Highly regioselective para-methylthiolation/bridging methylenation of arylamines promoted by NH4I

Article abstract of DOI:10.1039/c5ob01679g

Aryl methyl thioethers and methylene-bridged arylamines were synthesized via highly regioselective para-methylthiolation/bridging methylenation of arylamines using DMSO as the methylthio or methylene source in the presence of NH₄I under metal-free conditions. For the substrates with both electron-donating and electron-withdrawing substituents, the reaction proceeded smoothly and gave moderate to good yields.

Full text of DOI:10.1039/c5ob01679g

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DOI: 10.1039/C5OB01679G
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ARTICLE TYPE
Highly regioselective paraꢀmethylthiolation/bridging methylenation of
arylamines promoted by NH4I
Yinfeng Xu,a Tiantian Cong,a Ping Liua,b and Peipei Sun*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/c0xx00000x
compounds and DMSO in the presence of KF and 18ꢀcrownꢀ6 to
form aryl methyl thioethers.17 Fu et al reported an arylthiolation
50 of arylamines using (arylthio)pyrrolidineꢀ2,5ꢀdiones as the
arylthiolating reagents, but only aryl sulfides were synthesized by
this protocol.18 As the continuous study of our group on C−H
bond functionalization, especially the coupling reactions under
Aryl methyl thioethers and methyleneꢀbridged arylamines
were synthesized via highly regioselective
paraꢀmethylthiolation/bridging methylenation of arylamines
using DMSO as the methylthio or methylene source in the
10 presence of NH4I under metalꢀfree conditions. For the
substrates with both electronꢀdonating and
metalꢀfree conditions,19 herein we want to disclose
a
electronꢀwithdrawing substituents, the reaction proceeded
smoothly and gave moderate to good yields.
55 regioselective paraꢀmethylthiolation of arylamines promoted by
NH4I. And bridging methylenation products diaryl methanes were
also obtained for some reactants.
Aryl methyl thioethers are versatile and important structural
15 motifs in pharmaceutical chemistry since they often show
outstanding biological activity.1 They also have been found wide
application in organic synthesis, for example, as electrophiles in
transitionꢀmetal catalyzed C−C coupling2 and C−N coupling
reaction,3 and the carbothiolation of terminal alkynes.4 The
20 reduction of sulfoxides,5 the nucleophilic substitution to
iodomethane with aryl thiols6 and the electrophilic substitution to
aryl lithium with dimethyl disulfide7 are wellꢀestablished for the
synthesis of aryl methyl thioethers. Transitionꢀmetal catalyzed
crossꢀcoupling reaction of thiols or disulfides with aryl halides
25 provided a new route for the preparation of aryl sulfides,8 but the
methylthiolation using this strategy was limited. In 2011, Cheng
et al developed a methylthiolation of aryl halides by using a
widely available and cheap reagent DMSO as the “MeS” source
in the presence of CuBr/ZnF2.9 Subsequently, in 2013, Kantam et
Initially, aniline (1a) was employed as the reactant for the
reaction conditions research (Table 1). DMSO was used as both
60 methylthiolating reagent and the solvent. Without the promoter,
the reaction could not take place at all (entry 1). Thus, some
iodides or bromide, such as I2, KI, TBAI (tetrabutylammonium
iodide), TBAB (tetrabutylammonium bromide) and NH4I were
tested as the promoter for this reaction, in which NH4I gave the
65 best result, and the others showed very poor promotion effect for
this transformation (entries 2ꢀ6). A paraꢀmethylthiolation product
2a was obtained in 46% yield in the presence of 2 equiv. NH4I at
o
140 C after 16 h (entry 6). Encouraged by this result, further
optimization to the reaction conditions was attempted. To our
70 delight, a higher yield of 68% was further achieved when the
amount of NH4I was increased to 4 equiv. (entry 7). The solvent
was then screened. It was showed that the addition of water not
only did not lower the yield but also promoted the reaction in a
manner (entries 8, 9). When the reaction took place in a 1:1 (v/v)
75 DMSO/H2O mixed solvent, the highest yield of 80% was given
(entry 9). But excessive water might lead to the decrease of the
yield (entry 10). It should also be noted that the reaction was
strongly affected by the temperature. The lower reaction
temperature brought about the lower conversion (entry 11, 12).
80 The best result was achieved at 140 oC.
30 al performed this methylthiolation in CuI/Zn(OAc)2 system.10
A
CuI/DABCOꢀmediated methylthiolation of haloarenes with
DMSO was also reported very recently by Mal et al.11 Using
DMSO as the source of the thiomethyl moiety, Magolan et al
synthesized aryl methyl thioethers via a SNAr reaction in the
35 presence of diisopropylethylamine (DIPEA),12 It is noticeable
that the direct C−S bond formation via C−H bond activation
brought about a new insight in last decade, which provided a
straightforward and economical sequences to prepare sulfides
from nonꢀprehalogenated arenes.13 Several pyridyl directed
40 regioselective methylthiolations on aromatic C(sp2)−H bond were
reported.14 Employing DMSO as the methylthiolating reagent, the
methylthiolations on heteroarenes without coordinating
directingꢀgroups were developed in the presence or in absence of
Table 1 Screening of reaction conditionsa
Entry
Promoter
(equiv.)
