Iodine-Mediated Direct Generation of o-Quinone Methides at Room Temperature: A Facile Protocol for the Synthesis of ortho-Hydroxybenzyl Thioethers

Article abstract of DOI:10.1002/asia.201800233

An iodine-mediated preparation of ortho-quinone methides (o-QMs) from ortho-hydroxybenzyl alcohols by a C?O bond scission strategy is described. The in situ generated o-QMs were then employed for C?S bond formation by thio-Michael addition of thiols to provide the ortho-hydroxybenzyl thioethers (o-HBT) in moderate to excellent yields.

Full text of DOI:10.1002/asia.201800233

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Iodine-Mediated Direct C-O Bond Scission Generate o-Quinone
Methides under Room Temperature: A Facile Access to Efficient
Synthesis of Phenol-Thioethers
Authors: Chin-Fa Lee, Sidick Basha, Chia-Wei Chen, and Mallikarjuna
Reddy
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To be cited as: Chem. Asian J. 10.1002/asia.201800233
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10.1002/asia.201800233
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Iodine-Mediated Direct Generation of o-Quinone Methides at
Room Temperature: A Facile Protocol for the Synthesis of ortho-
Hydroxy Benzyl Thioethers
†
R. Sidick Basha,†[a] Chia-Wei Chen, Daggula Mallikarjuna Reddy, and Chin-Fa Lee*[a,b,c]
[a]
Abstract: An iodine-mediated preparation of ortho-quinone methides
(o-QMs) from ortho-hydroxybenzyl alcohols via a C-O bond scission
strategy is described. The in situ generated o-QMs were then
employed for C-S bond formation via thio-michael addition reaction of
thiols to provide the ortho-hydroxy benzyl thioethers (o-HBT) in
moderate to excellent yields.
temperature,9 harsh reaction conditions with peculiar leaving
groups in aromatic auxiliary systems. Therefore, the development
of a simple and efficient method for the synthesis of o-HBT is
highly desirable.
Introduction
Sulfur-containing compounds are privileged motifs possess
significant applications in pharmaceutical industry1a-c and material
sciences.1d-g In US retail sales and prescriptions of top 200 drugs,
above 20% of them are sulfur embedded drugs.1b The driven
pioneering efforts on C-S bond forming transformations could
access valuable chemical ingredients in drugs, and also act as
versatile precursor in construction of complex natural products.2
Thioethers have drawn much attention in recent years and it’s
array containing C(sp3)-S-C(sp3) or C(sp3)-S-C(sp2) are
ubiquitous structural patterns often found in bioactive drugs
(Figure 1).3 In particular, the ortho-hydroxy benzyl thioethers (o-
HBT) plays a vital role in chemical biology as anti-oxidant and
anti-inflammatory properties.4 In general, transition metal makes
strong coordination with sulfur which lead to catalyst poisoning,5
could deactivate the catalyst effect and harden the synthetic
methods. Recent studies on functionalized o-HBT prevail to act
as ligands to form complexes with varieties of metals and it is
used as catalyst in different polymerization of olefins6 and in ring-
opening polymerization of ε-caprolactone or lactide.7 The o-HBT
were mainly synthesized via thermal or photochemical
eliminations,8 low temperature desilylation,9a and deborylation
reactions.9b Recently, the organocatalyzed reactions have also
been employed for asymmetric synthesis of o-HBT.10 These
methods are not facile as they requires elevated8a or low
Figure 1. Biologically active thioether skeleton containing drugs.
o-Quinone methides (o-QMs) species are reactive, short-
lived intermediate exemplary utilised in organic synthesis11a-d and
in drug discovery.11e It acts as versatile key components in the
synthesis of natural products,12 and in cycloaddition reactions.13
The tailored o-QMs have served as DNA alkylator, and also
functioning as ideal cross-linker probes.14 The o-QMs were
generated by photolysis15 or thermal process,16 acid- or base-
induced reactions,17,9a chemical or enzymatic oxidation
reactions,18 Lewis acid19,9b or metal complex assisted reactions.11c
The generated active o-QMs were stimulate in advance in Michael
or conjugate addition reactions to access diverse functionalization
with various nucleophiles.20 Recently, the synthesis of α-aryl
ketones has been accomplished from michael addition reaction
through fluoride ion assisted generation of o-QMs and carbonyl
anion.21 Subsequently, Schneider’s group has employed o-QMs
along with β-diketones to synthesize 4H-chromenes via Michael
addition followed by dehydration reaction stratgey.22 In 2015,
Chain and co-workers have reported the synthesis of β-(2-
hydroxyphenyl)-carbonyl compounds via Michael addition
reaction between o-QMs and ketone or ester enolates.23 Kang
and co-workers have developed the synthesis of diaryl
phosphonates via Michael addition of trialkylphosphites on in-
situ generated orthoquinone methides (o-QMs).24
[a]
Dr. R. S. Basha, C.-W. Chen, Dr. D. M. Reddy, Prof. Dr. C.-F. Lee
Department of Chemistry, National Chung Hsing University (NCHU),
Taichung, Taiwan 402, R.O.C
[b]
[c]
Research Center for Sustainable Energy and Nanotechnology
(NCHU)
Innovation and Development Center of Sustainable Agriculture
(NCHU)
From this tremendous diverse functionalization of in-situ
generated o-QMs in conjugate addition reactions,20-24 we
envisaged that the iodine assisted method could unmask the
aromatic system to generate o-QMs under mild condition with
controllable rate to access Michael addition reaction. As our
E-mail: cfalee@dragon.nchu.edu.tw
†R.S.B and C.W.C contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document
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continuous on-going research interest on synthesis of sulfur-
containing compounds,25 we herein report a mild and efficient
method for the synthesis of o-HBT via a C-S bond formation
between thiols and in-situ generated ortho-quinone methides.
yield (Table 1, entry 9). A lower yield (40%) was obtained when
the loading of thiol was decreased to 2.0 equiv (Table 1, entry 10).
