3023,
1
2948, 2866, 1659, 1578 cm–1; H NMR (CDCl3, 500 MHz) δ 2.02–2.07 (apparent dt, J = 13.0,
6.0 Hz, 2 H), 2.35–2.38 (m, 2 H), 2.38 (s, 3 H), 2.52 (ddd, J = 6.0, 6.0, 1.0 Hz, 2 H), 5.46
(apparent t, J = 1.0 Hz, 1 H), 7.21–7.23 (m, 2 H), 7.35 (dt, J = 8.0, 2.0 Hz, 2 H); 13C NMR
(CDCl3, 125 MHz) δ 21.3 (q), 23.0 (t), 30.2 (t), 37.3 (t), 120.7 (d), 124.4 (s), 130.7 (d), 135.4 (d),
140.6 (s), 167.5 (s), 196.1 (s); exact mass (EI) m/z calcd for C13H14OS (M+) 218.0765, found
218.0766.
5.1.14. 2-Bromo-3-[(4-methylphenyl)sulfanyl]cyclohex-2-en-1-one (23a)
The procedure for making 14 was followed exactly, using thio enone 23 (209 mg, 1.00
mmol), freshly crystallized NBS (195 mg, 1.10 mmol) and dry MeCN (1.5 mL). Flash
chromatography of the crude product over silica gel (1.2 × 25 cm), using 4:1 hexane-EtOAc,

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13
gave 23a (210 mg, 74%) as a solid: mp 128–130 °C; FTIR (CDCl3, cast) 3052, 3033, 2956,
2931, 1662, 1542 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.91–2.0 (m, 2 H), 2.20 (dd, J = 6.0, 6.0
Hz, 2 H), 2.41 (s, 3 H), 2.55 (dd, J = 7.0, 7.0 Hz, 2 H), 7.23–7.25 (m, 2 H), 7.42–7.44 (m, 2 H);
13C NMR (CDCl3, 125 MHz) δ 21.4 (q), 22.5 (t), 32.1 (t), 37.2 (t), 116.5 (s), 125.6 (s), 130.4 (d),
135.9 (d), 140.9 (s), 164.9 (s), 187.7 (s); exact mass (EI) m/z calcd for C13H1381BrOS (M+)
297.9850, found 297.9851.
5.1.15. 3-[(4-Methylphenyl)sulfanyl]phenol (23b)19
The procedure for making 19 was followed exactly, using DBU (0.10 mL, 0.67 mmol)
and 23a (102 mg, 0.33 mmol) in dry MeCN (1.5 mL). Flash chromatography of the crude
product over silica gel (1 × 30 cm), using successively hexane (ca 20 mL), 5% EtOAc-hexane
(ca 50 mL), 10% EtOAc-hexane (ca 100 mL), gave 23b (56 mg, 75%) as an oil: FTIR (CDCl3,
1
cast) 3383, 3022, 2920, 2862, 1584, 1474 cm–1; H NMR (CDCl3, 500 MHz) δ 2.37 (s, 3 H),
4.90 (br s, 1 H), 6.63–6.68 (m, 2 H), 6.82–6.85 (m, 1 H), 7.11–7.17 (m, 3 H), 7.35 (dd, J = 6.5,
13
2.0 Hz, 2 H); C NMR (CDCl3, 125 MHz) δ 21.2 (q), 113.4 (d), 115.7 (d), 121.6 (d), 130.1 (d),
130.2 (d), 130.3 (s), 133.1 (d), 138.1 (s), 139.2 (s), 155.9 (s); exact mass (electrospray) m/z calcd
for C13H11OS (M – H)— 215.0536, found 215.0534.
