Copper-Catalyzed Ring Opening of Benzofurans and an Enantioselective Hydroamination Cascade

Article abstract of DOI:10.1002/anie.201809003

A copper(II) acetate/(R)-DTBM-SEGPHOS-catalyzed ring opening of benzofurans and enantioselective hydroamination cascade with dimethoxymethylsilane (DMMS) and hydroxylamine esters is described. Starting from readily available substituted benzofurans, a series of chiral N,N-dibenzylaminophenols, which are of high interest in pharmaceutical chemistry, were obtained with excellent enantioselectivities (up to 66 % yield, 94 % ee).

Full text of DOI:10.1002/anie.201809003

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Accepted Article
Title: Copper-Catalyzed Ring Opening of Benzofurans and
Enantioselective Hydroamination Cascade
Authors: Shuli You, Qing-Feng Xu-Xu, Qiang-Qiang Liu, and Xiao
Zhang
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10.1002/anie.201809003
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COMMUNICATION
Copper-Catalyzed Ring Opening of Benzofurans and Enantiose-
lective Hydroamination Cascade
Qing-Feng Xu-Xu, Qiang-Qiang Liu, Xiao Zhang,* and Shu-Li You*
Abstract: A copper (II) acetate/(R)-DTBM-SEGPHOS-catalyzed ring
opening of benzofurans and enantioselective hydroamination cas-
cade with dimethoxymethylsilane (DMMS) and hydroxylamine esters
was described. Starting from readily available substituted benzofu-
rans, a series of chiral N,N-dibenzylaminophenols of high potential in
pharmaceutical chemistry were obtained with excellent enantioselec-
tivity (up to 66% yield, 94% ee).
corresponding oxaborins (eq. 2, Scheme 1).[5d] In addition, the
Chang group seminally reported borane-catalyzed C(2)–O bond
cleavage of benzofurans to afford silicon-containing phenols (eq.
3, Scheme 1).[6] It is worth highlighting that the above examples
represent the breakthroughs within this domain.[5e] However, the
catalytic systems involving ring opening of benzofurans and
subsequent elaboration are still limited. More importantly, to the
best of our knowledge, the concomitant enantioselective trans-
formation with ring opening process remains as an unmet chal-
lenge.
Aromatic compounds are abundant, cheap and fundamental
synthetic starting materials, the chemistry involving their func-
tionalization and transformation is thus highly appreciated and of
prime importance. Recently, dearomatization reactions have
aroused continuing interest and been developed into a powerful
strategy for converting planar arenes into value-added mole-
cules in a straightforward fashion. Of particular note, the catalyt-
ic asymmetric dearomatization (CADA) reactions are aimed to
destroy the aromaticity and construct three-dimensional com-
pounds with high enantiomeric purity.[1],[2] However, the existing
strategies are typically restricted to those maintaining the ring
skeleton. The asymmetric dearomatization reactions involving
ring opening processes, more specifically, the cleavage of endo-
cyclic bonds, are scarcely explored due to remarkably high bond
strength and aromatic stabilization confronted. Undoubtedly,
manipulating the ubiquitous feedstocks by opening their rings
catalytically might bring novel and unprecedented reactivity.
In this regard, the limited racemic examples based on C(2)–
O bond cleavage of benzofurans and subsequent transfor-
mations are highly desirable, and constitute appealing strategies
to yield functionalized phenols. Generally, these approaches are
enabled by organometallic reagents in the presence of transition
metal complexes (eq. 1, Scheme 1).[3] The Studer group further
disclosed that the ring opening of benzofurans and indoles could
be promoted by silyl lithium under transition-metal-free[4] condi-
tions.[4b] Impressively, a recent emerging class of reactions is
“aromatic metamorphosis”, a term coined by the Yorimitsu
group.[5] They elegantly developed a Ni/NHC-catalyzed boron
insertion into the C(2)–O bond of benzofurans to deliver the
a) Previous work: C(2)-O bond cleavage of benzofuran
R
R-M
(eq. 1)
O
OH
M = Mg, Li, Al, SiLi
w or w/o transition metal
cat. Ni-NHC
B2(pin)2
(eq. 2)
(eq. 3)
B
O
O
O
OH
SiMe2Ph
borane, PhMe2SiH
OH
b) This work: Cu-catalyzed ring opening of benzofurans
and enantioselective hydroamination cascade
NR2
[CuH]
(eq. 4)
electrophilic amine source
O
OH
"+NR2"
Scheme 1. Ring opening reactions of benzofurans.
