Copper-catalyzed N=H insertion and oxidative aromatization cascade: Facile synthesis of 2-arylaminophenols

Article abstract of DOI:10.1002/asia.201402080

A copper-catalyzed cascade reaction of N-H insertion and oxidative aromatization has been developed. 2-Arylaminophenols have been prepared in moderate to high yields from the diazo substrates. Moreover, this newly established methodology allows efficient access to natural 1-oxygenated carbazole alkaloids, such as glycozolicine and murrayafoline A. Copper falls: A copper-catalyzed cascade reaction of N=H insertion and oxidative aromatization yields 2-arylaminophenols. This newly established methodology also allows efficient access to natural 1-oxygenated carbazole alkaloids, such as glycozolicine and murrayafoline A.

Full text of DOI:10.1002/asia.201402080

COMMUNICATION
DOI: 10.1002/asia.201402080
À
Copper-Catalyzed N H Insertion and Oxidative Aromatization Cascade:
Facile Synthesis of 2-Arylaminophenols
Dong Ding, Xiaobing Lv, Jian Li, Guangyang Xu, Bing Ma, and Jiangtao Sun*[a]
Abstract: A copper-catalyzed cascade reaction of N-H inser-
tion and oxidative aromatization has been developed. 2-Ar-
ylaminophenols have been prepared in moderate to high
yields from the diazo substrates. Moreover, this newly estab-
lished methodology allows efficient access to natural 1-oxy-
genated carbazole alkaloids, such as glycozolicine and mur-
rayafoline A.
Carbon–nitrogen bonds are ubiquitous in organic mole-
À
cules, and thus the construction of C N bonds is of consider-
able importance for the field of synthetic organic chemis-
try.[1] The insertion of metal carbene into N H bonds of
À
amine derivatives represents one of the most efficient ap-
proaches to prepare a-amino acids, a-amino ketones, and ni-
trogen-containing heterocycles.[2] Even though Yates report-
À
ed the first copper-catalyzed N H insertion (NHI) of diazo
acetates over 60 years,[3] the introduction of dirhodium(II)
catalysts made this reaction practical in organic synthesis.[4]
Recently, the groups of Zhou,[5] Fu,[6] and Feng[7] reported
the copper-catalyzed enantioselective NHI, in which privi-
leged ligands were required to achieve high enantioselectivi-
Scheme 1. Our synthetic plan towards 2-arylaminophenols.
ty as well as good reactivity. Recent reports highlighted the
combination of copper-catalyzed NHI with other transfor-
mations in one-pot,[8] which further broadened the applica-
tion of copper carbenoid chemistry. Copper complexes are
relatively cheap and readily available, so it is still highly de-
sirable to develop a novel organic transformation based on
copper-catalyzed NHI, instead of precious rhodium catalyst.
Palladium-catalyzed oxidative dehydrogenative aromati-
zation is a fundamental methodology to prepare aromatic
compounds from nonaromatic precursors (Scheme 1b,c).[9]
Although copper complexes have been widely utilized in
various aerobic oxidative reactions,[10] copper-catalyzed de-
hydrogenative aromatization reactions remain scare. In
2012, Li and co-workers reported an elegant copper-mediat-
ed intermolecular condensation/aromatization cascade pro-
cedure for synthesizing aromatic ethers.[11] However, this
procedure required one equivalent of copper complex, or
the addition of N-hydoxyphthalimide (NHPI) was essential
if a catalytic amount of copper complex was used. Just re-
cently, Zhai and co-workers described a Pd-catalyzed cross-
coupling reaction of aryl iodides and 6-diazo-2-cyclohexe-
nones to produce the 2-aryl-phenols,[12] which featured mi-
gratory insertion of Pd-carbene species followed by b-H
elimination to afford a newly formed C=C bond as the key
step.
Herein, we report a copper-catalyzed NHI and oxidative
dehydrogenative aromatization cascade process for the syn-
thesis of 2-arylaminophenols (Scheme 1d). This type of
phenol is a common motif in a variety of natural products
and pharmaceuticals with significantly biological activities.[13]
In our strategy, the remaining challenge is to realize these
two different transformations in one-pot catalyzed by only
one copper complex, but without the commonly used metals
rhodium and palladium. This protocol, which started from
the reaction of diazo substrates, represents an alternative
approach to the traditional Buchwald–Hartwig reaction,[14]
Ullmann-type amination[15] (Scheme 1a), and other method-
ologies to access the diarylamine scaffold.[16]
[a] D. Ding, X. Lv, Dr. J. Li, G. Xu, Dr. B. Ma, Prof. Dr. J. Sun
School of Pharmaceutical Engineering&Life Science
