Cu(II)-Catalyzed Ortho-Selective Amination of Simple Phenols with O-Benzoylhydroxylamines

Article abstract of DOI:10.1002/ijch.201900171

A Cu(II)-catalyzed ortho-selective amination of simple phenols with O-benzoylhydroxylamines has been developed, which provides access to 2-aminophenols under mild conditions. Various functional groups on the phenol and electrophilic amine are compatible, and the protocol typically delivers the products in moderate to good yields. The mechanistic detail of this process are discussed.

Full text of DOI:10.1002/ijch.201900171

Communication
DOI: 10.1002/ijch.201900171
Cu(II)-Catalyzed Ortho-Selective Amination of Simple
Phenols with O-Benzoylhydroxylamines
Nan-Qi Shao+,[a] Zhi-Li Yao+,[a] and Dong-Hui Wang*[a]
Abstract: A Cu(II)-catalyzed ortho-selective amination of and electrophilic amine are compatible, and the protocol
simple phenols with O-benzoylhydroxylamines has been typically delivers the products in moderate to good yields.
developed, which provides access to 2-aminophenols under The mechanistic detail of this process are discussed.
mild conditions. Various functional groups on the phenol
Keywords: Phenol · Cu-catalyzed · Ortho-selective · Amination · O-Benzoylhydroxylamines
BF3 at 140–145 C, albeit in low yield (Scheme 1a).[7] In 2004,
Johnson and coworkers disclosed for the first time that Cu-
catalysts could dramatically elevate the reactivity of O-
benzoylhydroxylamines in amination reactions of organo-
metallic nucleophiles.[8] Since that time, many useful protocols
have been developed based on Johnson’s original discovery,
and mechanisms involving single-electron or two-electron-
transfer processes have been proposed.[9]
°
25 years ago, the discovery of a general method for Pd-
catalyzed CÀ N bond formation employing simple and readily
available aryl halides and amines sparked a revolution the
synthesis of nitrogen-containing small molecules.[1] Since then,
many transition-metal-catalyzed CÀ N bond coupling protocols
have been developed, and these protocols have found utility in
the synthesis of natural products, biologically active com-
pounds, active pharmaceutical ingredients (APIs), and
materials.[2] Following a reaction design philosophy of the
converting structurally simple and readily available starting
materials to the useful molecules, we have focused our
research on simple phenols and have sought to develop
methods to achieve the exclusive positional-selectivity for
phenol functionalization.
Phenols represent an ideal and sustainable class of
substrates in synthetic chemistry. Phenolic moieties are widely
present in the fossil fuels, natural products, dyes, diets,
pharmaceutical molecules, and synthetic fabrics.[3] For exam-
ple, Aspirin® (acetylsalicylic acid), which occupies a unique in
medicine since its development in 1899, is a typical phenol
derivative. The industrial production of salicylic acid employs
the Kolbe-Schmitt process,[4] which is a carboxylation of
sodium phenoxide with carbon dioxide under high temperature
and high pressure. This process provides the desired salycilic
acid (2-carboxylic phenol), together with the inevitable side
products, namely 4-carboxylic phenol, 2,4-dicarboxylic
phenol, and 2,6-dicarboxylic phenol, and thus a sublimation of
salicylic acid must be performed during the purification.
Hence, achieving exclusive positional-selectivity in phenol
transformations is very important. To this end, we have
developed an ortho-selective aminomethylation of simple
phenols,[5] and an ortho-selective dearomative amination of
2,6-disubstituted phenols.[6] Herein, we report a Cu-catalyzed
direct ortho-amination of simple phenols with O-benzoylhy-
droxylamines under the mild reaction conditions.
Though many methods for amination of 2-naphthols at the
1-positions have been developed,[10] the direct amination of
simple phenols remains a challenge, most likely due to the
comparatively low reactivity of phenols. Recently, the Patur-
eauin, Xia, Lei, and Chen groups have independently
developed oxidative CÀ N coupling reactions of phenols with
amines (Scheme 1b),[11] and Luo reported an efficient Fe-
catalyzed alkylamination of phenols with O-benzoyl-N-alkyl-
hydroxylamines (Scheme 1c).[12] These protocols provided
facile access to various aminated phenol derivatives. However,
these transformations tolerated only naphthols, para-substi-
tuted electron-rich phenols, and specific amine partners.
Additionally in many cases the ortho- vs para-selectivity was
modest. Recently, we reported a Cu-catalysed dearomative
amination procedure, in which 2,6-disubstituted phenols
reacted exclusively at the ortho-position with O-benzoylhy-
droxylamines to provide α-aminocyclohexa-2,4-dienones
(Scheme 1d).[6] In a series of mechanistic studies, we moni-
tored the the reaction mixture with EPR and solvent-assisted
[a] N.-Q. Shao,+ Z.-L. Yao,+ D.-H. Wang
CAS Key Laboratory of Synthetic and Self-Assembly Chemistry
for Organic Functional Molecules; Center for Excellence in
Molecular Synthesis
University of Chinese Academy of Sciences; Shanghai Institute of
Organic Chemistry, CAS.
