Organocatalytic Para-Selective Amination of Phenols with Iminoquinone Monoacetals

Article abstract of DOI:10.1021/acs.orglett.7b01700

A highly selective para C-H amination of unprotected phenols with iminoquinone acetals was realized, giving the functional phenols in good to excellent yields. Overall, this transformation is operationally simple, proceeds with readily available phenols, and has wide substrate scope and low catalyst loading. The biarylamine product is stochastically formed via [5,5]-sigmatropic rearrangement of a mixed acetal species which is generated in situ under the reaction conditions.

Full text of DOI:10.1021/acs.orglett.7b01700

Letter
pubs.acs.org/OrgLett
Organocatalytic Para-Selective Amination of Phenols with
Iminoquinone Monoacetals
Liu Liu,† Kun Chen,† Wen-Zhen Wu, Peng-Fei Wang, Hang-Yu Song, Hongbin Sun, Xiaoan Wen,*
and Qing-Long Xu*
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China
Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China
S
* Supporting Information
ABSTRACT: A highly selective para C−H amination of
unprotected phenols with iminoquinone acetals was realized,
giving the functional phenols in good to excellent yields.
Overall, this transformation is operationally simple, proceeds
with readily available phenols, and has wide substrate scope
and low catalyst loading. The biarylamine product is
stochastically formed via [5,5]-sigmatropic rearrangement of a mixed acetal species which is generated in situ under the
reaction conditions.
ite-selective C(sp2)−H functionalizations of monosubsti-
Stuted benzenes have attracted considerable interest from
the organic community since they provide rapid and
straightforward access to many structurally different analogues.
Its importance in the late-stage modification of pharmaceuti-
cally active molecules is especially noteworthy.1 The develop-
ment of direct C−H functionalization approaches of
unprotected phenols has received significant attention in recent
years2 due to their wide occurrence in natural products and
medicinal drugs. They also serve as common and versatile
building blocks involved in numerous organic reactions.3 Over
the past decade, the indirect ortho-selective C−H functionaliza-
tion of phenols has been extensively investigated by installing
the directing group on the hydroxyl group.4 On the other hand,
the development of new methods for site-selective direct C−H
functionalization of unprotected phenols is highly interesting
but more challenging, since the unprotected phenols contain
several possible reaction sites. Thus far, only limited approaches
to site-selective C−H functionalization of unprotected phenols
have been reported. Among the reported examples, the para-
Figure 1. Para-selective C−H functionalization of phenols.
selective C−H functionalization of unprotected phenols was
focused on C−C bond couplings (Figure 1). In 2011, Gaunt’s
especially C−H amination. Until now, only electrophilic
amination of unprotected phenol was realized, but with low
site selectivity.9 As part of our interest in developing site-
selective direct C−H functionalization of unprotected phenols
via rearrangement, we recently utilized iminoquinones as
arylating reagents to give access to chiral non-C2-symmetric
BINOL-type biaryls from 2-naphthols.10 Encouraged by this
result, we envisioned that using new iminoquinone acetal
structures might lead to the para-selective C−H amination of
phenols via [5,5]-rearrangement.11 This constitutes a novel
group developed a highly para-selective copper-catalyzed direct
arylation of unprotected phenol, but with low yield.5 Later,
Zhang and co-workers reported highly para-selective direct C−
H bond functionalization of unprotected phenols with α-aryl α-
diazoacetates via gold catalysis.6 Recently, Wu and co-workers
realized para-selective direct C−C bond couplings reaction
between phenols and acetophenones, affording 4-hydroxybenzil
derivatives.7 Kita and co-workers reported para-selective direct
C−C bond cross-couplings of quinone monoacetal with
phenols.8
Given the importance of phenolic compounds, the develop-
ment of novel approaches to para-selective direct C−H
functionalization of unprotected phenols is highly desirable,
Received: June 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01700
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Letter
approach to para-selective C−H functionalization of unpro-
tected phenol, and it is completely different from the reported
examples.
Table 2. Examination of Different Iminoquinone
Monoacetals
a
On the basis of our previous work, we selected N-Ms-
protected iminoquinone acetal (2a) as the substrate that
reacted with 1-naphthol (1a). Gladly, a 10 mol % loading of
TsOH·H2O catalyzed the para-selective C−H amination of 1a
with 2a under mild conditions (room temperature) to afford
the desired amination product (3aa) in 31% yield. The
structure of 3aa was confirmed by single-crystal X-ray
crystallography (see the Supporting Information for details).12
Encouraged by this interesting result, we investigated different
acids to optimize the reaction condition further, and the results
are summarized in Table 1. DPP was found to be the best
a
Table 1. Reaction Optimization
b
entry
2
3
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
3aa
3ab
3ac
3ad
3ae
3af
2
2
98
trace
20
168
2
80
b
entry
acid
Sc(OTf)3
solvent
yield (%)
2
88
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
61
48
34
77
31
86
93
83
92
89
74
61
74
0
2
76
2
AlCl3
2g
2h
2i
3ag
3ah
3ai
2
85
3
PhCO2H
p-NO2C6H4CO2H
TsOH·H2O
TFA
2
97
4
2
70
5
a
Reaction conditions: 1a (1.2 equiv), 2 (0.2 mmol), DPP (1 mol %),
CH2Cl2 (3.0 mL), rt. Isolated yield.
