Nucleophilic Amination and Etherification of Aryl Alkyl Thioethers

Article abstract of DOI:10.1021/acs.orglett.8b01758

A transition-metal-free protocol capable of synthesizing diarylated aniline derivatives is reported. This method could be further employed to prepare aryl alkyl ethers. A wide range of thioethers, anilines, as well as alcohols were tolerated thanks to the mild reaction conditions. The strength of our method was demonstrated by performing a gram-scale reaction (20 mmol) followed by conversion of the nitrile group into synthetically useful aldehyde, ketone, and carboxylic acid.

Full text of DOI:10.1021/acs.orglett.8b01758

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nucleophilic Amination and Etherification of Aryl Alkyl Thioethers
Xia Wang,† Yue Tang,† Cheng-Yu Long,§ Wen-Ke Dong,† Chenchen Li,† Xinhua Xu,†
Wanxiang Zhao,*,† and Xue-Qiang Wang*,†
†Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of
Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, P. R. China
§College of Chemical Engineering, Northwest Minzu University, Lanzhou, Gansu 730030, P. R. China
S
* Supporting Information
ABSTRACT: A transition-metal-free protocol capable of
synthesizing diarylated aniline derivatives is reported. This
method could be further employed to prepare aryl alkyl
ethers. A wide range of thioethers, anilines, as well as alcohols
were tolerated thanks to the mild reaction conditions. The
strength of our method was demonstrated by performing a
gram-scale reaction (20 mmol) followed by conversion of the
nitrile group into synthetically useful aldehyde, ketone, and
carboxylic acid.
wing to the extensive existence of diarylamines in dyes,
pharmaceuticals, agrochemicals, materials, and nature
much less attention. Recently, transition-metal-catalyzed
conversion of the C(sp2)−S bond into C−H,8 C−C,9 and
C−X (X = P,10 B,11 S,12 N13) bonds have attracted great
attention due to the easy accessibility and handling of aromatic
thioethers. Given that the alkylthiolate can poison metal
catalysts, the whole catalytic cycle would be suppressed by the
in-situ generated alkylthiolate.14 This drawback greatly limits
the development of this research area. Therefore, developing
metal-free C(sp2)−S bond cleavage strategies is highly
desirable because these techniques could serve as attractive
supplements to the ones that need transition-metal catalysts.
At the beginning of our investigations, it was uncertain
whether such a protocol could be achieved as several
challenges still exist: (1) the electronegativity of sulfur is
very close to a sp2-hybridized carbon atom, and the C−S bond
thus is not significantly polarized; (2) the increased electron
density of the aromatic ring, which stems from strong electron-
donating −SR group might suppress the reaction; (3) the
nucleophilicity of aniline is quite low. We started our study by
evaluating the amination of 1a with 2a. After careful
optimization, we found that the use of KOt-Bu as base in
1,4-dioxane at 60 °C could generate the expected product in
23% isolated yield (Table 1, entry 1).15 NaOt-Bu was much
less efficient than KOt-Bu, and only a trace amount of product
was observed (entry 2). To our delight, the use of KHMDS
could improve the yield to 50% in 1,4-dioxane (entry 3), while
other solvents such as THF, diethyl ether, and methyl tert-
butyl ether afforded the targeted aniline in slightly lower yields
(entries 4−6). Interestingly, 85% of yield was detected when
the reaction conducted in a mixed solvent and lower
concentration in the presence of KHMDS (entry 7). Changing
O
products, intense effort has been dedicated to the exploration
of methods for the syntheses of aromatic amines (Scheme 1).1
Scheme 1. Methods for Aniline Syntheses
For instance, C−N bond construction has focused on
variations of Cu-catalyzed Ullmann−Goldberg coupling
between aryl halides and anilines2 and Chan−Evans−Lam
coupling between boronic acids and nitrogen nucleophiles.3,4
Nevertheless, not many transformations were achieved because
of the weak nucleophilicity of aryl amines as compared to
aliphatic amines and ammonia. In the past few decades,
Buchwald−Hartwig C−N coupling of aryl (pseudo)halides
with anilines has emerged as a powerful protocol for the
preparation of diarylated amines, allowing rapid development
of this significant research area.5,6 In addition, transition-metal-
catalyzed C(sp2)−H amination has exhibited its capability of
incorporating anilines onto arenes.7 Although transition-metal-
free anilines formation protocols are valuable complements to
the existing synthetic methods, this research field has received
Received: June 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01758
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Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Amination Reaction
c
conv
(%)
b
c
entry
base
solvent
yield (%)
d
1
2
3
4
5
6
7
8
KOt-Bu
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
Et2O
t-BuOMe
1,4-dioxane
100
30
70
64
62
23
NaOt-Bu
KHMDS
KHMDS
KHMDS
KHMDS
trace
50
48
42
46
85 (80 )
64
d
KHMDS (1 M in THF)
NaHMDS (2.0 M in THF) 1,4-dioxane
LiHMDS (1 M in THF)
KHMDS (1 M in THF)
KHMDS (1 M in THF)
none
100
100
100
99
100
0
84
60
35
9
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
e
10
11
12
f
33
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), base (1.0
b
mmol), 60 °C, 16 h. KHMDS = potassium hexamethyldisilazane;
NaHMDS = sodium hexamethyldisilazane; LiHMDS = lithium
hexamethyldisilazane. NMR conversions and yields using naphtha-
lene as internal standard. Isolated yield. KHMDS (1.5 equiv). 2a
c
d
e
f
(1.5 equiv).
