Mono/Dual Amination of Phenols with Amines in Water

Article abstract of DOI:10.1021/acs.orglett.0c02924

We herein describe a practical direct amination of phenols through a palladium-catalyzed hydrogen-transfer-mediated activation method to synthesize the secondary and tertiary amines. In this conversion, environmentally friendly water and inexpensive ammonium formate were used as solvent and reductant, respectively. A range of amines, including aliphatic amines, aniline, secondary amines, and diamines, could be coupled effectively by this method to achieve mono/dual amination and cyclization of phenols. This study not only provides a green and mild strategy for the synthesis of secondary and tertiary naphthylamines but also expands the synthesis of chloroquine in organic chemistry.

Full text of DOI:10.1021/acs.orglett.0c02924

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Letter
Mono/Dual Amination of Phenols with Amines in Water
Wanyi Liang,§ Feng Xie,§ Zhihai Yang, Zheng Zeng, Chuanjiang Xia, Yibiao Li, Zhongzhi Zhu,*
and Xiuwen Chen*
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ABSTRACT: We herein describe a practical direct amination of phenols through a palladium-catalyzed hydrogen-transfer-mediated
activation method to synthesize the secondary and tertiary amines. In this conversion, environmentally friendly water and
inexpensive ammonium formate were used as solvent and reductant, respectively. A range of amines, including aliphatic amines,
aniline, secondary amines, and diamines, could be coupled effectively by this method to achieve mono/dual amination and
cyclization of phenols. This study not only provides a green and mild strategy for the synthesis of secondary and tertiary
naphthylamines but also expands the synthesis of chloroquine in organic chemistry.
romatic amines are important structural motifs and
reactions are examples of Buchwald−Hartwig coupling or
Aintermediates because of their wide distribution in Ullmann-type aminations, wherein aryl halides are frequently
materials1 and bioactive molecules.2 Examples include the
anticancer drug chlornaphazine (A),3 depositing enrichment
agent thionalide (B),4 the pesticide naptalam (C),5 the
antiviral agent dasabuvir (D),6 and fluorescence labeling
reagent dansyl chloride (E)7 (Scheme 1).
utilized as electrophiles to couple with amines (Scheme 2a).9
However, the prefunctionalization of aryl halides, as well as the
production of halide byproducts, limits the utility of these
protocols.
The chemistry of phenolic compounds has attracted
continued interest over the past two centuries.10 Therefore,
the use of phenols instead of haloarenes is in great demand but
is still challenging. C−N bond construction by hydrogen
transfer has become a powerful tool in organic chemistry.11
Recently, a palladium catalyst system for the direct cross-
coupling of phenols with anilines was reported by the Li
group.12 Furthermore, there is also some progress on the
hydrogenative amination, which allowed facile construction of
cyclohexylamines from phenols.13 Despite these advances, the
utilization of ammonium formate as cost-effective reductant
and eco-friendly water as solvent to achieve mono/dual
The rapid construction of aromatic amines in a green
manner is an important research topic in organic and medicinal
chemistry. C−N bond formation is among the most efficient
strategies for constructing aryl amines.8 Most C−N bond
Scheme 1. Representative Compounds with a
Naphthylamine Framework
Received: September 1, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02924
© XXXX American Chemical Society
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A