6
b
7
DPP
8
DPP
9
DPP
substituents on the iminoquinone ring and nitrogen atom of
acetal 2 were evaluated. It was found that compound 2b
without substitution on the iminoquinone ring was unstable
and easy to be hydrolyzed. When 3,5-dimethyl-substituted
acetal (2c) was employed for this reaction, the desired product
was obtained in only 20% yield even with longer reaction time,
probably due to its steric hindrance (entry 3, Table 2), and 2,3-
dimethyl-substituted acetal (2d) with less steric hindrance
afforded the desired product in 80% yield (entry 4, Table 2).
The monosubstituted acetals (2e and 2f) were found to react
smoothly with 1-naphthol to furnish the corresponding
products in acceptable yields. Moreover, acetals (2g and 2h)
with electron-withdrawing groups (Boc and Ts) adjacent to the
nitrogen atom were found to be good substrates for this
transformation, affording the desired products in 85% and 97%
yields, respectively (entries 7 and 8, Table 2). It is noted that 1-
naphthol-derived iminoquinone acetal (2i) could be also
introduced to this transformation, affording the desired product
3ai in 70% yield (entry 9, Table 2).
Subsequently, a variety of substituted 1-naphthols (1) were
evaluated in the reaction with 2a, and the results are
summarized in Scheme 1. When the methyl group was
introduced at the β-position of 1-naphthol (1b), the reaction
proceeded smoothly, giving the amination product in 73%
yield. Electron-donating (3-Me, 6-OMe, 7-Ph) or electron-
withdrawing groups (7-Br) on the aryl ring were well tolerated,
and the corresponding products were obtained in excellent
yields (89−95%, 3ca−fa). Notably, reaction of naphthalene-
1,8-diol (1g) with 2a provided the corresponding product
(3ga) in 65% yield. Interestingly, reaction of 4-methyl-1-
naphthol (1k) possessing a blocked para-position afforded
ortho-amination product (3ka), albeit in low yield (36%).
10
11
12
13
14
DPP
THF
DPP
MeCN
toluene
MeOH
DMF
DPP
DPP
DPP
c
15
DPP
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
85
86
89
94
83
98
d
16
DPP
e
17
DPP
f
18
g
DPP
19
DPP
h
20
DPP
a
Reaction conditions: 1a (1.5 equiv), 2a (0.2 mmol), acid (10 mol %),
b
c
d
solvent (3.0 mL), rt. Isolated yield. Using DPP (5 mol %). Using
e
f
g
DPP (2 mol %). Using DPP (1 mol %). Using 1a (1.2 equiv). Using
1a (1.0 equiv). Reacted at 0 °C, using 1a (1.2 equiv) and DPP (1 mol
h
%). TFA = trifluoroacetic acid. DPP = diphenyl phosphate.
organocatalyst, giving the amination product in 93% yield
(entry 7, Table 1). Subsequently, common solvents were
evaluated in this transformation, and we found that most of the
solvents could be applied to the reaction, except DMF (entry
14, Table 1). CH2Cl2 was chosen as the optimal solvent due to
its simplicity for the operation. It was found that 1.2 equiv of 1a
and 1 mol % of DPP were sufficient for this transformation.
When the reaction was performed at 0 °C, the reaction
proceeded smoothly to give the product in high yield (entry 20,
Table 1).
With the optimal conditions in hand, we then examined the
generality of this para-selective C−H amination reaction. First,
the reaction of various iminoquinone acetals (2) with 1a was
investigated. The results are summarized in Table 2. Different
B
DOI: 10.1021/acs.orglett.7b01700
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Letter
a
providing moderate to excellent yields of the corresponding C−
H amination products (5a−o) in a regioselective manner.
Different electron-withdrawing and electron-donating substitu-
ents were well tolerated in this transformation. However, the
substrates with electron-withdrawing groups provided the
desired products in lower yields (e.g., 2,6-Cl2, 57%; 2-Br,
81%). It is noteworthy that the reaction of 3,5-dimethoxyl
phenol (4d) bearing a sterically hindered para C−H bond still
furnished the corresponding para C−H amination product
(5d) in 76% yield. Thymol (4l) and carvacrol (4m), two small
naturally occurring phenols, were evaluated in this trans-
formation, affording the desired products in 60% and 81% yield,
respectively. The reaction seems to tolerate the substrates
bearing dihydroxy groups such as catechol (4n) and resorcinol
(4o), leading to the direct para C−H amination products in
good yields (5n, 89% and 5o, 78%).