Chiral amines are widely distributed in pharmaceuticals.[7]
Since the pioneering works from the Buchwald group and the
Miura & Hirano group independently,[9a],[9b] copper hydride-
catalyzed enantioselective hydroamination reactions[8-10] repre-
sent one of the most attractive and efficient methods to access
chiral nitrogen-containing molecules with perfect control of regi-
oselectivity and enantioselectivity directly starting from alkenes
and alkynes. Inspired by these pioneering contributions and
given our research interest in catalytic asymmetric dearomatiza-
tion reactions, we are curious whether this robust method could
be extended to more challenging substrates such as benzofu-
rans, which are encountered with extra resonance stabilization
caused by aromaticity. Unexpectedly, a copper-catalyzed ring
opening and enantioselective hydroamination cascade was
found. The corresponding N,N-dibenzylaminophenols, which are
potential chiral ligands and biologically active molecules, were
obtained in moderate yields, perfect regioselectivity and good to
excellent enantioselectivity (eq. 4, Scheme 1). Herein, we report
our results from this study.
[*]
Q.-F. Xu-Xu, Q.-Q. Liu, Dr. X. Zhang, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: zhangxiao@sioc.ac.cn
slyou@sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
Prof. Dr. S.-L. You
Collaborative Innovation Center of Chemical Science and Engineer-
ing, Tianjin 300072 (China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201809003
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of the reaction conditions.[a]
yield was obtained when increasing the amounts of 1a and
(MeO)2MeSiH to five equivalents (38% yield, entry 7, Table 1).
Further investigation of solvents revealed that the reaction was
generally compatible with ether solvents (entries 9–11, Table 1,
and Supporting Information). Finally, an improved yield (55%)
was obtained when the reaction was performed under neat
conditions. As a consequence, the optimal conditions were
confirmed as follows: Cu(OAc)2 (10 mol%), (R)-DTBM-
SEGPHOS (L3) (11 mol%), 1a (1.0 mmol), 2a (0.2 mmol) and 3a
(1.0 mmol) were stirred under neat conditions at 45 ºC (entry 12,
Table 1).[11]
NBn2
OH
O
Cu(OAc)2 (10 mol%)
L3 (11 mol%)
NBn2
O
+
R
R
(MeO)2MeSiH (5 equiv)
neat, 45 oC, 36 h
O
Et2N
1 (5 equiv)
3
2a (0.4 mmol)
NBn2
NBn2
OH
Br
OH
3ad
3be
entry
1
ligand
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
x:y:z
3:1:3
3:1:3
3:1:3
3:1:3
3:1:3
5:1:3
5:1:5
5:1:10
5:1:5
5:1:5
5:1:5
5:1:5
solvent
THF
yield (%)[b]
ee (%)[c]
n.d.
n.d.
93
55% yield, 94% ee
66% yield, 84% ee
0
0
NBn2
OH
NBn2
NBn2
MeO
Ph
2
THF
OH
3dd
OH
3
THF
18
3ed
3c
51% yield, 70% ee
29% yield, 61% ee
18% yield, 92% ee
4
THF
18
4
Cl
NBn2
OH
NBn2
NBn2
MeS
MeO2C
5
THF
<5
96
OH
OH
6
THF
20
90
3hd
3g
3f
29% yield, 60% ee
41% yield, 84% ee
31% yield, 37% ee
7
THF
38
89
NBn2
OH
NBn2
8
THF
28
91
OH
9
1,4-dioxane
CPME
Et2O
34
93
Br
Cl
3j
3i
10
11
12
40
94
57% yield, 87% ee
61% yield, 87% ee
38
94
neat
56 (55)[d]
94
Scheme 2. Scope of benzofurans.[a-c] [a] Reaction conditions: Cu(OAc)2 (0.04
mmol), L3 (0.044 mmol), 1 (2.0 mmol), 2a (0.4 mmol) and (MeO)2MeSiH (2.0
mmol) were stirred under neat conditions at 45 ºC for 36 h. Catalyst was pre-
prepared by mixing Cu(OAc)2, L3 and (MeO)2MeSiH together under neat
conditions. [b] Isolated yield. [c] Ee value was determined by HPLC or SFC
analysis. [d] The reaction was run on 0.2 mmol scale. [e] Cu(OAc)2 (0.02 mmol)
and L3 (0.022 mmol) were used.