Other solvents such as EtOAc, THF, DMSO, DMF, 1,4-dioxane
and CH3CN were also scrutinized under identical reaction
condition, but none of these solvents were found superior over
DCM (Table 1, entries 11-16).
Results and Discussion
Table 2. Reaction of 2-(hydroxymethyl)phenol (1a) with various thiols (2).[a],[b]
The present study was commenced with reaction between
of 2-(hydroxymethyl)phenol 1a and ethanethiol 2a using
[bis(trifluoroacetoxy)iodo]benzene (PIFA) as a catalyst in 1,2-
dichloroethane (DCE) at room temperature. To our delight, the
desired product 3aa was isolated in 25% yield (Table 1, entry 1).
Conversely,
in
case
of
other
related
moiety
(diacetoxyiodo)benzene (PIDA), the reaction was failed to give
the desired product (Table 1, entry 2). Under the influence of
AgNO3 desired product was obtained in 37% yield (Table 1, entry
3). Other oxidants such as DDQ and K2S2O8 were failed to afford
3aa (Table 1, entries 4-5). When the same reaction was
performed in the presence of iodine, the product 3aa was
obtained in 56% yield (Table 1, entry 6) along with disulfide as a
by-product.
Table 1. Optimization of reaction conditions.[a]
Entry
substance (equiv)
thiol (equiv)
solvent
yield (%)[b]
1
PIFA (0.5)
PIDA (0.2)
AgNO3 (0.5)
DDQ (0.5)
K2S2O8 (0.2)
I2 (0.5)
4.0
4.0
4.0
4.0
4.0
4.0
6.0
4.0
4.0
2.0
4.0
4.0
4.0
4.0
4.0
4.0
DCE
25
0
2
DCE
3
DCE
37
0
4
DCE
5
DCE
0
6
DCE
56
60
39
77
40
15
8
7
I2 (0.5)
DCE
8
I2 (0.2)
DCE
[a] Reaction conditions: 2-(hydroxymethyl)phenol 1a (1.0 mmol), thiol 2 (4.0
9
I2 (0.5)
DCM
DCM
EtOAc
THF
equiv), I2 (0.5 equiv) in CH2Cl2 at room temperature. [b] Isolated yield.
10
11
12
13
14
15
16
I2 (0.5)
Once we have the optimized reaction conditions in hand, a
variety of alkyl or aryl thiols were examined for this interesting C-
S bond formation with 2-(hydroxymethyl)phenol under the
influence of iodine. The results are summarized in Table 2. Initial
studies with different alkyl thiol profiles such as linear 2a-2c,
branched 2d-2e, and cyclic 2f underwent reaction with 1a, which
smoothly afforded the product 3aa-3af in good yields. tert-Butyl
thiol 2g and benzyl thiols 2h-i were also reacted well with 1a to
provide the corresponding thioethers 3ag-3ai in 48-60% yields.
The fused ring 2j ensued well with 1a and afforded the desired
product 3aj in 66% yield. Aryl thiols 2k-2o with different electronic
substituents were also employed to react with 1a provided the
expected products 3ak-3ao in moderate to excellent yields. The
effect of substituents on thiophenols (2l-2o) did not inhibit the
reaction.
I2 (0.5)
I2 (0.5)
I2 (0.5)
DMSO
DMF
0
I2 (0.5)
trace
25
65
I2 (0.5)
1,4-dioxane
CH3CN
I2 (0.5)
[a] Reaction conditions: 2-(hydroxymethyl)phenol 1a (1.0 mmol), ethanethiol 2a,
solvent (5 mL) at room temperature. [b] Isolated yield. DCE = 1,2-dichloroethane.
DCM = dichloromethane, CH2Cl2. THF = tetrahydrofuran. DMSO = dimethyl
sulfoxide. DMF = dimethylformamide.
While elevating the amount of thiol to 6.0 equiv, the product
3aa was isolated in 60% yield (Table 1, entry 7). However, on
reducing the amount of iodine, the product yield was decreased
(Table 1, entry 8). Remarkably, dichloromethane (DCM) was
found superior solvent over DCE, provided the product 3aa 77%
The prime substituted o-HBT demand us for the evaluation
of the substrate scope (Table 3). 2,4-Di-tert-butyl substituted
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phenol 1b reacted with both aliphatic and aromatic thiols to afford
the corresponding products 3ba-3bd in 50-90% yields. The
phenol 1c, possessing halo group was also compatible with both
aliphatic and aromatic thiols to provide the corresponding
thioethers 3be-3bh in 45-94% yields. It is worth mentioning here
that electronic properties of thiol influenced the yield of the
product. Aromatic thiol encompass with electron rich group (p-
methoxy) affords higher yield of the product as compared with
electron deficient one (p-chloro). Further investigation on p-
methoxy substituted phenol 1d with 2k led to slight lower yield of
the product 3bi.
reaction with two ways switching of o-QMs in phenol 1e with 2q
in presence of 0.5 equiv I2, the exceptional intermolecular
dimercapto-phenol dithioether product 3bl was obtained in 55%
yield with no intramolecular cyclized product (Scheme 3).
Table 3. Reaction on substituted 2-(hydroxymethyl)phenol with thiols (2).[a],[b]
Scheme 1. Gram-scale synthesis of phenol-thioethers.
Scheme 2. Synthesis of phenol-thioethers with functionalised thiol.
[a] Reaction conditions: 1 (1.0 mmol), 2 (4.0 equiv), I2 (0.5 equiv) in CH2Cl2. [b]
Isolated yield.
The scalability of the reaction was executed for two different
types of phenol skeletons. Initially 2g scale reaction was
conducted between 1a and 2c by using 0.5 equiv I2 at room
temperature. The desired product 3ac was obtained in 81% yield.
Similarly, 2.5g scale reaction was implemented with substituted
phenol 1b under identical reaction conditions. The corresponding
product 3bj was afforded in 83% yield as shown in Scheme 1.
The present protocol was further extended to examine the
functionalized thiol 2p with 1a by employing 0.5 equiv I2 in DCM.