5.1.16. 3-[(2-Methylphenyl)sulfanyl]cyclohex-2-en-1-one (24)
The procedure for making 17 was followed exactly, using 2-methylbenzene-1-thiol (0.30
mL, 2.46 mmol), tosylate 18 (655 mg, 2.45 mmol), K2CO3 (1.70 g, 12.3 mmol) and dry MeCN
(4 mL). Flash chromatography of the crude product over silica gel (2 × 25 cm), using 4:1
hexane-EtOAc, gave 24 (500 mg, 93%) as an oil: FTIR (CDCl3, cast) 3059, 2949, 2866, 1656,
1
1578 cm–1; H NMR (CDCl3, 500 MHz) δ 2.06 (quintet, J = 6.5 Hz, 2 H), 2.37–2.39 (m, 5 H),
2.54 (td, J = 6.0, 1.0 Hz, 2 H), 5.32 (apparent t, J = 1.0 Hz, 1 H), 7.21–7.24 (m, 1 H), 7.30–7.37
(m, 2 H), 7.46 (ddd, J = 7.5, 1.0, 0.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 20.4 (q), 23.0 (t),
30.2 (t), 37.3 (t), 120.4 (d), 127.3 (s), 127.3 (d), 130.8 (d), 131.2 (d), 136.6 (d), 142.7 (s), 165.9
(s), 196.1 (s); exact mass (EI) m/z calcd for C13H14OS (M+) 218.0765, found 218.0765.
5.1.17. 2-Bromo-3-[(2-methylphenyl)sulfanyl]cyclohex-2-en-1-one (24a)
The procedure for making 14 was followed exactly, using thio enone 24 (224 mg, 1.03
mmol), freshly crystallized NBS (200 mg, 1.13 mmol) and dry MeCN (1.5 mL). Flash
chromatography of the crude product over silica gel (1.2 × 25 cm), using 4:1 hexane-EtOAc,
gave 24a (250 mg, 82%) as a solid: mp 111–113 °C; FTIR (CDCl3, cast) 3060, 3011, 2950,
2923, 1671, 1537 cm–1; 1H NMR (CDCl3, 500 MHz) δ 1.91–1.96 (m, 2 H), 2.1 (t, J = 6.0 Hz, 2
H), 2.45 (s, 3 H), 2.56 (dd, J = 7.5, 6.0 Hz, 2 H), 7.25–7.27 (m, 1 H), 7.33–7.37 (m, 1 H), 7.40

ACCEPTED MANUSCRIPT
14
13
(ddd, J = 7.5, 1.5, 1.5 Hz, 1 H), 7.54 (dd, J = 7.5, 1.5 Hz, 1 H); C NMR (CDCl3, 125 MHz) δ
21.2 (q), 22.5 (t), 31.7 (t), 37.2 (t), 117.3 (s), 127.2 (d), 128.7 (s), 130.9 (d), 131.2 (d), 137.0 (d),
143.1 (s), 164.4 (s), 187.7 (s); exact mass (EI) m/z calcd for C13H1379BrOS (M+) 295.9871, found
295.9872.
5.1.18. 3-[(2-Methylphenyl)sulfanyl]phenol (24b)
The procedure for making 19 was followed exactly, using DBU (0.10 mL, 0.67 mmol)
and 24a (95 mg, 0.32 mmol) in dry MeCN (1.5 mL). Flash chromatography of the crude product
over silica gel (1 × 30 cm), using successively hexane (ca 20 mL), 5% EtOAc-hexane (ca 50
mL), and 10% EtOAc-hexane (ca 100 mL), gave 24b (54 mg, 78%) as an oil: FTIR (CDCl3,
1
cast) 3376, 3060, 2961, 2923, 1584, 1473 cm–1; H NMR (CDCl3, 500 MHz) δ 2.41 (s, 3 H),
4.76 (br s, 1 H), 6.61–6.62 (m, 1 H), 6.66 (dd, J = 8.0, 1.0 Hz, 1 H), 6.80 (dd, J = 8.0, 1.0 Hz, 1
H), 7.15 (t, J = 8.0 Hz, 1 H), 7.18–7.21 (m, 1 H), 7.26–7.30 (m, 2 H), 7.41 (d, J = 8.0 Hz, 1 H);
13C NMR (CDCl3, 125 MHz) δ 20.7 (q), 113.3 (d), 115.5 (d), 121.4 (d), 126.8 (d), 128.5 (d),
130.2 (d), 130.8 (d), 132.8 (s), 134.0 (d), 138.3 (s), 140.8 (s), 156.0 (s); exact mass (electrospray)
m/z calcd for C13H11OS (M – H)– 215.0536, found 215.0538.