[a] Reaction conditions: Cu(OAc)2 (0.02 mmol), ligand (0.022 mmol), 1a, 2a
(0.2 mmol) and (MeO)2MeSiH in solvent or under neat conditions at 45 ºC for
36 h. Catalyst was pre-prepared by mixing Cu(OAc)2, ligand and
(MeO)2MeSiH together in solvent (0.4 mL, 0.5 M) or under neat conditions.
CPME = cyclopentyl methyl ether. n.d. = not determined. [b] 1H NMR yield was
determined by using Ph2CH2 (20 μL) as internal standard. [c] Ee value was
determined by HPLC analysis. [d] Isolated yield was shown in parentheses.
With the optimized conditions in hand, we set out to evaluate
the scope of benzofurans (Scheme 2). Weak electron-
withdrawing group such as bromo- at 5-position of benzofuran
gave good yield and enantioselectivity even with 5 mol% of
catalyst loading (3b, 66% yield, 84% ee). Benzofuran bearing a
phenyl group (5-Ph) proceeded in good yield albeit with moder-
ate enantioselectivity (3c, 51% yield, 70% ee). When introducing
an electron-donating (Me-, MeO-, MeS-) or electron-withdrawing
(-CO2Me) substituent at the 5-position of benzofurans, the yields
for the cascade sequence decreased significantly and in some
cases moderate enantioselectivity was obtained (3d-3g, 18–
Our attempt was commenced with the treatment of excess
benzofuran 1a with hydroxylamine ester 2a in the presence of
Cu(OAc)2/(S)-BINAP (L1), and with (MeO)2MeSiH as the hydro-
gen source in THF at 45 oC. Disappointingly, no desired product
was detected (entry 1, Table 1). After screening of various lig-
ands, we found that (R)-DTBM-SEGPHOS (L3) with a relatively
smaller bite angle and dispersion effect from tert-butyl groups[10c]
led to the formation of product 3a (18% yield, 93% ee, entry 3,
Table 1). Then, the ratio of 1a, 2a and (MeO)2MeSiH was inves-
tigated (entries 6–8, Table 1). It was found that an improved
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10.1002/anie.201809003
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COMMUNICATION
41% yields, 60–92% ee). Notably, an ortho,ortho-disubstituted
benzyl amine (3h) was obtained from 4-chlorobenzofuran direct-
ly albeit with decreased yield and enantioselectivity (31% yield,
37% ee). Finally, halogen groups including Br- and Cl- at the 7-
position of benzofurans were well tolerated, leading to the multi-
substituted phenols 3i and 3j in 57% yield with 87% ee and 61%
yield with 87% ee, respectively. In general, the scope of benzo-
furan appears sensitive to the electronic density of the intro-
duced substituents, which might be attributed to their multiple
roles involved in the cascade reaction (see the following pro-
posed mechanism). For instance, electron-donating groups
(EDG) may aid the C-N bond forming event, but overall, EDG
should be detrimental to the hydroamination step too because it
slows down the addition of CuH. Accordingly, the weak electron-
withdrawing groups seemed to be compatible with the balance
between the contradictory processes. The absolute configuration
of enantiomeric pure 3b was determined by X-ray crystallo-
graphic analyses.[11] Other products were assigned analogously.
in this reaction. Subjecting chiral hydroxylamine esters with
opposite configuration (2o and 2p) to standard conditions af-
forded the corresponding products 3o and 3p in 51% yield with
10:1 dr and 49% yield with >19:1 dr, respectively, suggesting
that the catalyst control is dominant. To our disappointment,
N,N-alkylaryl and dialkyl hydroxylamine esters only gave unde-
sired amines resulting from the side reactions between more
reactive electrophilic amination reagents and copper hy-
dride.[9h],[9o] In addition, 2-methylbenzofuran turned out to be a
poor substrate (<5% yield), which might be attributed to unfavor-
able sterically hindrance encountered with the hydrocupration
process.
Scheme 4. Transformations of product 3a.
In order to demonstrate the synthetic utility of this method,
transformations based on product 3a were carried out (Scheme
4). By treating 3a with CF3SO2Cl in the presence of triethylamine
at room temperature, the corresponding triflate-protected prod-
uct 4a was obtained in 73% yield with no erosion of ee value.