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and 140 °C) had no obvious effect on the yield (Table 1, entry
14), which established the optimal conditions.
Scheme 2. Methods for Direct Amine Arylations
Having establishing the reaction conditions, different amine
substrates were evaluated (Scheme 3). Different amines 1
a
Scheme 3. Substrate Scope of Amines
amination and cyclization of phenols remains unexplored.
Owing to our ongoing interest in hydrogen-transfer
reactions,14 we recently reported an N-arylation transformation
in which indoline reactants were treated as hydrogen donors
through hydrogen-transfer-mediated activation.15 Inspired by
this work, here we report a green and efficient approach to
synthesize aryl amines from phenols and amines via a direct
aqueous hydrogen-transfer coupling.
Initially, the reaction of benzylamine (1a) and 2-naphthol
(2a) was selected as a model system to screen effective
parameters. Using NaBH4 as hydride source and toluene as
solvent, additives including t-BuOK, NaHSO3, NaOCH3,
Na2S2O5, and K2S2O5 were examined under N2 at 120 °C
(entries 1−5). K2S2O5 afforded a higher yield of product 3aa
(61%) compared with other additives. Pd/C was the best
catalyst among the palladium catalysts evaluated (Table 1,
a
Standard conditions: 1 (0.45 mmol), 2 (0.3 mmol), HCO2NH4 (2
a
equiv), Pd/C (5 mol %), and additive (0.15 mol) in water (1.0 mL) at
Table 1. Screening Conditions
b
c
100 °C for 16 h, N2. 1 (0.9 mmol, 3 equiv). 5 bar of NH3.
reacted with 2-naphthol (2a) with high efficiency. Electron-
donating groups on the phenyl ring of the benzylamines
resulted in relatively high yields (81−83%, 3ba−3ca)
compared with the substituent-free (75%, 3aa) and fluoride-
substituted (71%, 3da) substrates. In these cases, the
nucleophilicity of the corresponding benzylamines was
enhanced by the increased electron density, which improved
the condensation process in this transformation. Similarly,
phenylethylamines (1e−1g) performed effective coupling to
produce desired products 3ea−3ga. Alkyl amines 3-amino-
propanol and butylamine reacted smoothly with 2-naphthol,
providing 3ha and 3ia in 85% and 81% yields, respectively.
Compounds 3ja and 3ka were obtained in moderate yields
when aniline and p-toluidine were employed to react with 2-
naphthol. In addition, we found that this amination method-
ology is suitable for use with secondary amines and 2-naphthol,
and we successfully synthesized a variety of 2-dialkylamino-
naphthalenes (3la−3na). The reaction of 2a with 4-
methylbenzamide afforded naphthylamine 3oa in a very low
yield. Pleasingly, desired product 3pa was detected when NH3
was applied under these reaction conditions.
We next explored the reactions of different amines 1 with
different phenols 2, producing arylamines 3ab−3bh in 46%−
81% isolated yields (Scheme 4). Electron-donating groups on
the naphthols led to higher yields compared with electron-
withdrawing groups (3ab−3ac). Both α-naphthol and phenol
were evaluated to produce arylamines 3ad−3ie in moderate
yields. Gratifyingly, benzylamine 3af was obtained in 58% yield
when using 2-hydroxyanthracene as substrate. Finally, the
scope of heterocyclic phenols was investigated, such as indol-5-
additive
3aa,
b
entry cat. (5 mol %)
(50 mol %)
HD
yield (%)
1
Pd/C
t-BuOK
NaHSO3
NaOCH3
Na2S2O5
K2S2O5
K2S2O5
K2S2O5
K2S2O5
K2S2O5
K2S2O5
K2S2O5
K2S2O5
K2S2O5
K2S2O5
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
trace
2
Pd/C
34
29
57
61
18
3
Pd/C
4
Pd/C
5
Pd/C
6
7
8
9
PdCl2
Pd(PPh3)4
Pd(dba)2
Pd/C
27
19
21
44
10
11
12
13
14
Pd/C
Pd/C
Pd/C
Pd/C
2-propanol
HCO2H
HCOONa
HCO2NH4
HCO2NH4
62
c
(68, 73, 71)
(74, 76, 63)
d
Pd/C
a
Reaction conditions: 1a (0.45 mmol), HD (1 equiv), 2a (0.3 mmol),
Pd catalyst (5 mol %), temperature (120 °C), and additive (50 mol
%) in water (1.0 mL) for 16 h, N2. Isolated yield. HCO2NH4 (1, 2,
b
c
d
and 4 equiv). Yields achieved at temperatures of 140, 100, and 80
°C, respectively.
entries 6−8). The reaction yield was greatly reduced when no
hydrogen source was used (entry 9). Next, several hydrogen
sources were examined in combination with K2S2O5; it was
found that the product was obtained in 73% yield when
HCO2NH4 was used as an alternative hydrogen source (Table
1, entries 10−13). Altering the reaction temperature (80, 100,
B
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a
We were interested in elucidating the utility of our synthetic
methods. Chloroquine phosphate, a broadly used antimalarial
drug, has been shown to have apparent efficacy and acceptable
safety against COVID-19.16 Therefore, we selected 2-amino-5-
diethylaminopentane (1t) and 7-chloroquinolin-4-ol (2m) as
substrates under standard conditions to obtain the target
product 4tm and dechlorinated product 4tm′ (see the SI),