5.1.19. Methyl 2-[(3-oxocyclohex-1-en-1-yl)sulfanyl]benzoate (25)
The procedure for making 17 was followed exactly, using methyl 2-sulfanylbenzoate29
(168 mg, 1.00 mmol), tosylate 18 (266 mg, 1.00 mmol), K2CO3 (826 mg, 5.00 mmol) and dry
MeCN (2 mL). Flash chromatography of the crude product over silica gel (3 × 15 cm), using 4:1
hexane-EtOAc, gave 25 (222.5 mg, 85%) as an oil: FTIR (CDCl3, cast) 1731, 1656, 1578, 1467,
1293, 1271 cm–1; 1H NMR (CDCl3, 500 MHz) δ 2.05 (quintet, J = 6.5 Hz, 2 H), 2.38 (t, J = 6.5
Hz, 1 H), 2.52–2.54 (m, 2 H), 3.88 (s, 3 H), 5.57 (s, 1 H), 7.46–7.53 (m, 2 H), 7.56–7.58 (m, 1
H), 7.89 (dd, J = 6.0, 1.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 22.9 (t), 30.4 (t), 37.2 (t), 52.5
(q), 122.4 (d), 129.2 (d), 129.8 (s), 131.2 (d), 132.4 (d), 135.2 (s), 137.1 (d), 165.6 (s), 166.5 (s),
196.3 (s); exact mass (EI) m/z calcd for C14H14O3S (M+) 262.0664, found 262.0663.
5.1.20. Methyl 2-[(2-bromo-3-oxocyclohex-1-en-1-yl)sulfanyl]benzoate (25a)
The procedure for making 14 was followed exactly, using thio enone 25 (204.4 mg, 0.780
mmol), freshly crystallized NBS (153.6 mg, 0.860 mmol) and dry MeCN (1 mL). Flash
chromatography of the crude product over silica gel (3 × 15 cm), using 4:1 hexane-EtOAc, gave
25a (160 mg, 60%) as a solid: mp 117–120 °C; FTIR (CDCl3, cast) 3089, 1726, 1668, 1569,
1351, 1136, 1118 cm–1; 1H NMR (CDCl3, 500 MHz) δ 1.95 (quintet, J = 6.0 Hz, 2 H), 2.26 (t, J
= 6.0 Hz, 2 H), 2.57 (t, J = 6.5 Hz, 2 H), 3.90 (s, 3 H), 7.54–7.56 (m, 2 H), 7.64–7.66 (m, 1 H),
7.87–7.89 (m, 1 H); 13C NMR (CDCl3, 125 MHz) δ 22.6 (t), 32.3 (t), 37.3 (t), 52.8 (q), 117.5 (s),

ACCEPTED MANUSCRIPT
15
129.2 (s), 130.5 (d), 130.8 (d), 132.1 (d), 136.7 (s), 137.8 (d), 164.4 (s), 166.9 (s), 188.0 (s);
exact mass (EI) m/z calcd for C14H1381BrO3S (M+) 341.9748, found 341.9752.
5.1.21. Methyl 2-[(3-hydroxyphenyl)sulfanyl]benzoate (25b)
The procedure for making 19 was followed exactly, using DBU (0.08 mL, 0.54 mmol)
and 25a (92 mg, 0.27 mmol) in dry MeCN (1 mL). Flash chromatography of the crude product
over silica gel (3 × 20 cm), using successively hexane (ca 100 mL), 5% EtOAc-hexane (ca 100
mL), and 10% EtOAc-hexane (ca 100 mL) and 20% EtOAc-hexane (ca 100 mL), gave 25b (50.5
1
mg, 72%) as an oil: FTIR (CDCl3, cast) 3409, 1714, 1693, 1587, 1307, 1273, 1255 cm–1; H
NMR (CDCl3, 500 MHz) δ 3.97 (s, 3 H), 5.24 (br s, 1 H), 6.89–6.92 (m, 2 H), 7.08–7.14 (m, 3
H), 7.24–7.31 (m, 2 H), 7.96 (dd, J = 6.5, 1.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 52.3 (q),
116.4 (d), 121.9 (d), 124.5 (d), 126.9 (s), 127.6 (d), 127.8 (d), 130.8 (d), 131.0 (d), 132.5 (d),
133.9 (s), 142.9 (s), 156.5 (s), 167.2 (s); exact mass (EI) m/z calcd for C14H12O3S (M+) 260.0507,
found 260.0508.