Subsequent removal of OTf group in 4a occurred smoothly to
afford the reduction product 4b in 88% yield and 95% ee under
Pd(II)/HCOOH catalytic system. Besides, treatment of 3a with
HCl and Pd/C under hydrogen atmosphere led to the secondary
benzylamine 4c in 64% yield and 93% ee. Furthermore, a 5
mmol-scale reaction between 1b and 2a was performed to show
its practicability. To our delight, the reaction proceeded in a
higher yield (72% versus 66%) even at a lower catalyst loading
(2 mol%) compared with that on 0.4 mmol scale.[11]
Scheme 3. Scope of hydroxylamine esters.[a-c] [a] Reaction conditions:
Cu(OAc)2 (0.04 mmol), L3 (0.044 mmol), 1a (2.0 mmol), 2 (0.4 mmol) and
(MeO)2MeSiH (2.0 mmol) were stirred under neat conditions at 45 ºC. Unless
otherwise noted, the reaction time was 36 h. Catalyst was pre-prepared by
mixing Cu(OAc)2, L3 and (MeO)2MeSiH together under neat condition. [b]
Isolated yield. [c] Ee value was determined by HPLC or SFC analysis. [d] The
reaction was run on 0.2 mmol scale. [e] The reaction time was 60 h. The dr
value was determined by 1H NMR.
To shed insights on the mechanism, the standard reaction
was monitored by GC-MS. The observation of ring opening
intermediate 5 indicated that o-vinylphenol 5 could be a possible
intermediate involved for the process.[11] This can be further
supported by the fact that o-vinylphenol 5 underwent asymmetric
hydroamination reaction under the standard conditions (a, Fig-
ure 1). Based on the experimental observations in combination
with previous literatures,[10] a plausible pathway for the copper-
catalyzed ring opening of benzofurans and enantioselective
hydroamination cascade was proposed with the reaction
between 1a and 2a as an example (b, Figure 1). First, the cop-
per hydride A is generated from copper acetate, ligand and
(MeO)2MeSiH. Insertion of copper hydride into C(2)–C(3) double
bond in benzofuran 1a affords benzyl copper species B, fol-
lowed by subsequent β-O elimination to give D. Notably, the
possible oxidative addition of copper hydride to C(2)–O bond of
The scope of hydroxylamine esters was next investigated
(Scheme 3). The benzene ring of benzyl groups bearing an
electron-withdrawing group gave similar results as those ob-
tained from standard substrate (3k, 46% yield, 92% ee). Mean-
while, the incorporation of an electron-donating MeO- group in
the benzyl group led to reasonable yield with slightly decreased
enantioselectivity (3l, 36% yield, 81% ee). By replacing benzene
ring of benzyl groups with other heterocycles such as 2-
thiophene and 2-benzofuran, the desired products 3m and 3n
were produced in moderate yields and excellent ee (3m, 39%
yield, 94% ee; 3n, 52% yield, 93% ee). Remarkably, the sub-
strates with a pre-existing chiral center were also well tolerated
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10.1002/anie.201809003
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COMMUNICATION
benzofuran 1a to form Cu(III) species C could not be completely
ruled out. Later, transmetalation between D and (MeO)2MeSiH
delivers E, accompanied with the regeneration of copper hydride
A. Next, E is inserted by copper hydride to form benzylcopper
intermediate F. Finally, the C-N bond could be formed enanti-
oselectively in the presence of hydroxylamine ester 2a. Mean-
while, the copper hydride A is generated for the next catalytic
cycle.
Keywords: asymmetric catalysis • benzofuran • copper •
dearomatization • hydroamination • ring opening
[1]
For selected reviews, see: a) A. R. Pape, K. P. Kaliappan, E. P. Kündig,
Chem. Rev. 2000, 100, 2917-2940; b) S. Quideau, L. Pouységu, D.
Deffieux, Synlett 2008, 467-495; c) L. Pouységu, D. Deffieux, S.
Quideau, Tetrahedron 2010, 66, 2235-2261; d) L. Pouységu, T. Sylla, T.
Garnier, L. B. Rojas, J. Charris, D. Deffieux, S. Quideau, Tetrahedron
2010, 66, 5908-5917; e) S. P. Roche, J. A. Porco Jr., Angew. Chem. Int.
