Nucleophilic Functionalizations of Aniline Derivatives: Aromatic Pummerer Reaction for Umpolung Halogenation and Hydroxylation on Benzene Ring

Article abstract of DOI:10.1021/acs.orglett.7b02720

In this paper, a metal-free protocol of nucleophilic ortho-halogenation and hydroxylation of anilines via an aromatic Pummerer process is reported.

Full text of DOI:10.1021/acs.orglett.7b02720

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Nucleophilic Functionalizations of Aniline Derivatives: Aromatic
Pummerer Reaction for Umpolung Halogenation and Hydroxylation
on Benzene Ring
Xingping Bao,†,‡ Jinzhong Yao,‡ Hongwei Zhou,*,‡ and Guangyu Xu*,†
†Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and
Chemical Engineering, Hunan Normal University, Changsha 410081, People’s Republic of China
‡College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing 314001, People’s Republic of China
S
* Supporting Information
ABSTRACT: In this paper, a metal-free protocol of
nucleophilic ortho-halogenation and hydroxylation of anilines
via an aromatic Pummerer process is reported.
a
Table 1. Optimization of Reaction Conditions
nilines are arguably the most ubiquitous electron-rich
Abenzenoid compounds, correspondingly, the ortho-func-
tionalizations of aniline derivatives generally belong to
electrophilic substitution. Halogenations using electrophilic
halogenating agents, albeit with disadvantages of functional
group tolerance and overhalogenations,1 are common tools for
electrophilic functionalization; however, nucleophilic substitu-
tions of halide ions on the benzene ring, i.e., nucleophilic
halogenations, are not well documented. On the other hand,
the direct hydroxylations of anilines are even rarer.2
The Pummerer reaction, first reported by Pummerer in
1909,3 has been widely applied in organic synthesis,4,5 which
typically involves a thionium ion generated by the treatment of
sulfoxide with acid anhydride. Based on our understanding of
organosulfur chemistry,6 we wish to report a realization of
umpolung via a thionium ion to make the electrophilic ortho-
position of anilines nucleophilic, which may allow facile
halogenation and hydroxylation under Pummerer conditions
(Scheme 1).
entry
anhydride
solvent
base
T (°C)
2a (%)
1
Ac2O
THF
rt
rt
0
5
30
43
0
2
TFAA
TFAA
Tf2O
THF
3
THF
4
THF
0
5
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
MeCN
acetone
DCM
DCM
DCE
0
39
10
47
70
40
12
0
6
0
7
rt
0
8
9
0
10
11
12
13
14
DCE
50
0
DCM
DCM
DCM
DCM
TEA
pyridine
DMAP
0
12
5
As a first attempt, we chose sulfinyl aniline (1a) as the
starting material, which could be readily prepared via a
sulfonylation and oxidation of 4-phenylthioaniline. We initiated
our study by treatment of 1a with acetic anhydride and
tetrabutylammonium bromide (TBAB) in THF at room
0
b
0
18
a
Conditions: 1a (0.5 mmol), base (1.0 mmol), and anhydrous solvent
(5.0 mL). A mixture of TBAB (0.1 mmol) and KBr (1 mmol) was
used.
b
Scheme 1. Proposal of Nucleophilic Halogenation and
Hydroxylation of Aniline
temperature and isolated bromide (2a) in 5% yield (Table 1,
entry 1). When acetic anhydride was replaced with trifluoro-
acetic anhydride (TFAA), the yield of 2a was raised to 30%
(Table 1, entry 2). Decreasing the temperature to 0 °C offered
a 43% yield (Table 1, entry 3), and the solvent screening
showed that DCM gave an acceptable yield of 70% (Table 1,
Received: September 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02720
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
entries 5−9). Addition of trimethylamine (TEA), pyridine, or
4-dimethylaminopyridine (DMAP) did not improve the
reaction but afforded sluggish results instead (Table 1, entries
11−13).
With this result in hand, the scope of the reaction was
examined. As shown in Scheme 2. The reaction was successful
Scheme 3. Loss of α-Proton
Our attention was diverted to hydroxylation, probably
because when base-sensitive TFAA was used as a promotor
as shown in Scheme 2 tetrabutylammonium hydroxide failed to
yield the expected hydroxyl aniline. We changed the reaction
solvent to THF and charged saturated aqueous NaHCO3 after
the addition of TFAA. The hydroxylation of anilines was
achieved in good yields (Scheme 4, 3a−h). Softer nucleophile
thiophenol also worked well to afford sulfides in good yields
(Scheme 4, 31 and 3j).
Scheme 2. Nucleophilic Brominations and Chlorinations of
Anilines
a
a
Scheme 4. Hydroxylation of Anilines
a
Method A: To 1 (0.5 mmol) and TFAA (1.0 mmol) in THF (5 mL)
was added saturated aqueous NaHCO3 (1 mL) at 0 °C. Method B: 1
(0.5 mmol), TFAA (1.0 mmol), p-methylthiophenol (0.75 mmol) in
THF at 60 °C
a
The reaction was carried out using 1 (0.5 mmol), TFAA (1.0 mmol),
and TBAB or TBAC (0.75 mmol) in DCM at 0 °C.
for TBAB as the bromide source (Scheme 2, 2a−e) and also for
TBAC as the chloride source (Scheme 2, 2f−n). The R1 group
could be a methanesulfonyl (Ms) or p-tolylsulfonyl (Ts); and
the R2 group could be an aryl group or alkyl group. Substituents
on the benzene ring of aniline even improved the yields slightly
(Scheme 2, 2e and 2n). Notably, using TBAI gave elementary
iodine instead of the corresponding iodide, showing that the
reaction system under the Pummerer conditions is compara-
tively oxidative.
We noticed that the yields decreased obviously in the cases of
methylsulfinyl substrates (Scheme 2, 2o and 2p). We quenched
the reaction over 1 h and isolated a highly unstable
(chloromethyl)thio byproduct (2r) in 11% yield, demonstrat-
ing that the loss of α-proton may occur as a classic Pummerer
process (Scheme 3).
Although the exact mechanism of this reaction is unclear at
this stage, we believe that the formation of aza-quinone
thionium intermediate would be involved in the pathway.7 First,
an aromatic Pummerer reaction gives aza-quinone thionium
intermediate A, which is attacked by the nucleophile to afford
B. Intermediate B undergoes aromatizatian to offer product 2
or 3 (Scheme 5).
Both o-halo anilines and o-hydroxyl anilines are useful
building blocks,8 and we chose 2a and 2c for further
functionalization. The classical Suzuki coupling (Scheme 6,
a), cyanation (Scheme 6, b), and intramolecular Heck reaction
(Scheme 6, c) proceeded smoothly. In addition, the phenylthio
group, which triggered the halogenation and hydroxylation,
could be used in transformations such as reduction,9 oxidation
to sulfoxide or sulfone,10 and hydrogenation.11
B
DOI: 10.1021/acs.orglett.7b02720
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Plausible Pathway
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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.7b02720.
General experimental procedures and characterization
data for new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gyxu@hunnu.edu.cn.
*E-mail: zhouhw@zju.edu.cn.
ORCID
Hongwei Zhou: 0000-0001-8308-960X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation of
China (No. 21606080) and Summit Program of Jiaxing
University for Leading Talents is greatly appreciated.
C
DOI: 10.1021/acs.orglett.7b02720
Org. Lett. XXXX, XXX, XXX−XXX