The expected product 3ap was obtained in 61% yield. It revealed
that ester moiety was well tolerated in this process. The triol 1e
was exemplarily utilized to inspect the sequential two ways
generation of o-QM in phenol via two C(sp3) and three C(sp2)
facet. The reaction was conducted between 1e and 2p under
similar reaction conditions. Interestingly, the di-functionalized
phenol dithioether product 3bk was obtained in 54% yield
(Scheme 2).
Scheme 3. Synthesis of mono and dimercapto phenol thioethers.
The competition experiments have been inspected and two
sets of reactions were performed. Two different phenols 1a and
1b reacted with thiophenol in the presence of 0.5 equiv I2 led to a
mixture of products 3ak and 3bd with a ratio 1:1.25. The
preferential selectivity has identified for electron rich phenolic
substrate (Scheme 4a). Subsequently, we have carried out the
reaction with two different thiols 2d and 2k with 1a under identical
The phenol bearing the mono- and di-mercapto groups
inspired us to examine the reaction between 1a and 2q under
standard reaction conditions. The product 3aq was isolated in
66% yield. Encouraged by this result, we have commenced the
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reaction conditions. The mixture of products 3ad:3ak was
attained in a ratio of 1.12:1. The higher selectivity was observed
for aliphatic thiol substrate (Scheme 4b).
6a). Further studies on radical scavenger experiment were
examined by involving TEMPO and BHT in the reactant profile.
Interestingly, the efficiency of the reaction was not affected and
the reaction might be not involved in radical pathway (Scheme 6b).
Scheme 6. Control experiment studies.
Based on the above experimental results, a plausible
mechanism is proposed in Scheme 7. Initially, 2-
(hydroxymethyl)phenol 1 reacted with iodine which would lead to
the intermediate I with the extrusion of HI. The HI further react
with I could regenerate iodine with the elimination of H2O. From I
the in-situ generated o-QM II favors to react with thiol 2 to give III.
Further proton abstraction by phenoxide ion in intermediate III
resulted to final product phenol thioether 3.
Scheme 4. Competition experiment studies.
The relative rate of thiolations was also investigated with
electronically differentiated thiols. The two sets of experimental
studies were performed by involving 1a and 2k with two
electronically varied thiols. As a result, the major selective product
was observed from electron-rich and electron-deficient thiols. This
indicates that both electron-rich and electron-deficient thiols react
at a higher rate with phenol than thiophenol (Scheme 5). Indeed,
the faster addition of thiol to o-QM might be not involved in the
rate determining step.
Scheme 7. Plausible mechanism for the formation of phenol thioether 3.
Scheme 5. Investigation on electronically varied thiol profiles.
Conclusions
We have developed a novel and efficient method for the
synthesis of ortho-hydroxy benzyl thioethers (o-HBT) via thio-
Michael addition reaction on iodine assisted in-situ generated
ortho-quinone methide at room temperature. This protocol
provides an access to functionalized o-HBT and dithioether. The
elongated pattern containing mercapto-phenol thioether and
The insights of the reaction mechanism were inspected by
a series of control experiments (Scheme 6). The standard
reaction conducted with 1a has proven futile. It implies that
reaction is not proceeding through iodination process. On the
other hand, the unsuccessful reaction between 5 and 2p discards
the conjecture nucleophilic substitution reaction pattern (Scheme
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3.78 (s, 2H), 6.80-6.89 (m, 2H), 6.94 (brs, 1H), 7.07 (dd, J = 7.2 & 1.6 Hz,
1H), 7.15-7.19 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 13.9, 22.4, 28.3,
28.8, 30.7, 31.2, 32.4, 116.9, 120.3, 122.6, 128.8, 130.3, 155.1. HRMS
(ESI) calcd for C13H19OS [M-H]+ 223.1157, found 223.1159.
dithioether has also been achieved by this unified method. A
preliminary series of competition and controlled experiments has
been analyzed. To the best of our knowledge, this is the first
reported method of iodine mediated ortho-quinone methides
generation at room temperature from 2-hydroxymethyl-
substituted phenols to synthesize o-HBT. The prominent features
of the present strategy are simple, scalable, wide substrate scope,
cheap starting materials, mild reaction conditions and good yields.
Furthermore, we anticipate that these o-HBT could be of great
interest in the synthesis of important molecules in the near future.
2-[(n-Dodecylthio)methyl]phenol (3ac)26b
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), dodecanthiol (0.978 mL, 4.0 mmol), iodine (0.127 g, 0.5 mmol)
and dichloromethane (5 mL), then purified by column chromatography
(SiO2, 10% ethyl acetate in hexanes) to provide 3ac as a yellow liquid (247
mg, 80% yield); 1H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 3H),
1.20-1.37 (m, 18H), 1.53 (quint, J = 6.8, 7.6 Hz, 2H), 2.37 (t, J = 7.6 Hz,
2H), 3.76 (s, 2H), 6.79-6.87 (m, 2H), 6.92 (s, 1H), 7.05 (dd, J = 7.6 & 1.2
Hz, 1H), 7.15-7.19 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 14.0, 22.6, 28.6,
28.9, 29.0, 29.2, 29.3, 29.4, 29.50, 29.52, 30.7, 31.8, 32.3, 116.8, 120.2,
122.7, 128.7, 130.2, 155.1. The above similar procedure was followed for
2 gram scale which affords 81% yield.
Experimental Section
Experiments were conducted under N2 atmosphere by using standard
Schlenk techniques. 1H, 13C and 19F NMR spectra were recorded on a
Varian Mercury-400 or a Varian Unity Inova-600 instrument. Standard
abbreviations of the signals were represented as s = singlet, d = doublet, t
= triplet, q = quartet, dd = double of doublet, m = multiplet and bs = broad.