ꢀ
I2 (2)
KI (2)
Solvent
T (oC)
Yield (%)b
transitionꢀmetal.15 Very recently, Cai et al reported
45 Pdꢀcatalyzed decarboxylation of benzoic acids with DMSO to
obtain aryl methyl thioethers.16 Xiao et al developed
a
1
2
3
4
5
DMSO
DMSO
DMSO
DMSO
DMSO
140
140
140
140
140
0
trace
<10
15
0
a
TBAI (2)
TBAB (2)
threeꢀcomponent coupling reaction of arynes, αꢀbromocarbonyl
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Table 2 The reaction results of anilines with DMSOa
6
7
8
NH4I (2)
NH4I (4)
NH4I (4)
DMSO
DMSO
DMSO/H2O 140
(2:1)
140
140
46
68
74
9
NH4I (4)
NH4I (4)
NH4I (4)
NH4I (4)
DMSO/H2O 140
(1:1)
DMSO/H2O 140
(1:2)
DMSO/H2O 100
(1:1)
DMSO/H2O 120
(1:1)
80
45
17
48
Entr
y
R1
R2
R3
Yield (2)b
Yield (3)b
10
11
12
1
H
H
H
80% (2a)
53% (2b)
56% (2c)
42% (2d)
67% (2e)
79% (2f)
82% (2g)
57% (2h)
34% (2i)
67% (2j)
42% (2k)
31% (2l)
46% (2m)
21% (2n)
ꢀꢀ
ꢀꢀ
2
2ꢀMe
2ꢀOMe
3ꢀMe
3ꢀOMe
3ꢀEt
H
H
36% (3b)
ꢀꢀ
3
H
H
aUnless otherwise specified, the reactions were carried out in a sealed
tube in the presence of 1a (0.3 mmol), promoter and solvent (2 mL) for
16 h. bIsolated yields based on 1a.
4
H
H
ꢀꢀ
5
H
H
ꢀꢀ
6
H
H
ꢀꢀ
7
3ꢀiPr
H
H
ꢀꢀ
With the optimized conditions in hand, we explored the scope
of this NH4I promoted reaction of arylamines with DMSO. The
results are summarized in Table 2. To our surprise, when
oꢀmethylaniline (1b) was used as the reactant, in addition to the
desired product 2b in 53% yield, a methyleneꢀbridged product
4,4'ꢀmethyleneꢀbis(2ꢀmethylaniline) 3b was also obtained in 36%
yield. Various anilines bearing electronꢀwithdrawing or
electronꢀdonating moieties on benzene ring were investigated. In
8
3ꢀtBu
3,5ꢀdiꢀMe
3ꢀF
H
H
ꢀꢀ
9
H
H
ꢀꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H
H
ꢀꢀ
5
2,6ꢀdiꢀMe
2,6ꢀdiꢀiPr
2ꢀFꢀ3ꢀMe
2ꢀPh
H
H
52% (3k)
60% (3l)
45% (3m)
63% (3n)
56% (3o)
69% (3p)
44% (3q)
66% (3r)
24% (3s)
71% (3t)
43% (3u)
55% (3v)
73% (3w)
71% (3x)
H
H
H
H
H
H
2ꢀCl
H
H
10 most cases, the reactions of anilines with electronꢀdonating group
(e.g., OMe, Me, Et, iꢀPr, tꢀBu) (1aꢀi) on the benzene ring mainly
gave methylthiolation products in moderate to good yields, and
the methylthiolation regioselectively took place on paraꢀposition.
Some disubstituted or phenyl substituted anilines (1kꢀn) gave
15 both methylthiolation (2kꢀn) and bridging methylenation (3kꢀn)
products. Specially, the reactions of anilines with some
electronꢀwithdrawing group (e.g., Cl, CN) (1oꢀq) on the benzene
ring only gave methyleneꢀbridged products (3oꢀq). However,
fluorinated substrate 1j afforded methylthiolation product 2j
20 simply. The relationship between the generation of the two
products (2 or 3) and the substituent on benzene ring did not
show evident regularity. Importantly, for the substrates with one
or two alkyls on amino group (1rꢀw), the reaction also proceeded.