Scheme 1. Substrate Scope of Substituted 1-Naphthols
Furthmore, the selective ortho C−H amination products
were obtained when substituted 2-naphthols (6) were
employed in the reaction as shown in Scheme 3. The reaction
of 6 with 2,5-dimethyliminoquinone acetal (2a) produced the
corresponding ortho C−H amination products in moderate
yields (44−60% yields).
a
Reaction conditions: 1 (1.2 equiv), 2a (0.2 mmol), DPP (1 mol %),
CH2Cl2 (3.0 mL), rt.
a
Scheme 3. Substrate Scope of Substituted Phenols
Next, the reactions of various substituted phenols (4a−o)
with 2,5-dimethyliminoquinone acetal (2a) were then exam-
ined. As shown in Scheme 2, the reactions proceeded smoothly,
a
Scheme 2. Substrate Scope of Substituted Phenols
a
Reaction conditions: 6 (1.2 equiv), 2a (0.2 mmol), DPP (1 mol %),
CH2Cl2 (3.0 mL), rt.
Notably, the DPP-catalyzed selective para C−H amination of
unprotected phenols was practical for scale-up. A gram-scale
reaciton of 4h (1.0 g) and 2a proceed smoothly with only low
catalyst loading (1 mol %), giving the desired product (5h) in
95% yield (Scheme 4). Importantly, the product (5h) could be
Scheme 4. Gram-Scale Preparation of Product 5h and
Transformation
easily converted to carbazole derivative (9) in two steps
(protected hydroxy group and Pd-catalyzed C−H fuctionaliza-
tion) in moderate yield.
On the basis of previous studies,10 a probable reaction
pathway of this transformation is illlustrated in Scheme 5. 2,5-
Dimethyliminoquinone acetal (2a) is converted to Int-1 or Int-
2 under acid condition. For pathway (a), the acetal exchange
reaction occurs, leading to the mixed acetal Int-1 that
a
Reaction conditions: 4 (1.2 equiv), 2a (0.2 mmol), DPP (1 mol %),
CH2Cl2 (3.0 mL), rt.
C
DOI: 10.1021/acs.orglett.7b01700
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
State Administration of Foreign Expert Affairs of China (No.
111-2-07) and program for Changjiang Scholars and Innovative
Research Team in University (IRT1193), Project Program of
State Key Laboratory of Natural Medicines, China Pharma-
ceutical University (No. SKLNMZZYQ201607), and the
Program for Jiangsu Province Innovative Research Team.
Scheme 5. Proposed Mechanism
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01700.
■
S
Detailed experimental procedures and spectral data for
all new compounds (PDF)
Crystallographic data for compounds 3aa (CIF)
(10) (a) Wang, J.-Z.; Zhou, J.; Xu, C.; Sun, H.; Kurti, L.; Xu, Q.-L. J.
̈
Am. Chem. Soc. 2016, 138, 5202. (b) Gao, H.; Xu, Q.-L.; Keene, C.;
Yousufuddin, M.; Ess, D. H.; Kurti, L. Angew. Chem., Int. Ed. 2016, 55,
566.
̈
AUTHOR INFORMATION
Corresponding Authors
■
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(b) Endo, Y.; Terashima, T.; Shudo, K. Tetrahedron Lett. 1984, 25,
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K. J. Am. Chem. Soc. 1998, 120, 10490. (d) Kang, H.-M.; Lim, Y.-K.;
Shin, I.-J.; Kim, H.-Y.; Cho, C.-G. Org. Lett. 2006, 8, 2047. (e) Kim,
H.-Y.; Lee, W.-J.; Kang, H.-M.; Cho, C.-G. Org. Lett. 2007, 9, 3185.
(12) CCDC 1540340 (3aa) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
*E-mail: wxagj@126.com.
*E-mail: qlxu@cpu.edu.cn.
ORCID
Hongbin Sun: 0000-0002-3452-7674
Xiaoan Wen: 0000-0001-7852-1154
Qing-Long Xu: 0000-0003-4450-6866
Author Contributions
†L.L. and K.C. contributed equally.
Notes
(13) When electron-rich nucleophiles 1-methoxynaphthalene and
N,N-dimethyl-1-naphthylamine were employed to this transformation,
no reaction occurred, since they cannot generate the mixed acetal
intermediate.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation of
China (Grant Nos. 81473080, 81573299, and 21502230) is
gratefully acknowledged. This project was also supported by the
Jiangsu Province Natural Science Foundation (BK20150688),
the “111 Project” from the Ministry of Education of China, the
D
DOI: 10.1021/acs.orglett.7b01700
Org. Lett. XXXX, XXX, XXX−XXX