Ed. 2011, 50, 4068-4093; Angew. Chem. 2011, 123, 4154-4179; f) C.-X.
Zhuo, W. Zhang, S.-L. You, Angew. Chem. Int. Ed. 2012, 51, 12662-
12686; Angew. Chem. 2012, 124, 12834-12858; g) D.-S. Wang, Q.-A.
Chen, S.-M. Lu, Y.-G. Zhou, Chem. Rev. 2012, 112, 2557-2590; h) C.-
X. Zhuo, C. Zheng, S.-L. You, Acc. Chem. Res. 2014, 47, 2558-2573; i)
R. Dalpozzo, Chem. Soc. Rev. 2015, 44, 742-778; j) C. Zheng, S.-L.
You, Chem 2016, 1, 830-857; k) W.-T. Wu, L. Zhang, S.-L. You, Chem.
Soc. Rev., 2016, 45, 1570-1580; l) W.-T. Wu, L. Zhang, S.-L. You, Acta
Chim. Sinica 2017, 75, 419-438; m) J.-B. Chen, Y.-X. Jia, Org. Biomol.
Chem. 2017, 15, 3550-3567; For a book, see: n) Asymmetric Dearoma-
tization Reactions; S.-L. You, Ed.; Wiley-VCH: Weinheim, Germany,
2016.
[2]
For selected examples on asymmetric dearomatization of benzofurans,
see: a) M. Maris, W.-R. Huck, T. Mallat, A. Baiker, J. Catal. 2003, 219,
52-58; b) S. Kaiser, S. P. Smidt, A. Pfaltz, Angew. Chem. Int. Ed. 2006,
45, 5194-5197; Angew. Chem. 2006, 118, 5318-5321; c) N. Ortega, S.
Urban, B. Beiring, F. Glorius, Angew. Chem. Int. Ed. 2012, 51, 1710-
1713; Angew. Chem. 2012, 124, 1742-1745; d) N. Dong, X. Li, F. Wang,
J.-P. Cheng, Org. Lett. 2013, 15, 4896-4899; e) J. Fu, H. Shang, Z.
Wang, L. Chang, W. Shao, Z. Yang, Y. Tang, Angew. Chem. Int. Ed.
2013, 52, 4198-4202; Angew. Chem. 2013, 125, 4292-4296; f) T.
Shibuta, S. Sato, M. Shibuya, N. Kanoh, T. Taniguchi, K. Monde, Y.
Iwabuchi, Heterocycles 2014, 89, 631-639; g) Y.-C. Xiao, C.-Z. Yue, P.-
Q. Chen, Y.-C. Chen, Org. Lett. 2014, 16, 3208-3211; h) Z. Li, Y. Shi,
Org. Lett. 2015, 17, 5752-5755; i) X.-W. Liang, C. Zheng, S.-L. You,
Adv. Synth. Catal. 2016, 358, 2066-2071; j) D. Janssen-Müller, M.
Fleige, D. Schlüns, M. Wollenburg, C. G. Daniliuc, J. Neugebauer, F.
Glorius, ACS Catal. 2016, 6, 5735-5739; k) Q. Tian, J. Bai, B. Chen, G.
Zhang, Org. Lett. 2016, 18, 1828-1831; l) Q. Cheng, H.-J. Zhang, W.-J.
Yue, S.-L. You, Chem 2017, 3, 428-436; m) B.-X. Xiao, W. Du, Y.-C.
Chen, Adv. Synth. Catal. 2017, 359, 1018-1027; n) T.-Z. Li, C.-A. Geng,
X.-J. Yin, T.-H. Yang, X.-L. Chen, X.-Y. Huang, Y.-B. Ma, X.-M. Zhang,
J.-J. Chen, Org. Lett. 2017, 19, 429-431; o) N. Hu, H. Jung, Y. Zheng, J.
Lee, L. Zhang, Z. Ullah, X. Xie, K. Harms, M.-H. Baik, E. Meggers, An-
gew. Chem. Int. Ed. 2018, 57, 6242-6246; Angew. Chem. 2018, 130,
6350-6354; p) J.-Q. Zhao, X.-J. Zhou, Y. Zhou, X.-Y. Xu, X.-M. Zhang,
W.-C. Yuan, Org. Lett. 2018, 20, 909-912.