the base to NaHMDS provided a similar yield of 84%, and a
moderate yield was observed with LiHMDS (entries 8 and 9).
Decreasing the loading of KHMDS or 2a to 1.5 equiv led to
inferior yields of 35% and 33%, respectively (entries 10 and
11). Not surprisingly, the control experiment without KHMDS
did not deliver any targeted aniline (entry 12).
With optimized conditions in hand, we then investigated the
generality of our newly developed amination protocol.
Notably, electron-deficient amines that possess halides such
as fluoride (Scheme 2, 3e, 3h, 3i), chloride (3b), and bromide
(3c) all reacted smoothly with 1a to produce the
corresponding products in excellent yields. The aminations
of 1a with a series of electron-rich or electron-neutral amines
competently afforded the diarylated amines (3a, 3d, 3f, 3g, 3j).
Furthermore, the mild reaction conditions are compatible with
a variety of heterocycles, such as quinoline (3k), pyrazole (3l),
and pyrazol-3-one (3m). In addition, we also tested the
substrate scope of aryl alkyl thioether, and a range of naphthyl
methyl thioethers possessing various substituents at the 6-
position were also suitable for this transformation, giving the
desired products in excellent yields (3n−r). Remarkably, we
found that secondary amines could also be used to provide
arylated products in moderate yields, which can be explained
by the increased bulkiness of the amines (3s−u). Unfortu-
nately, traces amount of desired amine could be observed
when benzonitrile was employed as starting material (3v).
Encouraged by these results, we questioned whether we
could further apply our method to prepare aryl alkyl ethers, not
only because of their significant roles in producing of catalysts,
cosmetics, fragrances, and functional materials16,17 but also
because of their wide existence in biologically active agents and
pharmaceutically significant compounds.18 After a quick
optimization, we found 86% yield of 6a was isolated, while
KOt-Bu served as base in dioxane at 80 °C. We next focused
our attention on the representative examples of this interesting
etherification reaction. As summarized in Scheme 3, all of the
a
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), KHMDS (1 M in
b
THF, 1.0 mmol), 1,4-dioxane (0.5 mL), 60 °C, 16 h. Isolated yield.
c
KHMDS = potassium hexamethyldisilazane
2-SMe-substituted benzonitriles produced the corresponding
products in high yields regardless of the nature of the
substituents on phenyl ring (Scheme 3, 6a−d). The reactions
of starting materials with heterocycles such as thiophene and
benzofuran occurred in high efficiency, affording 6e and 6f in
63% and 68% of yields, respectively. In addition, 4-SMe-
substituted benzonitriles could also take part in the reaction,
albeit with slightly lower yields (6g, 6h). Intriguingly, the
position of the −SMe group does have a profound influence on
reactivity for the naphthonitrile substrate, and 6j was delivered
in 55% yield while 93% of yield was obtained for 6i. We next
explored the scope of alcohols under otherwise identical
reaction conditions. A variety of primary alcohols were found
to be suitable for this transformation, generating the
corresponding ethers in good to excellent yields (6k−q). It
is worth noting that secondary alcohols reacted well with both
benzonitrile and naphthonitirles, resulting in the formation of
desired products (6r, 6s). Remarkably, tertiary alkoxides such
as KOt-Bu could be employed in this reaction, although their
reactivity is much lower than primary and secondary ones (6t−
v). Owing to the mild reaction conditions, good functional
group compatibility was observed, and a variety of groups such
B
DOI: 10.1021/acs.orglett.8b01758
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
method, we then conducted the etherifications of 4 with
various chiral alcohols, natural products, and pharmaceutical
related alcohols.12 As shown in Scheme 3, benzonitrile was
found to effortlessly react with (S)-(−)-2-methyl-1-butanol
(6aa) and secondary alcohol such as (+)-menthol (6ab). We
were pleased to find that the utilization of nitrogen- or oxygen-
containing alcohols could generate the desired ether products
in high yields (6ac, 6ad, 6af). Surprisingly, steric bulkier
secondary alcohols such as (−)-borneol and (+)-fenchol were
efficiently incorporated into arenes with 98% (6ag) and 93%
(6ah) of yields. Promoted by these promising results, estradiol
(6ai), perphenazine (6aj), diosgenin (6ak), and oleanolic acid
derivative (6al) were subjected to the standard reaction
conditions. Gladly, all the cases we tested were all reacted,
delivering the targeted aryl alkyl ethers in good yields.
