Copper-Catalyzed Hydroxyl-Directed Aminoarylation of Alkynes

Article abstract of DOI:10.1021/acscatal.6b00759

A facile, copper-catalyzed aminoarylation reaction of various aryl/alkyl alkynes was realized by utilizing N-fluoroarylsulfonimides (NFSI) as aminoarylation or amination reagent with hydroxyl as directing group. With this methodology, various α,β-unsatura

Full text of DOI:10.1021/acscatal.6b00759

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Letter
Copper-Catalyzed Hydroxyl-Directed Aminoarylation of Alkynes
Jiaqiong Sun, Guangfan Zheng, Tao Xiong, Qiao Zhang, Jinbo Zhao, Yan Li, and Qian Zhang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00759 • Publication Date (Web): 06 May 2016
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Copper-Catalyzed Hydroxyl-Directed Aminoarylation of Alkynes
Jiaqiong Sun, Guangfan Zheng, Tao Xiong, Qiao Zhang, Jinbo Zhao, Yan Li* and Qian Zhang
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Department of Chemistry, Northeast Normal University, Changchun 130024, China.
ABSTRACT: A facile, copper-catalyzed aminoarylation reaction of various aryl/alkyl alkynes was realized by utilizing N-
fluoroarylsulfonimides (NFSI) as aminoarylation or amination reagent with hydroxyl as directing group. With this methodology,
various -unsaturated carbonyl compounds and indenones were efficiently constructed and the synthetic application for indole
derivatives was also provided. The aminoarylation reactions operate via a regiospecific addition of copper coordinated nitrogen
radical to C–C triple bond/Cvinyl–Caryl bond formation followed by other series of radical processes.
Amines are ubiquitous functionality of overarching signifi-
cance for a number of important research areas, including me-
dicinal chemistry, total synthesis and material science.1 Evolu-
tion of mild and highly selective C–N bond formation methods
from readily available precursors is a long-standing goal of
chemical research. Metal-catalyzed amino-difunctionalization
reaction of alkynes represents a highly attractive amination
method since various functional groups could be introduced to
readily available starting materials besides the formation of a
versatile enamine moiety.2 Although metal-catalyzed hy-
Scheme 1. Metal Catalyzed Aminoarylation of Alkynes
droamination reaction of alkynes had made great achieve-
ment,3 their amino-difunctionalization reactions have re-
Radical reaction could be efficiently directed by alcohols
mained largely unexplored. Up to now, a reliable and predict-
and masked alcohols,10 therefore, propargylic alcohols, which
able amino-difunctionalization methodology of internal al-
are among the most useful bifunctional building blocks availa-
kynes to access tri-substituted enamine3c without forming N-
ble to the synthetic chemists,11 are chosen for our synthetic
heterocycles,4 remains a formidable challenge.
design (Scheme 1, b). Initially, the reaction of propargylic
alcohol 1aa (0.3 mmol) with NFSI (1.2 equiv.) was investigat-
ed in the presence of CuCN (10 mol%). When the reaction
Aminoarylation of alkynes can install nitrogen and aryl
sources simultaneously to C–C triple bonds. To date, only one
was performed at 40 oC for 24 hours with anhydrous di-
intermolecular aminoarylation example has been reported via
rhodium-catalyzed alkyne arylation followed by intramolecu-
chloromethane (DCM) as the solvent, only oxidation product
2aa (11%) was formed and 82% of 1aa was recovered (Table
1, entry 1). When 1.5 equiv. of pyridine was added to the
above reaction, aminoarylation product 3aa, containing an
lar amination reaction (Scheme 1, a).5 Recently, we realized an
interesting amino-multi-functionalization reaction of alkynes
for the synthesis of -amino--aryl ketones,6 although the
regioselectivity for unsymmetric alkynes remains elusive in
some examples. Based on the powerful selectivity control
strategy utilizing directing group to coordinate with metal,7
and our previous works of amination reaction based on nitro-
gen-centered radical,8 we envision that by choosing a suitable
directing group, the in-situ generated metal-coordinated nitro-
gen radical could be utilized to perform a highly regio-
selective amination reaction of unbiased alkynes (Scheme 1,
b). In this communication, a novel hydroxyl group directed
aminoarylation of alkynes with N-fluoroarylsulfonimides
(NFSI) initiated by regiospecific addition of nitrogen radical to
C–C triple bond, followed by radical Cvinyl–Caryl bond for-
mation to provide -unsaturated carbonyl compounds was
realized (Scheme 1, b). Notably, although amination based on