Figure 1. Mechanistic studies and proposed reaction pathway.
In conclusion, we have developed
a ring opening of
benzofurans and enantioselective hydroamination cascade with
Cu(OAc)2/(R)-DTBM-SEGPHOS as the catalyst in the presence
of silane. A series of chiral N,N-dibenzylaminophenols are ob-
tained in moderate yields, excellent regioselectivity and good to
excellent enantioselectivity. For the first time, the copper hydride
catalysis has been applied to C(2)–O bond cleavage of benzofu-
rans, concomitant with subsequent enantioselective transfor-
mations of the ring opening intermediates. The amenability to
scale-up and versatile elaborations further demonstrate its syn-
thetic utility.
[3]
For selected examples, see: a) E. Wenkert, E. L. Michelotti, C. S.
Swindell, J. Am. Chem. Soc. 1979, 101, 2246-2247; b) H. Kakiya, R.
Inoue, H. Shinokubo, K. Oshima, Tetrahedron 2000, 56, 2131-2137; c)
J. Barluenga, L. Álvarez-Rodrigo, F. Rodríguez, F. J. Fañanás, Angew.
Chem. Int. Ed. 2004, 43, 3932-3935; Angew. Chem. 2004, 116, 4022-
4025; d) J. Cornella, R. Martin, Org. Lett. 2013, 15, 6298-6301; e) L.
Guo, M. Leiendecker, C.-C. Hsiao, C. Baumann, M. Rueping, Chem.
Commun. 2015, 51, 1937-1940; f) K. Itami, S. Tanaka, K. Sunahara, G.
Tatsuta, A. Mori, Asian J. Org. Chem. 2015, 4, 477-481; g) M. Tobisu, T.
Takahira, T. Morioka, N. Chatani, J. Am. Chem. Soc. 2016, 138, 6711-
6714; h) T. Iwasaki, R. Akimoto, H. Kuniyasu, N. Kambe, Chem. Asian.
J. 2016, 11, 2834-2837; i) S. Tsuchiya, H. Saito, K. Nogi, H. Yorimitsu,
Org. Lett. 2017, 19, 5557-5560.
Acknowledgements
We thank the National Key Research and Development Program
of China (2016YFA0202900), the National Basic Research
Program of China (2015CB856600), the NSFC (21572252 and
21332009), the Program of Shanghai Subject Chief Scientist
(16XD1404300), Shanghai Sailing Program (18YF1428900) and
the CAS (XDB20000000, QYZDY-SSW-SLH012) for generous
financial support.
[4]
[5]
For selected examples, see: a) T. Nguyen, E.-i. Negishi, Tetrahedron
Lett. 1991, 32, 5903-5906; b) P. Xu, E.-U. Würthwein, C. G. Daniliuc, A.
Studer, Angew. Chem. Int. Ed. 2017, 56, 13872-13875; Angew. Chem.
2017, 129,14060-14063.
For reviews on aromatic metamorphosis, see: a) H. Yorimitsu, D. Vasu,
M. Bhanuchandra, K. Murakami, A. Osuka, Synlett 2016, 27, 1765-
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Angewandte Chemie International Edition
COMMUNICATION
1774; b) K. Nogi, H. Yorimitsu, Chem. Commun. 2017, 53, 4055-4065;
For selected examples, see: c) D. Vasu, H. Yorimitsu, A. Osuka, Angew.
Chem. Int. Ed. 2015, 54, 7162-7166; Angew. Chem. 2015, 127, 7268-
7272; d) H. Saito, S. Otsuka, K. Nogi, H. Yorimitsu, J. Am. Chem. Soc.
2016, 138, 15315-15318; e) During the preparation of this manuscript,
the Yorimitsu group disclosed an elegant copper-catalyzed ring-
opening silylation of benzofurans, see: H. Saito, K. Nogi, H. Yorimitsu,
Angew. Chem. Int. Ed. 10.1002/anie.201806237; Angew. Chem.
10.1002/ange.201806237.