Chemical shifts and Coupling constant (J) are reported in parts per million
(ppm) and in hertz (Hz). GC-MS analyses were conducted on Agilent
Technologies 5977A GC equipped with Agilent 7890B MS. High-resolution
mass spectra were recorded on a Jeol JMS-HX 110 spectrometer by the
services at the National Chung Hsing University. Melting points were
determined on Büchi 535 apparatus and are uncorrected. All commercial
chemicals were purchased and used as such. 2-(Hydroxymethyl)phenols
were all prepared through known literature procedures.26a
2-[(sec-Butylthio)methyl]phenol (3ad)
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), 2-mercaptobutane (0.444 mL, 4.0 mmol), iodine (0.127 g, 0.5
mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3ad as a
yellow liquid (133 mg, 68% yield); 1H NMR (400 MHz, CDCl3): δ 0.92 (t, J
= 7.2 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.42-1.62 (m, 2H), 2.55-2.60 (m,
1H), 3.80 (s, 2H), 6.80-6.91 (m, 2H), 7.04 (s, 1H), 7.08 (dd, J = 7.6 & 1.6
Hz, 1H), 7.11-7.19 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 11.0, 20.1, 29.1,
31.3, 40.7, 116.9, 120.3, 122.7, 128.8, 130.1, 155.2; HRMS (ESI) calcd for
C11H15OS [M-H]+ 195.0844, found 195.0845.
General procedure for synthesis of phenol-thioethers
A two-neck round bottom flask was charged with 2-(hydroxymethyl)phenol
(1) (1.0 mmol) and iodine (0.127 g, 0.5 mmol). The reaction flask was
evacuated and backfilled with nitrogen. To the reaction mixture was added
dichloromethane (5 mL) under nitrogen, and to the stirred solution was
added thiol (2) (4.0 mmol). The reaction mixture was stirred at room
temperature for 4 hours. After the reaction, the reaction mixture was diluted
with dichloromethane (20 mL), and the solution was washed with aq.
Na2S2O3 (2 x 10 mL). The organic layer was dried over anhydrous MgSO4,
filtered and concentrated under vacuum. The crude product was purified
by silica gel column chromatography to give the title product phenol-
thioether (3) (Eluent: 10% ethyl acetate in hexanes).
2-[((2-Methylbutyl)thio)methyl]phenol (3ae)
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), 2-methyl-1-butanethiol (0.517 mL, 4.0 mmol), iodine (0.127 g,
0.5 mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3ae as a
yellow liquid (151 mg, 72% yield).1H NMR (400 MHz, CDCl3): δ 0.81 (t, J
= 7.2 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H), 1.14-1.19 (m, 1H), 1.38-1.41 (m,
1H), 1.52-1.57 (m, 1H), 2.20-2.31 (m, 1H), 2.38-2.42 (m, 1H), 3.76 (s, 2H),
6.81-6.89 (m, 2H), 6.96 (s, 1H), 7.06 (d, J =7.6 Hz, 1H), 7.16-7.20 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 11.2, 18.7, 28.5, 32.9, 34.2, 37.7, 116.9,
120.3, 122.6, 128.9, 130.4, 155.2; HRMS (EI) calcd for C12H18OS [M]+
210.1078, found 210.1085.
2-[(Ethylthio)methyl]phenol (3aa)9b
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), ethanethiol (0.29 mL, 4.0 mmol), iodine (0.127 g, 0.5 mmol)
and dichloromethane (5 mL), then purified by column chromatography
(SiO2, 10% ethyl acetate in hexanes) to provide 3aa as a yellow liquid (130
mg, 77% yield); 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J = 7.2 Hz, 3H), 2.40
(q, J=7.2 Hz, 2H), 3.78 (s, 1H), 6.80-6.86 (m, 2H), 6.87-7.00 (br, 1H), 7.05-
7.21 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 14.2, 24.7, 32.2, 117.1, 120.5,
122.4, 129.0, 130.4, 155.4.
2-[(Cyclohexylthio)methyl]phenol (3af)
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), cyclohexyl mercaptan (0.488 mL, 4.0 mmol), iodine (0.127 g,
0.5 mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3af as a
yellow liquid (189 mg, 85% yield).1H NMR (400 MHz, CDCl3): δ 1.12-1.28
(m, 6H), 1.61-1.64 (m, 2H), 1.83 (d, J =12.8 Hz, 2H), 2.44-2.51 (m, 1H),
3.72 (s, 2H), 6.72-6.82 (m, 2H), 6.90 (s, 1H), 6.99 (d, J = 7.2 Hz, 1H), 7.05-
7.12 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 25.5, 25.6, 31.1, 32.9, 42.5,
116.9, 120.3, 122.8, 128.7, 130.0, 155.2; HRMS (EI) calcd for C13H18OS
[M]+ 222.1078, found 222.1082.
2-[(n-Hexylthio)methyl]phenol (3ab)
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), hexanethiol (0.586 mL, 4.0 mmol), iodine (0.127 g, 0.5 mmol)
and dichloromethane (5 mL), then purified by column chromatography
(SiO2, 10% ethyl acetate in hexanes) to provide 3ab as a yellow liquid (161
mg, 72% yield); 1H NMR (400 MHz, CDCl3): δ 0.86 (t, J = 7.2 Hz, 3H),
1.18-1. 36 (m, 6H), 1.53(quint, J = 7.2 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H),
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2-[(tert-butylthio)methyl]phenol (3ag)
4.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 35.3, 116.6, 120.7, 122.7,
126.9, 128.9, 129.0, 130.6, 130.7, 134.7, 154.5.
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), 2-methyl-2-propanethiol (0.451 mL, 4.0 mmol), iodine (0.127 g,
0.5 mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3ag as a
yellow solid (96 mg, 49% yield); m.p. 69-70 °C; 1H NMR (400 MHz, CDCl3):
δ 1.36 (s, 9H), 3.85 (s, 2H), 6.80 (s, 1H ), 6.85-6.88 (m, 2H), 7.13-7.17(m,
2H); 13C NMR (100 MHz, CDCl3): δ 30.3, 30.6, 43.6, 117.1, 120.7, 123.0,
128.9, 130.0, 155.3; HRMS (ESI) calcd for C11H15OS [M-H]+ 195.0844,
found 195.0845.
