Catalytic thioalkylation of phenols based on mannich-type phenol

Article abstract of DOI:10.1080/00397910701462971

A thioalkylation of phenols involving reactive phenols, aldehydes, and thiols is described under Mannich-type phenol catalysis to afford thiomethyl phenols in good yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701462971

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Catalytic Thioalkylation of Phenols Based on
Mannich‐Type Phenol
Peng Liu a b , Lunyu Zhu a b , Yan Fang a , Huaiping Zhang a b , Dehong Chen a
b , Tao He a b , Mingcai Chen b & Kai Xu b
a Key Laboratory of Organic Polymer Material for Electronics , Guangzhou
Institute of Chemistry, Chinese Academy of Sciences (CAS) , Guangzhou,
China
b Key Laboratory of Organic Polymer Material for Electronic , Guangzhou
Institute of Chemistry, Chinese Academy of Sciences , Guangzhou, China
Published online: 09 Aug 2007.
To cite this article: Peng Liu , Lunyu Zhu , Yan Fang , Huaiping Zhang , Dehong Chen , Tao He , Mingcai Chen
& Kai Xu (2007) Catalytic Thioalkylation of Phenols Based on Mannich‐Type Phenol, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:15, 2609-2613, DOI:
10.1080/00397910701462971
To link to this article: http://dx.doi.org/10.1080/00397910701462971
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Synthetic Communicationsw, 37: 2609–2613, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701462971
Catalytic Thioalkylation of Phenols Based
on Mannich-Type Phenol
Peng Liu and Lunyu Zhu
Key Laboratory of Organic Polymer Material for Electronics,
Guangzhou Institute of Chemistry, Chinese Academy
of Sciences (CAS), Guangzhou, China and Key Laboratory of Organic
Polymer Material for Electronic, Guangzhou Institute of Chemistry,
Chinese Academy of Sciences, Guangzhou, China
Yan Fang
Key Laboratory of Organic Polymer Material for Electronics,
Guangzhou Institute of Chemistry, Chinese Academy
of Sciences (CAS), Guangzhou, China
Huaiping Zhang, Dehong Chen, and Tao He
Key Laboratory of Organic Polymer Material for Electronics,
Guangzhou Institute of Chemistry, Chinese Academy
of Sciences (CAS), Guangzhou, China and Key Laboratory of Organic
Polymer Material for Electronic, Guangzhou Institute of Chemistry,
Chinese Academy of Sciences, Guangzhou, China
Mingcai Chen and Kai Xu
Key Laboratory of Organic Polymer Material for Electronic, Guangzhou
Institute of Chemistry, Chinese Academy of Sciences, Guangzhou, China
Abstract: A thioalkylation of phenols involving reactive phenols, aldehydes, and thiols is
described under Mannich-type phenol catalysis to afford thiomethyl phenols in good yields.
Keywords: catalytic reaction, Mannich-type phenol, thioalkylation
Received in Japan January, 2007
Address correspondence to Mingcai Chen, Key Laboratory of Organic Polymer
Material for Electronic, Guangzhou Institute of Chemistry, Chinese Academy of
Sciences, Guangzhou, China. E-mail: mcchen@gic.ac.cn
2609