Changzhou University
Changzhou 213164 (P. R. China)
Fax : (+86)519-86334598
E-mail: jtsun08@gmail.com
We initially tested the reaction of 1a and 2a in the pres-
ence of 10 mol% CuI in 1,4-dioxane at room temperature in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402080.
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Jiangtao Sun et al.
Table 1. Optimization of the reaction conditions.[a]
Entry Cu complex
(equiv)
Solvent
T [8C] t [h] 3aa (3a’a) [%][b]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
CuI (0.1)
1,4-dioxane 25
1,4-dioxane 25
1,4-dioxane 25
1,4-dioxane 25
1,4-dioxane 25
12
12
12
12
12
12
12
12
8
3
3
3
3
3
3
3
3
3
3
32 (48)
12 (53)
14 (35)
26 (45)
25 (48)
12 (31)
26 (22)
46 (45)
74 (12)
93 (0)
<5 (57)
<5 (63)
48 (<5)
42 (<5)
62 (0)
CuBr (0.1)
CuCl (0.1)
CuO (0.1)
CuBr2 (0.1)
[CuACHTUNGTRENNUNG(acac)2] (0.1) 1,4-dioxane 25
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
N
1,4-dioxane 25
1,4-dioxane 25
1,4-dioxane 40
1,4-dioxane 80
9[c]
10[d]
11[c]
12[d]
13[d]
14[d]
15[d]
16[d]
17[d]
18[d]
19[d]
CH2Cl2
DCE
DMF
DMSO
toluene
CH3CN
THF
40
80
80
80
80
80
66
66 (0)
60 (<5)
82 (0)
11 (0)
[a] Reaction conditions: 1a (1 mmol), 2a (0.5 mmol), copper catalyst
(0.05 mmol), solvent (3 mL) under air at 258C unless otherwise noted.
[b] Isolated yields of 3aa. The yields in parenthesis refer to the yield of
3a’a. [c] The reaction was performed at 408C under O2 in a sealed tube
for 8 h. [d] The reactions were performed at 808C under O2 in a sealed
tube. acac=pentane-2,4-dione, OTf=CF3SO3.
an air atmosphere. After 12 h, 3aa was isolated in 32%
yield along with 48% 3a’a (Table 1, entry 1). Next, catalyst
screening showed Cu
entry 8). Other copper catalysts such as CuBr, CuCl, CuO,
CuBr2, Cu(acac)2, and Cu(OTf)2 were inferior to Cu(OAc)2
ACHTUNGERTN(NUNG OAc)2 gave the best result (Table 1,
Scheme 2. Substrate scope. Reaction conditions:
1
(1 mmol),
2
(0.5 mmol), Cu(OAc)2 (0.05 mmol), in 1,4-dioxane (3 mL) with O2 in
AHCTUNGTRENNUNG
G
A
ACHTUNGTRENNUNG
a sealed tube at 808C for 3 h. Yields of isolated product are given. [a] Re-
(Table 1, entries 2–7). Given the large amount of 3a’a pro-
duced in the reaction, we reasoned that higher reaction tem-
perature and an atmosphere of molecular oxygen would
probably improve the oxidative aromatization to minimize
the amount of 3a’a. To our delight, after careful examina-
tions, we found that the reaction could be finished in 3 h at
evaluated temperature under O2 in a sealed tube. Moreover,
the reaction was clean and afforded 3aa in 93% yield
(Table 1, entry 10). Next, solvent screening indicated that
3a’a was obtained as the major product in dichloromethane
and 1,2-dichloroethane (DCE) (Table 1, entries 11 and 12).
In contrast, lower yield of 3aa was observed when the reac-
tions were conducted in N,N-dimethylformamide (DMF), di-
methyl sulfoxide (DMSO), toluene, acetonitrile, and THF
(Table 1, entries 13–17). Notably, the use of a stoichiometric
action time is 8 h.
the electron-deficient anilines even with shorter reaction
time. The ortho-substituted anilines displayed lower reactivi-
ty than para and meta-substituted anilines (Scheme 2, 3ab,
3ae, 3ak, 3al and 3bo). In addition, N-methyl substituted
aniline (2p) was also tolerated in the reaction and gave 3ap
in 59% yield. For the diazo substrates investigated, the sub-
stituents did not affect the reactivity significantly. Even for
the more sterically hindered diazo cyclohexenone, the reac-
tions still proceeded smoothly to afford the desire diaryla-
mines in moderate to high yields (Scheme 2, 3ca, 3cd, 3ch).
1-Oxygenated carbazole alkaloids have been found
mainly in Rutaceae family plants such as Murraya, Clausena,
and others (Scheme 3).[13] These alkaloids have received
considerable attention due to their diverse and significant
biological activities. Thus much effort has been paid toward
a general and flexible approach to access this 1-oxygenated
carbazole scaffold.[17]
amount of Cu
entry 19).
ACHTUNGTRENNUNG(OAc)2 resulted in much lower yield (Table 1,
With the optimized reaction conditions in hand, we next
examined the substrate scope. An array of anilines and
diazo substrates were subjected to this cascade procedure
(Scheme 2). Generally, the electron-rich anilines delivered
the corresponding 2-arylaminophenols in higher yields than
Using our newly established methodology, we pursued
a simple and efficient route to two natural 1-oxygenated car-
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ÝÝ These are not the final page numbers!