5.1.22. 3-(Benzylsulfanyl)cyclohex-2-en-1-one (26)30
The procedure for making 17 was followed exactly, using phenylmethanethiol (0.12 mL,
1.0 mmol), tosylate 18 (266 mg, 1.00 mmol), K2CO3 (826 mg, 5.00 mmol) and dry MeCN (2
mL). Flash chromatography of the crude product over silica gel (3 × 15 cm), using 4:1 hexane-
EtOAc, gave 26 (179 mg, 82%) as a solid: mp 75–77 °C; FTIR (CDCl3, cast) 3054, 1654, 1573,
1452, 1295, 1264 cm–1; 1H NMR (CDCl3, 500 MHz) δ 2.03 (quintet, J = 6.0 Hz, 2 H), 2.40 (t, J
= 6.0 Hz, 2 H), 2.45–2.47 (m, 2 H), 4.03 (s, 2 H), 5.95 (s 1 H), 7.26–7.34 (m, 5 H; 13C NMR
(CDCl3, 125 MHz) δ 23.0 (t), 30.7 (t), 35.9 (t), 37.4 (t), 120.0 (d), 127.8 (d), 128.9 (d), 134.7 (s),
165.2 (s), 195.8 (s); exact mass (EI) m/z calcd for C13H14OS (M+) 218.0765, found 218.0767.
5.1.23. 3-(Benzylsulfanyl)-2-bromocyclohex-2-en-1-one (26a)
The procedure for making 14 was followed exactly, using thio enone 26 (54.5 mg, 0.250
mmol), freshly crystallized NBS (49.2 mg, 0.275 mmol) and dry MeCN (1.0 mL). Flash
chromatography of the crude product over silica gel (3 × 15 cm), using 4:1 hexane-EtOAc, gave
26a (54 mg, 72%) as a solid: mp 112-114 °C; FTIR (CDCl3, cast) 2950, 2666, 1667, 1532,
1
1494, 1453, 1261, 1184 cm–1; H NMR (CDCl3, 500 MHz) δ 2.07 (quintet, J = 6.5 Hz, 2 H),
2.55–2.58 (m, 2 H), 2.70 (t, J = 6.0 Hz, 2 H), 4.15 (s, 2 H), 7.30–7.38 (m, 5 H); 13C NMR
(CDCl3, 125 MHz) δ 22.4 (t), 31.2 (t), 36.6 (t), 36.9 (t), 117.1 (s), 127.9 (d), 128.8 (d), 129.0 (d),
135.0 (s), 163.7 (s), 187.3 (s); exact mass (EI) m/z calcd for C13H1381BrOS (M+) 297.9850, found
297.9856.

ACCEPTED MANUSCRIPT
16
5.1.24. 3-(Benzylsulfanyl)phenol (26b)24
The procedure for making 19 was followed exactly, using DBU (0.050 mL, 0.318 mmol)
and 26a (31.5 mg, 0.106 mmol) in dry MeCN (1.0 mL). Flash chromatography of the crude
product over silica gel (1 × 15 cm), using 3:7 hexane-CH2Cl2, gave 26b (15 mg, 65%) as an oil:
1
FTIR (CDCl3, cast) 3386, 3084, 3061, 1581, 1493, 1475, 1247, 1216 cm–1; H NMR (CDCl3,
400 MHz) δ 4.12 (s, 2 H), 4.90 (br s, 1 H), 6.64 (dd, J = 8.0, 2.0 Hz, 1 H), 6.78 (t, J = 2.0 Hz, 1
13
H), 6.88 (d, J = 8.0 Hz, 1 H), 7.13 (t, J = 8.0 Hz, 1 H), 7.23–7.33 (m, 5 H); C NMR (CDCl3,
125 MHz) δ 38.7 (t), 113.4 (d), 116.1 (d), 121.8 (d), 127.3 (d), 128.6 (d), 128.9 (d), 129.9 (d),
137.3 (s), 138.2 (s) 155.8 (s); exact mass (EI) m/z calcd for C13H12OS (M+) 216.0609, found
216.0605.