2-[((2-Fluorophenyl)thio)methyl]phenol (3al)
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), 2-fluorothiophenol (0.440 mL, 4.0 mmol), iodine (0.127 g, 0.5
mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3al as a
1
yellow liquid (140 mg, 60% yield); H NMR (400 MHz, CDCl3): δ 4.14 (s,
2H), 6.02 (bs, 1H), 6.75-6.85 (m, 2H), 6.98-7.06 (m, 3H), 7.10-7.17 (m, 1H),
7.18-7.24 (m, 1H), 7.30-7.38 (m, 1H); 13C NMR (150 MHz, CDCl3): δ 34.3,
115.5 (d, J = 22.5 Hz ), 116.4, 120.6, 121.3 (d, J = 17.9 Hz ), 122.5, 124.4
(d, J = 3.75 Hz ), 129.1, 129.4 (d, J = 7.7 Hz ), 130.5, 133.6, 154.3, 161.8
(d, J = 244.4 Hz ); 19F NMR (376 MHz, CDCl3): δ -110.3; HRMS (EI) calcd
for C13H11FOS [M]+ 234.0515, found 234.0516.
2-[(Benzylthio)methyl]phenol (3ah)
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), benzyl mercaptan (0.470 mL, 4.0 mmol), iodine (0.127 g, 0.5
mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3ah as a
2-[((4-Methoxyphenyl)thio)methyl]phenol (3am)
1
yellow liquid (138 mg, 60% yield); H NMR (400 MHz, CDCl3): δ 3.57 (s,
2H), 3.65 (s, 2H), 6.63 (s, 1H), 6.80-6.92 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H),
7.17-7.20 (m, 1H), 7.21-7.31 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 31.8,
35.0, 117.0, 120.4, 122.2, 127.1, 128.5, 128.9, 129.0, 130.7, 137.3, 155.1;
HRMS (ESI) calcd for C14H13OS [M-H]+ 229.0687, found 229.0690.
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), 4-methoxybenzenethiol (0.507 mL, 4.0 mmol), iodine (0.127 g,
0.5 mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3am as
a yellow liquid (162 mg, 66% yield); 1H NMR (400 MHz, CDCl3): δ 3.76 (s,
3H), 4.04 (s, 2H), 6.09 (bs, 1H), 6.74-6.19 (m, 3H), 6.85-6.90 (m, 2H), 7.14-
7.18 (m, 1H), 7.27 (dd, J = 8.4 & 2.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ 37.2, 55.2, 114.5, 116.6, 120.5, 123.2, 124.5, 128.9, 130.6, 134.4, 154.5,
159.4; HRMS (EI) calcd for C14H14O2S [M]+ 246.0715, found 246.0709.
2-[((4-Chlorobenzyl)thio)methyl]phenol (3ai)
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), 4-chlorobenzenemethanethiol (0.539 mL, 4.0 mmol), iodine
(0.127 g, 0.5 mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3ai as a
2-[((3-Fluorophenyl)thio)methyl]phenol (3an)
1
yellow liquid (127 mg, 48% yield); H NMR (400 MHz, CDCl3): δ 3.56 (s,
2H), 3.68 (s, 2H), 6.46 (s, 1H), 6.82-6.89 (m, 2H), 6.98 (dd, J =7.6 & 1.6
Hz, 1H), 7.15-7.28 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 31.5, 34.4,
116.7, 120.4, 122.4, 128.5, 128.9, 130.2, 130.6, 132.7, 136.0, 154.9;
HRMS (EI) calcd for C14H13ClOS [M]+ 264.0376, found 264.0373.
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), 3-fluorothiophenol (0.356 mL, 4.0 mmol), iodine (0.127 g, 0.5
mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3an as a
1
yellow liquid (210 mg, 90% yield); H NMR (400 MHz, CDCl3): δ 4.15 (s,
2-[(Naphthalene-2-ylthio)methyl]phenol (3aj)
2H), 5.95 (bs, 1H), 6.79-6.87 (m, 3H), 7.01-7.19 (m, 5H); 13C NMR (150
MHz, CDCl3): δ 33.7, 133.2 (d, J = 21.0 Hz ), 116.0, 116.2 (d, J = 4.4 Hz ),
120.7, 122.4, 125.0, 129.0, 130.0 (d, J = 8.4 Hz ), 130.5, 137.9 (d, J = 7.8
Hz ), 154.0, 162.5 (d, J = 246.5 Hz ); 19F NMR (376 MHz, CDCl3): δ -113.6;
HRMS (EI) calcd for C13H11FOS [M]+ 234.0515, found 234.0514.
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), 2-naphthalenethiol (0.640 mL, 4.0 mmol), iodine (0.127 g, 0.5
mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3aj as a
gray solid (176 mg, 66% yield); m.p. 75-78 °C; 1H NMR (400 MHz, CDCl3):
δ 4.10 (s, 2H), 6.14 (s, 1H), 6.60-6.72 (m, 2H), 6.95-6.99 (m, 2H), 7.25-
7.29 (m, 3H), 7.52-7.55 (m, 2H), 7.59-7.62 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 34.7, 116.4, 120.7, 122.6, 125.9, 126.4, 127.1, 127.6, 127.8,
128.3, 128.5, 129.0, 130.6, 131.9, 132.4, 133.5, 154.3; HRMS (EI) calcd
for C17H14OS [M]+ 266.0765, found 266.0769.
2-[(((3-Trifluoromethyl)phenyl)thio)methyl]phenol (3ao)
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), 3-(trifluoromethyl)thiophenol (0.450 mL, 4.0 mmol), iodine
(0.127 g, 0.5 mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3ao as a
1
yellow liquid (255 mg, 90% yield); H NMR (400 MHz, CDCl3): δ 4.18 (s,
2-[(Phenylthio)methyl]phenol (3ak)9a
2H), 5.76 (s, 1H), 6.80-6.84 (m, 2H), 7.07 (d, J = 7.6 Hz, 1H), 7.11-7.18
(m, 1H), 7.28-7.35 (m, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.6 Hz,
1H), 7.56 (s, 1H); 13C NMR (150 MHz, CDCl3): δ 34.1, 116.3, 121.0, 122.4,
123.2 (q, J = 3.8 Hz ), 123.7 (q, J = 270.9 Hz ), 126.5 (d, J = 4.1 Hz ), 129.1,
129.2, 130.7, 131.1 (q, J = 32.3 Hz ), 133.1, 136.8, 154.0; 19F NMR (376
MHz, CDCl3): δ -64.1; HRMS (EI) calcd for C14H11F3OS [M]+ 284.0483,
found 284.0480.