345 Lingling Rd. Shanghai 200032, China
E-mail: dhwang@sioc.ac.cn
In 1961, Kovacic demonstrated that O-benzoylhydroxyl-
amines were an effective family of electrophilic amination
reagents, demonstrating that phenol could be aminated at the
ortho-position in the presence of O-benzoylhydroxylamine and
[+] These authors contribute equally.
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/ijch.201900171
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Table 1. Optimization of Reaction Conditions a.
Scheme 1. Ortho-Selective CÀ N Bond Formation with Phenols.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Cu-catalyst
(10 mol%), base (3 equiv.), in 50 mL sealed tube, N2 atmosphere,
electrospray ionization mass spectrometric (SAESI-MS) tech-
*
nologies, and observed evidence for the presence of OtBu and
b
1
*
6 h. Determined by H NMR analysis of crude reaction mixture
using CH2Br2 as internal standard; isolated yield is given in
parenthesis.
NR1R2 radicals, but not phenolic radical or derivatives
thereof. We also observed the a (ArO)CuIII(NR1R2)(OBz)
intermediate from the reaction mixture with SAESI-MS. Based
on these observations and the high levels of ortho-selectivity,
we proposed that the reaction proceeded through a mechanism
involving amino-radical attacking the ortho-oposition of the
phenol via an inner-sphere electron transfer pathway. Based on
these results, we envisioned that this type of reaction model
might be applicable to the ortho-selective amination of simple
phenols to provide the 2-aminophenols (Scheme 1e).
solvents at room temperature. Cyclohexane was found to be a
superior solvent for the transformation compared to THF,
DCM, 1,4-dioxane, and PhMe, giving 51% isolated yield of
3a (entries 6–10). we also reexamined the solvent effect for
these tert-butoxides bases, we found that reaction yields
followed the same trend as that of in THF, and LiOtBu is the
most effective base for the transformation. Both 1a and 2a
have poor solubility in cyclohexane, so we elevated the
reaction temperature in order to increase the reactants’
solubility. Indeed, it turned out that a higher isolated yield of
We began our investigation by exploring the reaction
between 4-isopropylphenol (1a) and N-benzoyloxymorpholine
(2a) (Table 1). When using 10 mol% Cu(OAc)2 as the
t
°
catalyst, 3 equiv. of LiO Bu as the base, and THF at 80 C, the
°
reaction provided the desired ortho-aminated product, 4-
isopropyl-2-N-morpholinylphenol (3a), in 41% isolated yield
(entry 1). Using THF as the solvent, we examined the reaction
parameters, and found that no reaction took place in the
absence of either Cu(OAc)2 or base (entries 2–3). Various
bases were then examined, and we found that tert-butoxide
salts were efficient in affording the desired CÀ N coupling
product 3a, with LiOtBu proving superior to NaOtBu and KO
tBu (entries 4–5). Other bases, such as NaOMe, NaHCO3,
Na2CO3, NaOAc, K2CO3, Cs2CO3, Li2CO3 were ineffective to
the reaction. When the reaction temperature was decreased to
room temperature, a similiar yield of desired product of 3a
was obtained (41%, entry 6). Hence, we next screened
3a (67%) was obtained at 60 C (entry 11). Further increasing
the reaction temperature did not lead to improvement
(entry 12). Various copper-catalysts were examined, and we
found that most of these Cu-salts could catalyze the trans-
formation, with Cu(OAc)2 proving optimal among the tested
catalysts (entries 11–16). It should be noted that when using
cyclohexane as solvent, the reaction provided 35% yields of
3a, even when no Cu(OAc)2 was employed (entry 17), this is
different phenomenon compared to the THF solvent (entry 2).
We speculate that the reaction might proceed via different
mechanisms in different types of solvent. Furthermore, no
reaction took place in cyclohexane solvent in the absence of
LiOtBu (entry 18). Based on these screening results, we chose
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entry 11 as the optimal reaction conditions and examined the
substrate scope.
Phenols bearing para-substituents tolerated the conditions
well and provided good yield of the corresponding products
(67% for 3a, and 74% for 3j). Various functional groups on
the phenol were compatible, including TBDMS-protected
alcohol, alkyne, and ester (3k–3m). Halides, such as chloro-
and bromo- groups, were also compatible in the reaction,
though in these cases the yields of the desired CÀ N coupling
products were low (3k, and 3n–3p).
The scope of aminating reagent was examined with 4-
isopropylphenol (1a) (Table 3). Six-membered cyclic O-
benzoylhydroxylamines were compatible under standard con-
ditions, providing the CÀ N coupling products in moderate
yields (38–56%, 4a–4h). Various functional groups on the
aminating reagents were compatible, including Boc-protected
piperazine (4b), an acetal group (4c), carboxylic esters (4d,
4e), an amino-substituted piperidine (4f), and N-aryl sub-
stituted piperazines (4g, and 4h).