5.1.25. 5-Phenyl-3-(phenylsulfanyl)cyclohex-2-en-1-one (27)
(a) 3-Oxo-5-phenylcyclohex-1-en-1-yl 4-methylbenzene-1-sulfonate31
Et3N (0.5 mL, 3.6 mmol) was added to a stirred solution of commercial 3-hydroxy-5-
phenylcyclohex-2-en-1-one (565 mg, 3.00 mmol) and TsCl (573 mg, 3.00 mmol) in dry THF (10
mL), and stirring was continued overnight (N2 atmosphere). Water (15 mL) was added and
stirring was continued for 30 min. The mixture was extracted with Et2O (3 × 20 mL). The
combined organic extracts were washed with brine, dried (MgSO4) and evaporated to afford 3-
oxo-5-phenylcyclohex-1-en-1-yl 4-methylbenzene-1-sulfonate (946.5 mg, 92%) as a solid, which
was used directly in the next step. The material had: mp 86–88 °C; FTIR (CDCl3, cast) 3063,
1678, 1635, 1426, 1376, 1194, 1179 cm–1; 1H NMR (CDCl3, 500 MHz) δ 2.48 (s, 3 H), 2.56 (dd,
J = 16.0, 13.0 Hz, 1 H), 2.65 (dd, J = 16.0, 4.0 Hz, 1 H), 2.74 (dd, J = 6.5, 1.5 Hz, 2 H), 3.31–
3.38 (m, 1 H), 5.90 (s, 1 H), 7.17–7.20 (m, 2 H), 7.25–7.29 (m, 1 H), 7.32–7.35 (m, 2 H), 7.37–
7.39 (m, 2 H), 7.81–7.84 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 21.8 (d), 36.4 (t), 39.2 (q),
43.6 (t), 116.6 (d), 126.6 (d), 127.4 (d), 128.3 (d), 129.0 (d), 130.2 (d), 132.5 (s), 141.6 (s), 146.3
(s), 167.3 (s), 197.8 (s); exact mass (EI) m/z calcd for C19H18O4S (M+) 342.0926, found
342.0926.
(b) 5-Phenyl-3-(phenylsulfanyl)cyclohex-2-en-1-one (27)
The procedure for making 17 was followed exactly, using PhSH (0.105 mL, 1.00 mmol),
3-oxo-5-phenylcyclohex-1-en-1-yl 4-methylbenzene-1-sulfonate (342 mg, 1.00 mmol), K2CO3
(826 mg, 12.3 mmol) and dry MeCN (2 mL). Flash chromatography of the crude product over
silica gel (3 × 15 cm), using 4:1 hexane-EtOAc, gave 27 (234.2 mg, 80%) as a solid: mp 85–87
°C; FTIR (CDCl3, cast) 3059, 3028, 1653, 1577, 1440, 1290, 1255, 1040 cm–1; 1H NMR (CDCl3,
500 MHz) δ 2.58–2.83 (m, 4 H), 3.37–3.44 (m, 1 H), 5.56 (d, J = 1.5 Hz, 1 H), 7.24–7.29 (m, 3
H), 7.34–7.37 (m, 2 H), 7.42–7.45 (m, 3 H), 7.49–7.51 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ
37.8 (s), 41.0 (d), 44.2 (s), 120.7 (d), 126.8 (d), 127.2 (d), 127.9 (d), 128.9 (s), 130.0 (d), 130.3

ACCEPTED MANUSCRIPT
17
(d), 135.5 (d), 142.6 (s), 166.0 (s), 195.5 (s); exact mass (EI) m/z calcd for C18H16OS (M+)
280.0922, found 280.0923.
5.1.26. 3-Bromo-5-phenyl-3-(phenylsulfanyl)cyclohex-2-en-1-one (27a)
The procedure for making 14 was followed exactly, using thio enone 27 (200 mg, 0.714
mmol), freshly crystallized NBS (140.6 mg, 0.786 mmol) and dry MeCN (1.0 mL). Flash
chromatography of the crude product over silica gel (3 × 15 cm), using 9:1 hexane-EtOAc, gave
27a (197 mg, 77%) as a solid: mp 128–132 °C; FTIR (CDCl3, cast) 3059, 1671, 1538, 1453,
1
1440, 1264, 1242 cm–1; H NMR (CDCl3, 500 MHz) δ 2.39–2.48 (m, 2 H), 2.76 (dd, J = 16.0,
13.0 Hz, 1 H), 2.87 (ddd, J = 11.5, 4.0, 1.5 Hz, 1 H), 3.30–3.37 (m, 1 H), 7.06–7.08 (m, 2 H),
7.20–7.30 (m, 3 H), 7.38–7.46 (m, 3 H), 7.52–7.55 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ
39.2 (t), 40.4 (d), 43.9 (t), 116.9 (d), 126.6 (d), 127.3 (d), 128.8 (d), 128.9 (s), 129.8 (d), 130.6
(d), 135.9 (d), 141.8 (s), 163.0 (s), 187.2 (s); exact mass (EI) m/z calcd for C18H1581BrOS (M+)
360.0006, found 360.0002.