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124g,
1.0 mmol), thiophenol (0.410 mL, 4.0 mmol), iodine (0.127 g, 0.5 mmol)
and dichloromethane (5 mL), then purified by column chromatography
(SiO2, 10% ethyl acetate in hexanes) to provide 3ak as a yellow liquid (184
mg, 85% yield).1H NMR (400 MHz, CDCl3): δ 4.15 (s, 2H), 6.04 (brs, 1H),
6.75-6.85 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 7.11-7.26 (m, 4H), 7.34 (d, J =
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2,4-Di-tert-butyl-6-[(ethylthio)methyl]phenol (3ba)
purified by column chromatography (SiO2, 10% ethyl acetate in hexanes)
to provide 3be as a yellow liquid (140 mg, 50% yield); 1H NMR (400 MHz,
CDCl3): δ 1.24 (t, J = 7.6 Hz, 3H), 2.47 (q, J = 7.6 Hz, 2H), 3.74 (s, 2H),
6.31 (s, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 14.1, 25.4, 30.9, 110.9, 125.2, 126.8, 129.3, 130.2,
149.5; HRMS (EI) calcd for C9H10BrClOS [M]+ 279.9324, found 279.9334.
Following
the
general
procedure,
using
2,4-di-tert-butyl-6-
(hydroxymethyl)phenol (0.236 g, 1.0 mmol), ethanethiol (0.29 mL, 4.0
mmol), iodine (0.127 g, 0.5 mmol) and dichloromethane (5 mL), then
purified by column chromatography (SiO2, 10% ethyl acetate in hexanes)
to provide 3ba as a yellow liquid (232 mg, 83% yield); 1H NMR (400 MHz,
CDCl3): δ 1.22 (t, J = 7.2 Hz, 3H), 1.30 (s, 9H), 1.44 (s, 9H), 2.41 (q, J =
7.6 Hz, 2H), 3.83 (s, 2H), 6.86 (s, 1H), 6.94 (d, J = 2.0 Hz, 1H), 7.27 (d, J
= 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 24.8, 29.7, 31.5, 33.7,
34.1, 34.9, 121.5, 123.4, 125.1, 136.9, 141.8, 152.1; HRMS (EI) calcd for
C17H28OS [M]+ 280.1861, found 280.1854.
2-Bromo-4-chloro-6-[(phenylthio)methyl]phenol (3bf)
Following the general procedure,
using 2-bromo-4-chloro-6-
(hydroxymethyl)phenol (0.236 g, 1.0 mmol), thiophenol (0.410 mL, 4.0
mmol), iodine (0.127 g, 0.5 mmol) and dichloromethane (5 mL), then
purified by column chromatography (SiO2, 10% ethyl acetate in hexanes)
to provide 3bf as a brown liquid (259 mg, 79% yield); 1H NMR (400 MHz,
CDCl3): δ 4.07 (s, 2H), 5.89 (s, 1H), 7.01 (s, 1H), 7.14-7.38 (m, 6H); 13C
NMR (100 MHz, CDCl3): δ 34.0, 110.5, 125.3, 126.3, 126.9, 128.8, 129.5,
130.1, 130.5, 134.9, 149.0; HRMS (EI) calcd for C13H10BrClOS [M]+
327.9324, found 327.9319.
2,4-Di-tert-butyl-6-[(n-Hexylthio)methyl]phenol (3bb)
Following
the
general
procedure,
using
2,4-di-tert-butyl-6-
(hydroxymethyl)phenol (0.236 g, 1.0 mmol), hexanethiol (0.586 mL, 4.0
mmol), iodine (0.127 g, 0.5 mmol) and dichloromethane (5 mL), then
purified by column chromatography (SiO2, 10% ethyl acetate in hexanes)
to provide 3bb as a yellow liquid (269 mg, 80% yield);1H NMR (400 MHz,
CDCl3): δ 0.86 (t, J = 7.2 Hz, 3H), 1.18-1.40 (m, 5H), 1.29 (s, 9H), 1.43 (m,
9H), 1.46-1.60 (m, 3H), 2.38 (t, J = 7.2 Hz, 2H), 3.81 (s, 2H), 6.83 (s, 1H),
6.92 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 14.0, 22.5, 28.4, 29.2, 29.8, 30.8, 31.3, 31.6, 34.16, 34.23, 35.0,
121.7, 123.5, 125.1, 137.1, 141.9, 152.2; HRMS (EI) calcd for C21H36OS
[M]+ 336.2487, found 336.2493.
2-Bromo-4-chloro-6-[((4-methoxyphenyl)thio)methyl]phenol (3bg)
Following the general procedure,
using 2-bromo-4-chloro-6-
(hydroxymethyl)phenol (0.236 g, 1.0 mmol), 4-methoxybenzenethiol
(0.507 mL, 4.0 mmol), iodine (0.127 g, 0.5 mmol) and dichloromethane (5
mL), then purified by column chromatography (SiO2, 10% ethyl acetate in
hexanes) to provide 3bg as a yellow liquid (335 mg, 94% yield); 1H NMR
(400 MHz, CDCl3): δ 3.73 (s, 3H), 3.95 (s, 2H), 6.03 (s, 1H), 6.77 (dd, J =
6.8 & 1.6 Hz, 2H), 6.84 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 6.8 & 2.0 Hz, 2H),
7.29 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 36.0, 55.1, 110.5,
114.3, 124.6, 125.0, 126.7, 129.5, 129.9, 134.4, 149.0, 159.3; HRMS (EI)
calcd for C14H12BrClO2S [M]+ 357.9430, found 357.9439.