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Jiangtao Sun et al.
Scheme 5. Control experiments.
pounds, those catalytic systems involve prior reduction from
CuII to CuI by the diazo substrates.[18] The actual catalytically
active copper species is CuI in copper carbenoid chemis-
try.[4,8d,18] So a plausible reaction mechanism is proposed in
Scheme 6. The first catalytic step is Cu-mediated NHI to
Scheme 3. Natural 1-oxygenated carbazole alkaloids.
bazole alkaloids (glycozolicine and murrayafoline A) on
a gram scale (Scheme 4). It was easy to prepare the key dia-
rylamine intermediates 3ad and 3ba in high yields. After
methylation and palladium-catalyzed annulation, glycozoli-
cine was obtained in 67% yield[17a] and 76% yield[17b] in
three steps, murrayafoline A in 60% yield[17a] and 42%
yield.[17b] Obviously, this approach can be employed to pre-
pare other 1-oxygenated carbazole alkaloids.
Scheme 4. Synthesis of glycozolicine and murrayafoline A on a gram
scale. Reaction conditions: i) 1 (20 mmol),
(1 mmol), O2, 1,4-dioxane, sealed tube, 808C, 3 h. ii) MeI, K2CO3,
Me2CO, reflux, 3 h. iii) A: Pd(OAc)2, HOAc, 1408C, 10 h. B: Pd(OAc)2
(5 mol%), K2CO3 (10 mol%), pivalic acid, 1108C, 14 h.
2 (10 mmol), CuCATHUNTGNRUEGN(OAc)2
A
ACHTUNGTRENNUNG
To further understand the reaction process, we conducted
control experiments (Scheme 5). Under a nitrogen atmos-
phere, 3a’a was isolated as the sole product (Scheme 5a). In
addition, when 3a’a was subjected to standard reaction con-
Scheme 6. Proposed reaction mechanism.
afford the insertion intermediate 3a’a. Secondly, 3a’a’ is gen-
erated through tautomerization of 3a’a; subsequent electro-
philic addition of [Cu]OAc produces intermediate A. Elimi-
nation of HOAc gives intermediate B, which undergoes de-
protonation to deliver intermediate C and Cu0 species. Fi-
nally, intermediate C would quickly tautomerize to its more
stable isomer 3aa, while the Cu0 species could be reoxidized
to a higher oxidative state in the presence of molecular
oxygen to complete the second catalytic cycle.
ditions in the absence of Cu
(Scheme 5b). In addition, the reaction gave a complex mix-
ture when the Cu(OAc)2 was added (Scheme 5b). As de-
scribed in Table 1, the use of a stoichiometric amount of Cu-
ACHTUNGTRENNUNG(OAc)2 gave 3a’a in very low yield (Table 1, entry 19).
ACHTUNGRTEN(NUNG OAc)2, no 3aa was detected
ACHTUNGTRENNUNG
These experiments revealed that the formation of 3a’a
served as the key step during the cascade process. Moreover,
the actual active copper species was not Cu
ACHTUNGRTENUN(NG OAc)2, which
could explain why a large amount of Cu(OAc)2 led to
G
In summary, we have demonstrated here a novel and effi-
cient strategy for the synthesis of 2-arylaminophenols. A va-
riety of aniline derivatives with different substituents afford-
ed the desired phenols in moderate to high yields. Notably,
this one-pot cascade procedure involves a copper-carbene
a much lower yield and the stepwise oxidation of 3a’a gave
a complex mixture of products.
As reported by Kochi and Salomon, although CuII com-
plexes are highly active catalysts in reactions of diazo com-
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These are not the final page numbers! ÞÞ