5.1.27. 5-Phenyl-3-(phenylsulfanyl)phenol (27b)
The procedure for making 19 was followed exactly, using DBU (0.025 mL, 0.17 mmol)
and 27a (30.6 mg, 0.085 mmol) in dry MeCN (1.0 mL). Flash chromatography of the crude
product over silica gel (1 × 15 cm), using 3:7 hexane-CH2Cl2, gave 27b (17 mg, 63%) as an oil:
1
FTIR (CDCl3, cast) 3391, 3059, 2953, 1586, 1570, 1476, 1449, 1196 cm–1; H NMR (CDCl3,
500 MHz) δ 4.83 (s, 1 H), 6.71 (dd, J = 2.0, 1.5 Hz, 1 H), 6.91 (dd, J = 2.0, 1.5 Hz, 1 H), 7.15 (t,
J = 1.5 Hz, 1 H), 7.27–7.36 (m, 4 H), 7.40–7.45 (m, 4 H), 7.50–7.52 (m, 2 H); 13C NMR (CDCl3,
125 MHz) δ 112.9 (d), 115.7 (d), 121.6 (d), 127.1 (d), 127.6 (d), 127.8 (d), 128.8 (d), 129.4 (d),
132.0 (d), 134.7 (s), 138.4 (s), 140.1 (s), 143.7 (s), 156.3 (s); exact mass (EI) m/z calcd for
C18H14OS (M+) 278.0765, found 279.0771.
5.1.28. 3-(tert-Butylsulfanyl)cyclohex-2-en-1-one (28)
The procedure for making 17 was followed exactly, using 2-methylpropane-2-thiol (0.11
mL, 1.00 mmol), tosylate 18 (266 mg, 1.00 mmol), K2CO3 (826 mg, 5.00 mmol) and dry MeCN
(2 mL). Flash chromatography of the crude product over silica gel (3 × 15 cm), using 4:1
hexane-EtOAc, gave 28 (73.4 mg, 40%) as an oil: FTIR (CDCl3, cast) 2963, 1659, 1570, 1457,
1338 cm–1; 1H NMR (CDCl3, 500 MHz) δ 1.48 (s, 9 H), 1.99 (quintet J = 6.0 Hz, 2 H), 2.36–2.38
13
(m, 4 H), 6.11 (s, 1 H); C NMR (CDCl3, 125 MHz) δ 22.8 (t), 30.4 (q), 31.7 (t), 37.2 (t), 47.4
(s), 122.6 (d), 164.5 (s), 196.0 (s); exact mass (EI) m/z calcd for C10H16OS (M+) 184.0922, found
184.0922.

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5.1.29. 2-Bromo-3-(tert-butylsulfanyl)cyclohex-2-en-1-one (28a)
The procedure for making 14 was followed exactly, using thio enone 28 (65 mg, 0.35
mmol), freshly crystallized NBS (63.2 mg, 0.350 mmol) and dry MeCN (0.5 mL). Flash
chromatography of the crude product over silica gel (3 × 15 cm), using 4:1 hexane-EtOAc, gave
28a (40 mg, 42%) as a solid: mp 102–103 °C; FTIR (CDCl3, cast) 2965, 1661, 1517, 1472,
1
1262, 1248 cm–1; H NMR (CDCl3, 500 MHz) δ 1.56 (s, 9 H), 2.09 (quintet, J = 6.0 Hz, 2 H),
13
2.60 (t, J = 6.0 Hz, 2 H), 2.93 (t, J = 6.0 Hz, 2 H); C NMR (CDCl3, 125 MHz) δ 22.8 (t), 32.3
(q), 32.9 (t), 37.4 (t), 49.6 (s), 119.2 (s), 164.6 (s), 187.8 (s); exact mass (EI) m/z calcd for
C10H1581BrOS (M+) 264.0006, found 264.0004.