2,4-Di-tert-butyl-6-[(cyclohexylthio)methyl]phenol (3bc)26c
Following
the
general
procedure,
using
2,4-di-tert-butyl-6-
(hydroxymethyl)phenol (0.236 g, 1.0 mmol), cyclohexyl mercaptan (0.488
mL, 4.0 mmol), iodine (0.127 g, 0.5 mmol) and dichloromethane (5 mL),
then purified by column chromatography (SiO2, 10% ethyl acetate in
hexanes) to provide 3bc as a yellow liquid (300 mg, 90% yield); 1H NMR
(400 MHz, CDCl3): δ 0.90-1.2 (m, 5H), 1.04 (m, 9H), 1.18 (m, 9H), 1.28-
1.36 (m, 1H), 1.42-1.54 (m, 2H), 1.62-1.72 (m, 2H), 2.26-2.35 (m, 1H), 3.59
2-Bromo-4-chloro-6-[((4-chlorophenyl)thio)methyl]phenol (3bh)
Following the general procedure,
using 2-bromo-4-chloro-6-
(hydroxymethyl)phenol (0.236 g, 1.0 mmol), 4-chlorobenzenethiol (0.596
mL, 4.0 mmol), iodine (0.127 g, 0.5 mmol) and dichloromethane (5 mL),
then purified by column chromatography (SiO2, 10% ethyl acetate in
hexanes) to provide 3bh as a brown liquid (162 mg, 45% yield); 1H NMR
(400 MHz, CDCl3): δ 4.06 (s, 2H), 5.82 (s, 1H), 7.04 (d, J = 2.4 Hz, 1H),
7.20-7.22 (s, 4H), 7.33 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
34.1, 110.6, 125.5, 126.0, 129.0, 129.1, 129.5, 130.3, 131.9, 133.0, 133.5,
148.9; HRMS (EI) calcd for C13H9BrCl2OS [M]+ 361.8935, found 361.8931.
(s, 2H), 6.60 (s, 1H), 6.70 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H); 13
C
NMR (100 MHz, CDCl3): δ 25.7, 25.8, 29.7, 31.6, 33.0, 33.1, 34.2, 35.0,
43.2, 122.1, 123.4, 124.9, 137.0, 142.0, 152.1.
2,4-Di-tert-butyl-6-[(phenylthio)methyl]phenol (3bd)6
Following
the
general
procedure,
using
2,4-di-tert-butyl-6-
(hydroxymethyl)phenol (0.236 g, 1.0 mmol), thiophenol (0.410 mL, 4.0
mmol), iodine (0.127 g, 0.5 mmol) and dichloromethane (5 mL), then
purified by column chromatography (SiO2, 10% ethyl acetate in hexanes)
to provide 3bd as a yellow liquid (164 mg, 50% yield); 1H NMR (400 MHz,
CDCl3): δ 1.20 (s, 9H), 1.43 (s, 9H), 4.13 (s, 2H), 6.14 (s, 1H), 6.79 (d, J =
2.0 Hz, 1H), 7.21-7.23 (m, 4H), 7.27-7.35 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 29.8, 31.5, 34.1, 34.9, 37.7, 121.7, 123.7, 125.4, 127.3, 128.8,
131.5, 133.9, 137.0, 142.3, 151.4.
4-Methoxy-2-[(phenylthio)methyl]phenol (3bi)4
Following the general procedure, using 2-(hydroxymethyl)-4-
methoxyphenol (0.154 g, 1.0 mmol), thiophenol (0.410 mL, 4.0 mmol),
iodine (0.127 g, 0.5 mmol) and dichloromethane (5 mL), then purified by
column chromatography (SiO2, 10% ethyl acetate in hexanes) to provide
1
3bi as a yellow liquid (98 mg, 40% yield); H NMR (400 MHz, CDCl3): δ
3.66 (s, 3H), 4.11 (s, 2H), 5.84 (s, 1H), 6.61 (d, J = 2.8 Hz, 1H), 6.63-6.70
2-Bromo-4-chloro-6-[(ethylthio)methyl]phenol (3be)
(m, 1H), 6.76 (d, J = 8.8 Hz, 1H), 7.18-7.27 (m, 3H), 7.32-7.35 (m, 2H); 13
C
NMR (100 MHz, CDCl3): δ 35.3, 55.6, 114.2, 115.7, 117.3, 123.9, 126.9,
Following the general procedure,
using 2-bromo-4-chloro-6-
128.9, 130.6, 134.8, 148.2, 153.3.
(hydroxymethyl)phenol (0.236 g, 1.0 mmol), ethanethiol (0.29 mL, 4.0
mmol), iodine (0.127 g, 0.5 mmol) and dichloromethane (5 mL), then
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10.1002/asia.201800233
Chemistry - An Asian Journal
FULL PAPER
2,4-Di-tert-butyl-6-[(n-Dodecylthio)methyl]phenol (3bj)26d
CDCl3): δ 1.32 (t, J = 8.0 Hz, 2H), 1.84-1.89 (m, 4H), 2.24 (s, 3H), 2.54-
2.62 (m, 8H), 3.75 (s, 4H), 6.83 (s, 1H), 6.89 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ 20.4, 23.3, 29.4, 31.7, 32.8, 124.1, 129.3, 130.3, 130.4, 151.1.;
HRMS (ESI) calcd for C15H23OS4 [M-H]- 347.0632, found 347.0632.
Following
the
general
procedure,
using
2,4-di-tert-butyl-6-
(hydroxymethyl)phenol (2.5 g, 6.0 mmol), dodecanthiol (23.688 mL, 24
mmol), iodine (0.762 g, 3.0 mmol) and dichloromethane (30 mL), then
purified by column chromatography (SiO2, 10% ethyl acetate in hexanes)
to provide 3bj as a colorless liquid (3.7g, 83% yield); 1H NMR (400 MHz,
CDCl3): δ 0.87 (t, J = 6.4 Hz, 3H), 1.23-1.30 (m, 27H), 1.42 (s, 9H), 1.50-
1.54 (m, 2H), 2.37 (t, J = 7.6 Hz, 2H), 3.81 (s, 2H), 6.83 (s, 1H), 6.91 (s,
1H), 7.26 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 22.7, 28.7, 29.2,
29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 30.7, 31.6, 31.9, 34.1, 34.2, 35.0, 121.7,
123.4, 125.1, 137.0, 141.8, 152.2.