providing a new synthetic route to access chloroquine
derivatives (Scheme 6).
Scheme 4. Substrate Scope
Scheme 6. Synthetic Application
With the aim of investigating the reaction mechanism,
several control experiments were performed (Scheme 7). First,
Scheme 7. Control Experiments
a
Standard conditions: 1 (0.45 mmol), 2 (0.3 mmol), HCO2NH4 (2
equiv), Pd/C (5 mol %), and K2S2O5 (0.5 equiv) in water (1.0 mL) at
100 °C for 16 h.
ol and quinolin-6-ol, affording the aminoindole and amino-
quinoline target products in moderate yields.
To further evaluate the synthetic utility, this catalytic system
was applied to the direct deamination of phenols. 1,6-
Dihydroxynaphthalene, 2,7-dihydroxynaphthalene, and 2,6-
dihydroxynaphthalene were examined, affording the corre-
sponding diamination products in 67%−75% yields (4ei−4aj).
Interestingly, the reactions of 2,3-diamines (1q, 1r, and 1s)
with 2,3-dihydroxynaphthalene 2 (2k, 2l) were tested, giving
the cyclization products (4qk−4sl) (Scheme 5).
cyclohexanone and cyclohexenone were used instead of
phenols, reacting smoothly with benzylamine to afford 3aa
and 3ah′ in 41% and 65% yields, respectively (eqs 1 and 2),
indicating that 2a-1 and 2a-2 are reaction intermediates. In
another reaction to further understand the mechanism, in the
presence of K2S2O5 (0.5 equiv) and no hydride source in water
(1.0 mL) at 100 °C, benzylamine and phenol failed to give the
target product (eq 3). Further, the deuterium-labeling
experiment of NaBD4 with 2a led to 3ea-dn deuterated on
the naphthalene ring, which suggested that hydrogen transfer
occurred from NaBD4 to 2-naphthol 2a (eq 4).
Scheme 5. Dual Amination and Cyclization of
a
Dihydroxynaphthalene
We proposed a possible reaction pathway for this hydrogen-
transfer amination (Scheme 8). To begin with, HCO2NH4
Scheme 8. Plausible Reaction Pathways
a
Standard conditions: 1 (0.9 mmol), 2 (0.3 mmol), HCO2NH4 (2
equiv), Pd/C (5 mol %), and K2S2O5 (0.5 equiv) in water (1.0 mL) at
100 °C for 16 h.
C
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reacts with the palladium catalyst to generate an active HPdIIH
species. Next, 2-naphthol is hydrogenated to give ketone 2i-1,
regenerating the palladium catalyst. In the presence of K2S2O5,
intermediate 2i-1 performs the first amination with benzyl-
amine (1a) to give key intermediate 4ai-1. Then, the
dehydrogenation of 4ai-1 produces intermediate 4ai-2 and
releases the [HPdIIH] species (see path a). Finally, tautomer
4ai-3 undergoes a second amination to form the final product
4ai. Moreover, K2S2O5 is crucial for product formation (see
path b) because using K2S2O5 as the sole additive resulted in
only a small amount of amination product (see the SI). The
addition of K2S2O5 and H2O enables the formation of a
cyclohexenone intermediate from naphthol under these
conditions.
In summary, we have developed a simple, green, and highly
efficient direct mono/dual amination and cyclization using a
hydrogen-transfer strategy. Various phenols and amines were
evaluated using inexpensive HCO2NH4 as reductant in water,
providing green and mild access to secondary/tertiary
naphthylamines and chloroquine with different functionalities.
ACKNOWLEDGMENTS
■
Financial support by the “Climbing Program”Special Funds
(pdjh2020a0596), the Youth Talent Fund (No.
2018KQNCX272, 2018KQNCX273), Guangdong Basic and
Applied Basic Research Foundation (2019A1515110866,
2019A1515110522), Young Teacher Team of Wuyi University
(2019td06), and the Guangdong Provincial Department of
Education Fund (2019KZDXM052, 2017KZDXM085, and
2018KZDXM070).
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AUTHOR INFORMATION
■
Corresponding Authors
Zhongzhi Zhu − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529020, China;
Email: chenxiuwen2010@126.com
Xiuwen Chen − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529020, China; orcid.org/0000-
0003-3301-6730; Email: wyuchemzzz@126.com
Authors
Wanyi Liang − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529020, China
Feng Xie − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, China
Zhihai Yang − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529020, China
Zheng Zeng − Affiliated Hospital of Guilin Medical University,
Guilin 541001, China
Chuanjiang Xia − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529020, China
Yibiao Li − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, China
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2015, 6, 4174−4178. (b) Wang, Z.; Niu, J.; Zeng, H.; Li, C. J. Org.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02924
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Author Contributions
§W.L. and F.X. contributed equally to this work.
Notes
The authors declare no competing financial interest.
D
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