In order to gain some mechanistic details about this ortho-
selective amination of phenols, we performed several experi-
ments. We found that the addition of radical scarvenger into
the standard reaction only slightly inhibited the transformation.
For example, when 1 equiv. of TEMPO was added into the
standard reaction mixture of 1a and 2a, the desired product,
3a, was obtained in 61% yield (compared to 67% yield under
standard conditions); when amount of TEMPO was further
increased to 2 equiv., the reaction gave 56% yield of 3a.
(Eq. 1). Both results are different compared to those obtained
in Luo’s FeCl3-catalyzed system (Scheme 1c) where the
reaction was completely inhibited upon addition of 1 equiv. of
TEMPO. This indicates that our reaction might proceed via a
different pathway from Luo’s method.[12] Next, we used 4-
methylanisole as the strating material and treated it under the
standard conditions; in this case, 4-methylanisole was recov-
ered, and no animation product was detected (Eq. 2). This
The substrate scope of simple phenols was examined with
N-benzoyloxymorpholine (2a). Various substituted simple
phenols showed good reactivity, and exclusive ortho-selectiv-
ity was achieved under these mild reaction conditions,
providing the corresponding 2-amino-substituted phenols in
moderate to good yields (Table 2). Substituents at the 2-
position of the phenols, such as 2-methyl, 2-phenyl, and 2-
benzyl phenol provided the desired 2-amino-6-subsitituted
phenol products in 49–63% yields (3b–3d). Multiply alkyl-
substituted phenol substrates, such as 5-methyl-2-isopropyl-
phenol, 2,3-dimethylphenol, tetrahydronaphalen-1-ol, and 3,5-
dimethylphenol afforded the desired 2-amino-dialkyl-substi-
tuted phenols in 53–75% yields.[13] When phenol (1i) was
used as the starting material (1 mmol scale), the reaction gave
only 30% yield of the desired 2-N-morpholinylphenol product
(3i), and the majority of unreacted phenol was recovered; we
also isolated 2% yield of 2,6-di-morpholinylphenol (3i–di). It
should be noted that in these phenol substrates (1a–1i), only
the ortho-positions were selective aminated, and the para-
positions in these substrates remained untouched. We further
verified the exclusive formation of 3i by comparing the crude
reaction mixture with an authentic, independently prepared
1
sample of 4-N-morpholinylphenol with H NMR and GC-MS
(See SI).
Table 2. Phenol Scope for ortho-Selective Amination a.
Table 3. Amine Scope for ortho-Selective Amination a.
a
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Cu(OAc)2
°
Reaction conditions: 1i (0.2 mmol), 2 (0.4 mmol), Cu(OAc)2
°
t
(10 mol%), LiO Bu (3 equiv.), 60 C, N2 atmosphere, sealed-tube,
6 h.b 1 mmol scale.
t
(10 mol%), LiO Bu (3 equiv.), 60 C, N2 atmosphere, sealed-tube,
6 h.
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Based on our previous mechanistic study of the dearoma-
tive amination of phenols,[6] we believe that this transformation
might involve a mechanism of an aminyl radical attacking
phenol at the ortho-position via an inner-sphere electron
transfer model. However, other possible pathways cannot be
ruled out, including but not limited to: 1) electrophilic addition
of phenol to an (ArO)CuIII(NR1R2)(OBz) species; 2) copper-
promoted SN2-type attack of phenol on to the O-
benzoylhydroxylamines;[8c] and 3), Ullman-type OÀ N cou-
pling, followed by rearrangement via a tight ion pair (for
details, see SI). Detailed mechanistic investigations are on-
going.
In conclusion, we have developed a practical Cu-catalyzed
procedure that provides 2-aminophenols under mild condi-
tions. This transformation takes place exclusively at the ortho-
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mechanistic details of the transformation are ongoing.
[7] P. Kovacic, R. Bennett, J. Foote, J. Org. Chem. 1961, 26, 3013.
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Acknowledgements
We gratefully acknowledge support from the National Key
R&D Program of China (2016YFA0202900), the Strategic
Priority Research Program of the Chinese Academy of
Sciences (XDB20000000), and the CNSF 21871286.
[12] L. Jia, S. Gao, J. Xie, M. Luo, Adv. Synth. Catal. 2016, 358,
3840.
References
[13] It should be noted that in all cases only the ortho-CÀ C coupled
product was detected; no para-position products were observed.
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Manuscript received: February 20, 2020
Revised manuscript received: February 8, 2020
Version of record online: ■■■, ■■■■
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N.-Q. Shao, Z.-L. Yao, D.-H. Wang*
1 – 5
Cu(II)-Catalyzed Ortho-Selective
Amination of Simple Phenols with
O-Benzoylhydroxylamines
Direct ortho-position amination of
simple phenols is developed. The
reaction proceeds under mild reaction
conditions, and good to high yields are
achieved. Only ortho-position to the
phenolic hydroxyl groups are active for
this transforation, while para-positions
are inactive.