Scheme 3. Substrate Scope of Thioethers and Alcohols
To shed light on the mechanism of our protocols, we next
decided to carry out mechanistic studies. The addition of
radical scavengers such as TEMPO, BHT, and 1,1-diphenyl-
ethylene to the etherification reaction did not suppress the
reaction, and the targeted product 6a was obtained in slightly
lower yields as shown in Scheme 4. These results might allow
Scheme 4. Mechanistic Studies of Etherification
us to exclude the possibility of a radical pathway. We also
trapped MeS− by adding benzyl bromide, and benzyl methyl
thioether was detected in 40% yield. Although the proposal of
a detailed mechanism should await further investigations, we
suggest this transformation should take a nucleophilic aromatic
substitution course.
The practicality of our synthetic method is demonstrated in
Scheme 5. As shown, the reaction could be scaled up to 20
mmol, affording the desired product 6ab in 73% isolated yield
(3.76 g). The practicality of this protocol was further verified
by converting the etherification product 6a into reduced
product 7a in 98% yield and carboxylic acid 7c in 60% yield
under basic reaction conditions. Additionally, 6ab could
undergo reduction with DIBAL-H and addition with MeMgBr,
generating the aldehyde 7b and ketone 7d in 97% and 95% of
yield, respectively.
a
Reaction conditions: 4 (0.5 mmol), 5 (1.0 mmol), KOt-Bu (1.0
b
c
mmol), dioxane (0.5 mL, 1M), 60 °C, 16 h. Isolated yield. 1.5 mL
1,4-dioxane, 30 °C
In summary, we described a transition-metal-free protocol
capable of efficiently incorporating weak nucleophilic anilines
into nitrile substituted aryl alkylthio ethers. It is worth noting
that the mild reaction conditions could tolerate a variety of aryl
alkylthio ethers and anilines. Moreover, secondary amine also
participated the amination reactions, generating the targeted
as alkyne (6l), alkene (6m, 6p, 6r), amine (6s), ether (6p),
and pyridine (6q) were well tolerated. It is noteworthy that the
other alkyl thioethers such as n-PrS−, n-hexylS−, and i-BuS−
could also participate the etherification, generating 6a in
excellent yields. To further validate the generality of our
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01758.
Experimental procedures, characterization data, and
spectra of products (PDF)
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Lett. 2009, 11, 1607. (b) Zhao, H.; Wang, M.; Su, W.; Hong, M. Adv.
Synth. Catal. 2010, 352, 1301.
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Chem. - Eur. J. 2013, 19, 3125. (b) Barbero, N.; Martin, R. Org. Lett.
2012, 14, 796.
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D.; Pernik, I.; Weller, A. S.; Willis, M. C. Chem. Sci. 2013, 4, 1568.
(b) Pawley, R. J.; Huertos, M. A.; Lloyd-Jones, G. C.; Weller, A. S.;
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(10) Yang, J.; Xiao, J.; Chen, T.; Yin, S.; Han, L. Chem. Commun.
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(15) The loss of mass balance can be explained by the formation of a
mixture of several products which cannot be identified.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhaowanxiang@hnu.edu.cn.
*E-mail: wangxq@hnu.edu.cn.
ORCID
Chenchen Li: 0000-0002-2956-7639
Wanxiang Zhao: 0000-0002-6313-399X
Xue-Qiang Wang: 0000-0003-1631-9158
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Hunan University for startup funding to support this
work and Prof. Tao Wang (Shanxi Normal university) for the
HRMS measurements. We also thank Prof. Qilong Shen
(SIOC) for his kind discussions.
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