5.1.30. 3-(tert-Butylsulfanyl)phenol (28b)
The procedure for making 19 was followed exactly, using DBU (0.034 mL, 0.226 mmol)
and 28a (29.5 mg, 0.113 mmol) in dry MeCN (1 mL). Flash chromatography of the crude
product over silica gel (1 × 15 cm), using 2:8 hexane-CH2Cl2, gave 28b (5 mg, 25%) as an oil:
1
FTIR (CDCl3, cast) 3355, 2961, 1583, 1469, 1456, 1245, 1210, 1159 cm–1; H NMR (CDCl3,
500 MHz) δ 1.29 (s, 9 H), 4.76 (s, 1 H), 6.84 (dd, J = 8.0, 2.5 Hz, 1 H), 7.03 (t, J = 1.5 Hz, 1 H),
7.11 (d, J = 7.5 Hz, 1 H), 7.20 (t, J = 8.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 31.0 (q), 46.1
(s), 115.9 (d), 124.0 (d), 129.4 (d), 129.9 (d), 134.1 (s), 155.2 (s); exact mass (EI) m/z calcd for
C10H14OS (M+) 182.0765, found 182.0764.
Acknowledgements
We thank NSERC for financial support.
Appendix A. Supplementary data
Supplementary data related to this article can be found at https://doi.org/
References
(1) Shao, W.; Clive, D. L. J. J. Org. Chem. 2015, 80, 3211–3216.
(2) Shao, W.; Clive, D. L. J. J. Org. Chem. 2015, 80, 12280–12287.
(3) Yu, G.; Clive, D. L. J. J. Org. Chem. 2016, 81, 8470–8484.
(4) (a) Kohno, Y.; Tanaka, K.; Kuriyama, K.; Hori, W. European Patent 1602660 A1,
December 7, 2005. (b) Scott, I. L.; Ralph, J. M.; Voss, M. E. WO Patent 2005/055939 A2,
June 23, 2005. (c) Scott, I. L.; Ralph, J. M.; Voss, M. E. WO Patent 2005/055943 A2,
June 23, 2005.

ACCEPTED MANUSCRIPT
19
(5) (a) Karkola, S.; Lilienkampf, A.; Wähälä, K. ChemMedChem 2008, 3, 461–472. (b) Jílek,
J.; Šindelář, K.; Pomykáček, J.; Kmoníček, V.; Šedivý, Z.; Hrubantová, M.; Holubek, J.;
Svátek, E.; Ryska, M.; Koruna, I.; Valchář, M.; Dlabač, A.; Metyšová, J.; Dlohožková, N.;
Protiva, M. Coll. Czech. Chem. Commun. 1989, 54, 3294–3338. (c) Šindelář, K.;
Pomykáček, J.; Holubek, J.; Svátek, E.; Valchář, M.; Dobrovský, K.; Metyšová, J.;
Polívka, Z. Coll. Czech. Chem. Commun. 1991, 56, 459–477. (d) Šindelář, K.; Kmoníček,
V.; Hrubantová, M.; Polívka, Z. Coll. Czech. Chem. Commun. 1992, 57, 194–203.
(6) Alexander, R.; Balasundaram, A.; Batchelor, M.; Brookings, D.; Crépy, K.; Crabbe, T.;
Deltent, M.-F.; Driessens, F.; Gill, A.; Harris, S.; Hutchinson, G.; Kulisa, C.; Merriman,
M.; Mistry, P.; Parton, T.; Turner, J.; Whitcombe, I.; Wright, S. Bioorg. Med. Chem. Lett.
2008, 18, 4316–4320.
(7) (a) Piers, E.; Grierson, J. R.; Lau, C. K.; Nagakura, I. Can. J. Chem. 1982, 60, 210—223.
(b) Algi, F.; Hökelek, T.; Balci, M. J. Chem. Res. 2004, 658–660.
(8) Joseph, J. T.; Sajith, A. M.; Ningegowda, R. C.; Nagaraj, A.; Rangappa, K. S.;
Shashikanth, S. Tetrahedron Lett. 2015, 56, 5106–5111.