1661; f) S.-L. Shi, S. L. Buchwald, Nat. Chem. 2015, 7, 38-44; g) D. Niu,
S. L. Buchwald, J. Am. Chem. Soc. 2015, 137, 9716-9721; h) D. Nishi-
kawa, K. Hirano, M. Miura, J. Am. Chem. Soc. 2015, 137, 15620-15623;
i) Y. Yang, S.-L. Shi, D. Niu, P. Liu, S. L. Buchwald, Science 2015, 349,
62-66; j) S. Zhu, N. Niljianskul, S. L. Buchwald, Nat. Chem. 2016, 8,
144-150; k) S.-L. Shi, Z. L. Wong, S. L. Buchwald, Nature 2016, 532,
353-356; l) D. Nishikawa, R. Sakae, Y. Miki, K. Hirano, M. Miura, J. Org.
Chem. 2016, 81, 12128-12134; m) Y. Xi, T. W. Butcher, J. Zhang, J. F.
Hartwig, Angew. Chem. Int. Ed. 2016, 55, 776-780; Angew. Chem.
2016, 128, 786-790; n) H. Wang, J. C. Yang, S. L. Buchwald, J. Am.
Chem. Soc. 2017, 139, 8428-8431; o) S. Ichikawa, S. Zhu, S. L. Buch-
wald, Angew. Chem. Int. Ed. 2018, 57, 8714-8718; Angew. Chem. 2018,
130, 8850-8854; p) T. Takata, D. Nishikawa, K. Hirano, M. Miura, Chem.
Eur. J. 10.1002/chem.201802491.
[6]
[7]
[8]
C. K. Hazra, N. Gandhamsetty, S. Park, S. Chang, Nat. Commun.
2016, 7, 13431.
For a selected review, see: E. Vitaku, D. T. Smith, J. T. Njardarson, J.
Med. Chem. 2014, 57, 10257-10274.
For reviews on copper hydride-catalyzed hydroamination reactions,
see: a) M. T. Pirnot, Y.-M. Wang, S. L. Buchwald, Angew. Chem. Int.
Ed. 2016, 55, 48-57; Angew. Chem. 2016, 128, 48-57; b) Z. Sorádová,
R. Šebesta, ChemCatChem 2016, 8, 2581-2588.
[10] For selected examples on mechanistic studies of copper hydride-
catalyzed hydroamination, see: a) J. S. Bandar, M. T. Pirnot, S. L.
Buchwald, J. Am. Chem. Soc. 2015, 137, 14812-14818; b) S. Tobisch,
Chem. Eur. J. 2016, 22, 8290-8300; c) G. Lu, R. Y. Liu, Y. Yang, C.
Fang, D. S. Lambrecht, S. L. Buchwald, P. Liu, J. Am. Chem. Soc.
2017, 139, 16548-16555; d) S. Tobisch, Chem. Sci. 2017, 8, 4410-4423;
e) Y. Gao, P. Wang, Y. Zhao, Q. Liu, W. Liu, Y. Wang, ChemistrySelect
2018, 3, 2157-2161.
[9]
For selected examples on copper hydride-catalyzed hydroamination
reactions, see: a) S. Zhu, N. Niljianskul, S. L. Buchwald, J. Am. Chem.
Soc. 2013, 135, 15746-15749; b) Y. Miki, K. Hirano, T. Satoh, M. Miura,
Angew. Chem. Int. Ed. 2013, 52, 10830-10834; Angew. Chem. 2013,
125, 11030-11034; c) S. Zhu, S. L. Buchwald, J. Am. Chem. Soc. 2014,
136, 15913-15916; d) Y. Miki, K. Hirano, T. Satoh, M. Miura, Org. Lett.
2014, 16, 1498-1501; e) N. Niljianskul, S. Zhu, S. L. Buchwald, Angew.
Chem. Int. Ed. 2015, 54, 1638-1641; Angew. Chem. 2015, 127, 1658-
[11] See the Supporting Information for more details.
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10.1002/anie.201809003
Angewandte Chemie International Edition
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Qing-Feng Xu-Xu, Qiang-Qiang Liu,
Xiao Zhang,* and Shu-Li You*
Page No. – Page No.
Copper-Catalyzed Ring Opening of
Benzofurans and Enantioselective
Hydroamination Cascade
A copper (II) acetate/(R)-DTBM-SEGPHOS-catalyzed ring opening of benzofurans
and enantioselective hydroamination cascade with dimethoxymethylsilane (DMMS)
and hydroxylamine esters was described. Starting from readily available substituted
benzofurans, a series of chiral N,N-dibenzylaminophenols of high potential in phar-
maceutical chemistry were obtained with excellent enantioselectivity (up to 66%
yield, 94% ee).
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