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Jiangtao Sun et al.
À
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Experimental Section
À
Typical Procedure for Copper-Catalyzed N H Insertion and Oxidative
Aromatization Cascade
A 25 mL Schlenk tube was charged with copper(II) acetate (10 mol%),
evacuated, and refilled with molecular oxygen (three cycles) by using
a balloon. Aniline (0.5 mmol), 6-diazo-2cyclohexenone (1 mmol), and
1,4-dioxane (3 mL) were added by syringe. Then the balloon was re-
moved and the tube was sealed, and the reaction mixture was stirred at
808C for 3–8 h. After the mixture was cooled to room temperature, sol-
vents were removed under vacuum. The residue was purified by column
chromatography on silica gel and eluted with petroleum ether and ethyl
acetate to give the pure product.
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We gratefully acknowledge the National Natural Science Foundation of
China (21172023, 2102010), a project funded by the Priority Academic
Program Development of Jiangsu Higher Education Institutions (PAPD),
and STD of Jiangsu Province for their financial supports.
Keywords: aromatization · copper · diazo compounds ·
domino reactions · homogeneous catalysis
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Received: February 19, 2014
Published online: && &&, 0000
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Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

COMMUNICATION
Homogeneous Catalysis
Dong Ding, Xiaobing Lv, Jian Li,
Guangyang Xu, Bing Ma,
Jiangtao Sun*
&&&& — &&&&
À
Copper-Catalyzed N H Insertion and
Oxidative Aromatization Cascade:
Facile Synthesis of 2-Arylaminophe-
nols
Copper falls: A copper-catalyzed cas-
cade reaction of N H insertion and
oxidative aromatization yields 2-aryla-
minophenols. This newly established
methodology also allows efficient
access to natural 1-oxygenated carba-
zole alkaloids, such as glycozolicine
and murrayafoline A.
À
5
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Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