(9) Neises, B.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1978, 17, 522–524.
(10) Dinesh, B.; Manjunath, H. R.; Naveen, S.; Abiraj, K.; Ramesh Baba, A.; Channe Gowda,
D.; Sridhar, M. A.; Shashidhara Prasad, J. Mol. Cryst. Liq. Cryst. 2010, 517, 161–166.
(11) Kumari, K.; Singh, K. N. Synlett 2014, 25, 213–216.
(12) Thomas, J. B.; Mascarella, S. W.; Rothman, R. B.; Partilla, J. S.; Xu, H.; McCullough, K.
B.; Dersch, C. M.; Cantrell, B. E.; Zimmerman, D. M.; Caroll, F. I. J. Med. Chem. 1998,
41, 1980–1990.
(13) Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem. Int. Ed. 2006, 45, 3109–3112.
(14) (a) Shepard, M. S.; Carreira, E. M. Tetrahedron 1997, 53, 16253–16276. (b) Van Dort, P.
C.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116, 5657–5661.
(15) Koreeda, M.; Wang, Y.; Zhang, L. Org. Lett. 2002, 4, 3329–3332.
(16) (a) Kirchlechner, R. Chem. Ber. 1982, 115, 2461–2466. (b) Arnoldi, A.; Bonsignori, A.;
Melloni, P.; Merlini, L.; Quadri, M. L.; Rossi, A. C.; Valsecchi, M. J. Med. Chem. 1990,
33, 2865–2869.
(17) (a) Ali, M. H.; Hartman, M.; Lamp, K.; Schmitz, C.; Wencewicz, T. Synth. Commun. 2006,
36, 1769–1777. (b) Harville, R.; Reed, Jr., S. F. J. Org. Chem. 1968, 33, 3976–3977.
(18) (a) Mitchell, R. H.; Lai, Y.-H.; Williams, R. V. J. Org. Chem. 1979, 44, 4733–4735. (b)
Townsend, C. A.; Davis, S. G.; Christensen, S. B.; Link, J. C.; Lewis, C. P. J. Am. Chem.
Soc. 1981, 103, 6885–6888.
(19) Zhang, J.; Jiang, Q.; Yang, D.; Zhao, X.; Dong, Y.; Liu, R. Chem. Sci. 2015, 6, 4674–4680.
(20) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517–3520.

ACCEPTED MANUSCRIPT
20
(21) Fernández-Rodríguez, M. A.; Hartwig, J. F. J. Org. Chem. 2009, 74, 1663–1672.
(22) Musolino, B. J.; Kabalka, G. W. Heterocycles 2015, 90, 271–297.
(23) Ko, J.; Ham, J.; Yang, I.; Chin, J.; Nam, S.-J.; Kang, H. Tetrahedron Lett. 2006, 47, 7101–
7106.
(24) (a) Mahfouz, A. M. M.; Metcalf, R. L.; Fukuto, T. R. J. Agr. Food Chem. 1969, 17, 917–
922. (b) Bartkovitz, D. J.; Chen, Y.; Chu, X.-J.; Luk, K.-C.; Rossman, P. L.; So, S.-S US
Patent 2007060607 A1, March 15, 2007.
(25) Liu, Y.; Kim, J.; Seo, H.; Park, S.; Chae, J. Adv. Synth. Catal. 2015, 357, 2205–2212.
(26) Chen, X.; Liu, X.; Martinez, J. S.; Mohr, J. T. Tetrahedron 2016, 72, 3653–3665.
(27) Amarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals, 7th ed.; Elsevier:
Oxford, 2013; p 121.
(28) Guo, S.-R.; Yuan, Y.-Q. Synth. Commun. 2008, 38, 2722–2730.
(29) Viani, F.; Rossi, B.; Panzeri, W.; Merlini, L.; Martorana, A.; Polissi, A.; Galante, Y. M.
Tetrahedron 2017, 73, 1745–1761.
(30) Kowalski, C. J.; Fields, K. W. J. Org. Chem. 1981, 46, 197–201.
(31) Wang, F.; Chiba, K.; Tada, M. J. Chem. Soc., Perkin Trans. 1 1992, 1897–1900.