2610
P. Liu et al.
Thioalkylation is an important and widely used procedure for carbon–carbon
bond formation and the production of unsymmetrical sulfides.[1] Usually, thioalk-
ylationofphenol proceedsthrough hydroxymethyl, halomethyl, or Mannich-type
phenol as an intermediate.[2] Among them, pyrolysis of Mannich-type phenol
provides a powerful procedure for preparation of thioalkylated phenol. Displace-
ment of dialkylamine by a thiol gives the thioalkylated product. However, this
powerful procedure involves equimolar amounts of Mannich-type phenol and
thiol. In this article, we disclose a more atom-economical reaction for thioalkyla-
tion of phenols. We directly prepared thioalkylated phenol from phenol,
para-formaldehyde thiol, using Mannich-type phenol as a catalyst.
The results in Table 1 reveal that the reaction temperature and the solvent are
critical to the thioalkylation. When a solvent was not employed in the model
reaction, full conversion was not obtained until 18 h. Raising temperature might
improve the reaction rate. However, when the temperature was raised above
1208C, a lot of para-formaldehyde was sublimed at the top of the reaction
vessel. During the experimentation, we found that the sublimation of para-formal-
dehyde could be avoided by adding alcohol. Although it has been said the protic
solvents such as alcohol would accelerate the Mannich reaction,[3] the reactions
proceeded more sluggishly with increasing alcohol content (Table 1, entries 5–8).
Under the optimized conditions, the scope of the 2,6-di-tert-butyl-
4-dimethylaminomethyl phenol–catalyzed thioalkylation of thiols was
extended. Investigation of representative thiols demonstrated that the
procedure was feasible for aliphatic and hetero atom-containing thiols
(Table 2, entries 1–6). The thiols with electron-donating groups generally
gave satisfactory results. It is worthwhile to note that this new approach
works well with hetero atom-containing thiols (Table 2, entries 2 and 3).
Table 1. Optimization of thioalkylation of 2,6-dibutylphenol catalyzed by
2,6-dibutyl-4-dimethylaminophenol
Entry
Temp. (8C)
Solvent
Timea (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
100
120
140
160
120
120
120
120
120
none
none
none
none
1:7d
18
14
c
92
93
67
59
93
93
92
93
94
c
9
3:5d
8
5:3d
7:1d
DMF
7
5
4
aTime for 100% conversion.
bIsolated yield.
cStopped the reaction after 15 h.
dw (DMF): w(ETOH).

Catalytic Thioalkylation of Phenols
2611
On the other hand, it is worth noting that the reaction gave low reaction rate for
thiols with an electron-withdrawing group, such as b-thioglycolic acid or
b-mercaptoethanol. In these cases, a considerable amount of unreacted
starting materials were recovered after reacting for 15 h. Obviously the low
efficiency is due to the low nucleophilicity of the thiols. Among these
thiols, the isopropylthiol showed a relatively low conversion because of its
volatility.
It was observed that use of the corresponding Mannich-type phenol as a
catalyst was effective for the thioalkylation of phenols such as 2,6-dimethyl
phenol and 2,4-di-tert-butyl phenol. The full conversion time of thioalkylation
of 2,4-di-tert-butyl phenol was much longer than that of 2,6-disubstitued
phenols (Table 2, entries 1, 7, and 8). It is well known that deamination of
Mannich-type phenols leads to intermediate quinone methides.[4] It is
probably due to para-quinone methides (p-QMs) that are less polarized and
more stable than their corresponding o-QMs. Accordingly, p-QMs are
formed more readily than o-QMs.[5]
Table 2. Thioalkylation of phenols catalyzed by Mannich-type phenols
Timea
(h)
Yieldb
(%)
Entry
1
Cat.
Phenols
Thiols
HSC12Hn25
4
94
2
3
4
5
6
7
HS(CH2)3Si(OEt)3
HSCH2COOC8Hi17
HSCH2COOH
HSCH2CH2OH
HSC3Hi7
4
4
15c
15c
15c
4
93
92
47
53
HSC12Hn25
91
8
HSC12Hn25
20
84
aTime for 100% conversion.
bIsolated yield.
cStopped the reaction after 15 h.