Acknowledgements
The Ministry of Science and Technology, Taiwan (Most 106-2113-
M-005-001-), National Chung Hsing University (NCHU),
Research Center for Sustainable Energy and Nanotechnology
(NCHU), and Innovation and Development Center of Sustainable
Agriculture (NCHU) are gratefully acknowledged for financial
support.
Methyl 2-((2-hydroxybenzyl)thio)acetate (3ap)9a
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), methyl mercaptoacetate (0.367 mL, 4.0 mmol), iodine (0.127 g,
0.5 mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3ap as a
colorless liquid (129 mg, 61% yield); 1H NMR (400 MHz, CDCl3): δ 3.17 (s,
2H), 3.73 (s, 3H), 3.88 (s, 2H), 6.86-6.90 (m, 2H), 6.97 (s, 1H), 7.15-7.18
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 31.7, 32.0, 52.7, 116.8, 120.5,
122.4, 129.1, 130.7, 154.8, 171.6.
Conflict of interest
The authors declare no conflict of interest.
Keywords: 2-Hydroxymethyl-substituted phenol • Thioether •
Michael reaction • Iodine •ortho-quinone methide
[1]
a) M. Feng, B. Tang, S. H. Liang, X. Jiang, Curr. Top. Med. Chem. 2016,
16, 1200-1216; b) E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med. Chem.
2014, 57, 2832-2842; c) B. R. Smith, C. M. Eastman, J. T. Nijardarson,
J. Med. Chem. 2014, 57, 9764-9773; d) M. E. Cinar, T. Ozturk, Chem.
Rev. 2015, 115, 3036-3140; e) K. Takimiya, I. Osaka, T. Mori, M. Nakano,
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Organosulfur Compounds, Academic Press, New York, 1978; g) R. J.
Cremlyn, in An Introduction to Organo sulfur Chemistry, Wiley, New York,
1996.
Dimethyl2,2'-(((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))
bis(sulfanediyl)) diacetate (3bk)
Following the general procedure, using (2-hydroxy-5-methyl-1,3-
phenylene)dimethanol (0.168 g, 1.0 mmol), methyl mercaptoacetate
(0.367 mL, 4.0 mmol), iodine (0.127 g, 0.5 mmol) and dichloromethane (5
mL), then purified by column chromatography (SiO2, 10% ethyl acetate in
hexanes) to provide 3bk as a colorless liquid (186 mg, 54% yield); 1H NMR
(400 MHz, CDCl3): δ 2.24 (s, 3H), 3.19 (s, 4H), 3.75 (s, 6H), 3.86 (s, 4H),
6.94 (s, 2H), 7.23 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 20.2, 31.5, 32.2,
52.5, 123.6, 129.3, 130.7, 151.1, 171.3; HRMS (ESI) calcd for
C15H20O5NaS2 [M+Na]+ 367.0650, found 367.0654.
[2]
[3]
a) C.-F. Lee, Y.-C. Liu, S. S. Badsara, Chem. Asian J. 2014, 9, 706-722;
b) H. Liu, X. Jiang, Chem. Asian J. 2013, 8, 2546-2563; c) C. C. Eichman,
J. P. Stambuli, Molecules 2011, 16, 590-608; d) S. V. Ley, A. W. Thomas,
Angew. Chem. 2003, 115, 5558-5607; Angew. Chem. Int. Ed. 2003, 42,
5400-5449; e) T. Kondo, T-a. Mitsudo, Chem. Rev. 2000, 100, 3205-
3220.
K. A. Scott, J. T. Njardarson, Top. Curr. Chem. 2018, 376, 5.
10.1007/s41061-018-0184-5.
2-(((3-Mercaptopropyl)thio)methyl)phenol (3aq)
[4] M. L. Hammond, R. A. Zambias, M. N. Chang, N. P. Jensen, J. McDonald,
K. Thompson, D. A. Boulton, I. K. Kopka, K. M. Hand, E. E. Opas, S.
Luell, T. Bach, P. Davies, D. E. MacIntyre, R. J. Bonney, J. L. Humes, J.
Med. Chem. 1990, 33, 908-918.
Following the general procedure, using 2-(hydroxymethyl)phenol (0.124 g,
1.0 mmol), 1,3-propanedithiol (0.402 mL, 4.0 mmol), iodine (0.127 g, 0.5
mmol) and dichloromethane (5 mL), then purified by column
chromatography (SiO2, 10% ethyl acetate in hexanes) to provide 3aq as a
black liquid (141 mg, 66% yield); 1H NMR (400 MHz, CDCl3): δ 1.30 (t, J =
8.0 Hz, 1H), 1.79-1.86 (m, 2H), 2.50-2.57 (m, 4H), 3.78 (s, 2H), 6.59 (s,
1H), 6.83-6.88 (m, 2H), 7.09 (dd, J=7.6 Hz, 1H), 7.15-7.19 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 23.2, 29.0, 32.1, 32.7, 116.8, 120.5, 122.6,
129.0, 130.4, 154.9; HRMS (ESI) calcd for C10H13OS2 [M-H]- 213.0408,
found 213.0410.
[5]
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R. Sidick Basha, Chia-Wei Chen,
Daggula Mallikarjuna Reddy, and Chin-
Fa Lee*
Page No. – Page No.
Iodine Mediated Direct Generation of o-
Quinone methides at Room
Temperature: A Facile Protocol for the
Synthesis of ortho-Hydroxy Benzyl
Thioethers
Unmask it and interconnect it: An one-pot elegant synthesis of ortho-hydroxy
benzyl thioethers (o-HBT) has been developed via Michael addition of thiols on in-
situ generated o-QMs. The o-QMs were generated from 2-hydroxymethyl-
substituted phenols under the influence of iodine.
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