Furthermore, nitrogenous heterocycle substituted arene
25 derivatives 1ꢀphenylpiperidine (1x), 4ꢀphenylmorpholine (1y) and
1,2,3,4ꢀtetrahydroquinoline (1z) could also react with DMSO to
3ꢀCl
H
H
ꢀꢀ
2ꢀCN
H
H
H
ꢀꢀ
H
Me
Me
Me
Me
Et
nꢀBu
ꢀꢀ
3ꢀMe
H
H
63% (2s)
ꢀꢀ
Me
Me
Et
nꢀBu
3ꢀMe
H
41% (2u)
34% (2v)
ꢀꢀ
H
ꢀꢀ
25
26
38% (2y)
35% (2z)
ꢀꢀ
39% (3z)
aThe reactions were carried out in a sealed tube in the presence of 1
(0.3 mmol), NH4I (1.2 mmol) in DMSO/H2O (2 mL, 1:1) at 140 oC for
16 h. bIsolated yields based on 1.
give
the
corresponding
methylthiolation
or/and
methyleneꢀbridged products in moderate yields.
In order to investigate the reaction mechanism, a series of
30 control experiments were carried out (Scheme 1). The deuterium
labeling experiment with DMSOꢀd6 confirmed that methylthio
group (MeSꢀ) in the product 2 originated from DMSO (eq. (1)).
When 3ꢀchloroaniline was used to react with DMSOꢀd6,
d2ꢀ4,4'ꢀmethylenebis(3ꢀchloroaniline) (D2ꢀ3p) was obtained,
35 which confirmed that the methylene in the product 3 also
originated from DMSO (eq. (2)). Using triformol to replace
DMSO in water solution, 4,4'ꢀmethylenebis(2,6ꢀdimethylaniline)
(3k) was obtained in 21% yield (eq. (3)), which indicated that the
methylene in 3 might come from HCHO that was generated from
40 the decomposition of DMSO. In addition, when the reaction was
performed in the presence of 4.0 equiv. of TEMPO under the
standard reaction conditions, 2k was almost not formed, but 3k
was obtained in 48% yield (eq. (4)). These results suggested that
the methylthiolation presumably proceeded through a radical
45 pathway, but this radical pathway was not involved in the
bridging methylenation process.
50
55
Scheme 1 Control experiments.
Based on the above results and the related reports,15ꢀ17
plausible reaction mechanism for the formation of 2 was
a
proposed in Scheme 2. First, the precursor I2 was generated
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through the decomposition of NH4I and the subsequent reaction
determination of HRMS.
with DMSO; meanwhile the decomposition of DMSO formed
MeSH and HCHO.14c,20 Then the homolysis of I2 produced iodine
radical, followed to react with MeSH to give a methylthio radical
MeS·.20b Subsequently, the addition of radical MeS· to the
paraꢀposition of aniline generated a radical intermediate I. The
methylthiolated product 2 finally produced via the elimination of
hydrogen radical from I.
45
aCollege of Chemistry and Materials Science, Jiangsu Provincial Key
Laboratory of Material Cycle Processes and Pollution Control, Nanjing
Normal University, Nanjing 210097, China
5
bJiangsu Collaborative Innovation Center of Biomedical Functional
50 Materials, Nanjing 210023, China
Fax: 86-25-85891767; Tel: 86-25-85891767;
E-mail: sunpeipei@njnu.edu.cn
† Electronic Supplementary Information (ESI) available: [details of any
55 supplementary information available should be included here]. See DOI:
10.1039/b000000x/
Notes and references
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Scheme 2 Proposed reaction mechanism for the formation of 2.
70
As shown above, the thermal decomposition of DMSO
15 generated HCHO. Several ammoniumꢀpromoted formylations by
DMSO were also reported.21 Based on these works, we therefore
proposed that a Mannichꢀtype reaction mechanism might be
involved in the formation of the methyleneꢀbridged product 3
(Scheme 3). The nucleophilic addition of aniline to HCHO and
20 next elimination of H2O formed methylenated intermediate II,
and the nucleophilic substitution of this electronꢀdeficient
intermediate to another aniline on the paraꢀposition generated 3.
75
3
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Scheme 3 Proposed reaction mechanism for the formation of 3.
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Conclusions
95
In conclusion, we developed the highly regioselective
paraꢀmethylthiolation/bridging methylenation of arylamines by
30 using DMSO as the methylthio or methylene source in the
presence of NH4I. A series of aryl methyl thioethers and
methyleneꢀbridged arylamines were synthesized via this very
simple procedure in moderate to good yields. The reaction was
applicable to various aromatic amine derivatives. The mild
35 reaction conditions and convenient operation provided possibility
for future research to apply this methodology in the synthesis of
pharmaceuticals and other useful compounds.
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Acknowledgements
40 This work was supported by the National Natural Science
Foundation of China (Project 21272117) and the Priority
Academic Program Development of Jiangsu Higher Education
Institutions. The authors also thank Mr. Hailong Liu for the
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