2612
P. Liu et al.
In conclusion, we have developed a new simple approach to thioalkyla-
tion of phenols using appropriate readily available Mannich-type phenol as
a catalyst. The reaction is more atom-economical and easier to prepare.
EXPERIMENTAL
All 1H spectra were recorded at 400 MHz with CDCl3 as solvent. All reagents
were used directly as obtained commercially.
Typical Procedure
Reactions were carried out in a test tube (20 mL) under an N2 atmosphere
with gentle magnetic stirring. Phenol (18 mmol), catalyst (2 mmol), para-
formaldehyde (0.9 g, 30 mmol), and n-dodecanethiol (4.04 g, 20 mmol) in
N,N-dimethylformamide (4.0 g) was heated at 100–1608C. After completion
of the reaction, the mixture was cooled to room temperature, washed with
water, and dried. Then the yellowish products were analyzed using 1H NMR.
Data
1
2,6-Di-tert-butyl-4-((dodecylthio)methyl)phenol (yellowish oil). H NMR
(CDCl3): 7.068 (s, 2H, C6H2), 5.103 (s, 1H, Ph-OH), 3.636 (s, 2H,
PhCH2S), 2.442–2.405 (t, J ¼ 7.2, 2H, PhCH2SCH2), 1.569–1.530
[(m, 2H, SCH2CH2), 1.398 (s, 18H, C(CH3)3], 1.280–1.234 [m, 18H,
(CH2)9], 0.878–0.844 (t, J ¼ 6.8, 3H, CH2CH3).
2,6-Di-methyl-4-((dodecylthio)methyl)phenol (white solid, mp: 54–558C).
1H NMR (CDCl3): 6.892 (s, 2H, C6H2), 3.573 (s, 2H, PhCH2S), 2.227
(t, 2H, PhCH2SCH2), 1.57–1.519 (m, 2H, SCH2CH2), 1.308 (s, 6H, CH3),
1.232–1.1.170 [m, 18H, (CH2)9], 0.875–0.841 (t, J ¼ 6.8, 3H, CH2CH3).
2,6-Di-tert-butyl-4-((isopropylthio)methyl)phenol (yellowish oil). 1H NMR
(CDCl3): 7.096 (s, 2H, C6H2), 5.102 (s, 1H, Ph-OH), 3.684 (s, 2H, PhCH2S),
2.870-2.820 (m, 1H, PhCH2SCH), 1.444 [s, 18H, C(CH3)3], 1.276–1.259
[d, J ¼ 6.8, 6H, CH(CH3)2].
2-((3,5-Di-tert-butyl-4-hydroxybenzyl)sulfanyl)acetic acid (yellowish oil).
1H NMR (CDCl3): 7.093 (s, 2H, C6H2), 5.116 (s, 2H, SCH2COOH), 3.605
(s, 2H, PhCH2S), 1.442 [s, 18H, C(CH3)3].
4-((3-(Triethoxysilyl)propylthio)methyl)-2,6-di-tert-butylphenol (yellowish
1
oil). H NMR (CDCl3): 7.068 (s, 2H, C6H2), 5.106 (s, 1H, Ph-OH), 3.817–
3.728 (q, J ¼ 7.8, 6H, OCH2CH3), 3.632 (s, 2H, PhCH2S), 2.488–2.451

Catalytic Thioalkylation of Phenols
2613
(t, J ¼ 7.8, 1H, PhCH2SCH2), 1.713–1.673 (m, 2H, SCH2CH2) 1.391 [s, 18H,
C(CH3)3], 1.218–1.173 (t, J ¼ 7.8, 6H, OCH2CH3), 0.726–0.684 (t, J ¼ 8.4,
2H, CH2Si).
4-((2-Hydroxyethylthio)methyl)-2,6-di-tert-butylphenol (yellowish oil).
1H NMR (CDCl3): 7.078 (s, 2H, C6H2), 5.147 (s, 1H, Ph-OH), 3.691–3.662
(m, 4H, PhCH2SCH2CH2), 2.209–1.929 (t, J ¼ 6, 2H, PhCH2SCH2), 1.418
[s, 18H, C(CH3)3].
1
2,4-Di-tert-butyl-6-((dodecylthio)methyl)phenol (yellowish oil). H NMR
(CDCl3): 7.235–7.229 (d, J ¼ 2.4, 1H, C6H2), 6.898–6.892 (d, J ¼ 2.4, 1H,
C6H2), 6.796 (s, 1H, Ph-OH), 3.783 (s, 2H, PhCH2S), 2.377–2.339
(t, J ¼ 7.6, 2H, PhCH2SCH2), 1.523–1.486 (m, 2H, SCH2CH2), 1.401
[s, 9H C(CH3)3], 1.248 [s, 9H C(CH3)3], 1.230–1.212 [s, 18H, (m, 18H,
(CH2)9], 0.877–0.843 (t, J ¼ 6.8, 3H, CH2CH3).
2-Ethylhexyl 2-(3,5-di-tert-butyl-4-hydroxybenzylthio)acetate (yellowish
oil). 1H NMR (CDCl3): 7.091 (s, 2H, C6H2), 5.147 (s, 1H, C6H2OH),
4.189 (s, 1H, PhCH2SCH2), 4.049 (d, 2H, OCH2CH), 3.754 (s, 2H,
PhCH2S), 1.159 (m, 1H, OCH2CH), 1.424–1.279 (m, 8H, CH(CH2CH3)
CH2CH2CH2CH3), 0.905–0.897 (m, 6H, CH3).
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