metal-coordinated nitrogen radical has attracted much atten-
tion and some significant progress has been made,9 so far, to
our knowledge, amination reaction utilizing the double role of
metal to coordinate with both nitrogen radical and directing
group for site selectivity has never been demonstrated.
enamine moiety, was generated in 35%, along with 56% yield
of 2aa (Table 1, entry 2). There are some interesting features
for above reactions: 1) a well known Meyer-Schuster rear-
rangement of propargylic alcohols through hydroxyl group
migration11a,11d could also afford unsaturated carbonyl
compounds, however, carbonyl group in 3aa was formed by
direct oxidation; 2) the common substitution reaction of hy-
droxyl group to form propargylic amide was not observed;12 3)
the reaction of oxidation product 2aa and NFSI under the
same conditions (Table 1, entry 2) did not afford 3aa.13
Further carefully investigation of the amazing aminoaryla-
tion reaction was next performed (to see Table S1). The yield
of 3aa could be increased to 53% under nitrogen atmosphere
(Table 1, entry 3). With Et3N or DBU as the additive, no de-
sired aminoarylation product 3aa was detected (Table 1, en-
tries 4 and 5). In the absence of the copper catalyst, no reac-
tion occurred (Table 1, entry 6). Other copper salts, such as
CuCl and CuOTf did not improve the yields of 3aa (Table 1,
entries 7 and 8). Solvent screening showed that reactions in
chloroform and dichloroethane (DCE) gave 3aa in 30% and
35% yields, respectively (Table 1, entries 9 and 10); while no
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desired 3aa was detected in CH3CN (Table 1, entry 11). To (N-fluoro-4-methyl-N-tosylbenzenesulfonamide) and NFR2
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our delight, upon adding 0.3 g 4Å molecular sieves to the re-
action, 83% of 3aa was isolated (Table 1, entry 12). It should
be noted that this aminoarylation reaction provides a facile and
efficient access to enamides which are widely encountered in
the scaffolds of natural products and functional materials.14
(N-fluoro-4-tert-butyl-N-tosylbenzenesulfonamide), the de-
sired aminoaylation products 3ca and 3cb were obtained in
73% and 94% yields, respectively. For NFR3 (4-chloro-N-((4-
chlorophenyl)sulfonyl)-N-fluorobenzenesulfonamide), product
3cc was formed in a yield of 65%. These results showed that
the transformation is more efficient for electron-rich aromatic
rings than electron-poor ones in NFSI derivatives. In addition,
the reaction between a masked alcohol, propargylic ether 1b
and NFSI provided aminoaylation product 3ap in 29% yield
(eq. 1). Under the same conditions, starting from propargylic
ester 1c, only a trace amount of 3ap was detected (eq. 1).
Table 1. Optimization of Reaction Conditions of 1aa with
NFSIa
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Table 2. The Synthesis of -Amino--aryl Unsaturated
Carbonyl Compounds 3a
Entry Catalyst Additive Solvent
2aa (%) 3aa (%)
1b
2b
3
CuCN
CuCN
CuCN
CuCN
CuCN
None
None
Py
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
DCE
11
56
28
0
0
35
53
0
Py
4
Et3N
DBU
Py
5
0
0
6
0
0
7
CuCl
Py
0
46
20
30
35
0
8
CuOTf
CuCN
CuCN
CuCN
CuCN
Py
0
9
Py
0
10
11
12c
Py
0
Py
CH3CN
DCM
0
Py
0
83
aGeneral reaction conditions: 1aa (0.3 mmol), NFSI (1.2 equiv.),
catalyst (10 mol%), additive (1.5 equiv.), solvent (3 mL), 40 C
for 24 h under nitrogen atmosphere. Yields were determined after
o
b
isolation of products by column chromatography. The reaction
was conducted under air. c0.3 g 4Å Molecular sieves were used.
With the optimized reaction conditions in hand (Table 1, en-
try 12), we turned to examine the generality of this alkyne
aminoarylation reaction. As shown in Table 2, the te
3-
phenyl propargylic alcohol derivatives 1aa-am with electron-
donating group or electron-withdrawing group on aromatic
ring reacted smoothly with NFSI to afford 3aa-am in moder-
ate to good yields. The structure of 3ai was confirmed by X-
ray diffraction analysis.15 Aliphatic groups at C1 of propar-
gylic alcohols, such as n-butyl (1an) and cyclopropyl (1ao)
were compatible and the corresponding -amino--aryl
enones 3an and 3ao were obtained in a same yield. We also
found that a primary propargylic alcohol (1ap) also proceeded
under the optimal conditions to give the corresponding -
unsaturated aldehyde 3ap in a reasonable yield (39%). Starting
from 3-aryl substituted propargylic alcohols 1ba-bj, the de-
sired aminoarylative products 3ba-bj were smoothly formed.
In addition, we found that E/Z-isomerization of the C–C dou-
ble bond in 3ba-bj readily takes place,16 even at room temper-
ature in CDCl3. The isomeric mixtures of 3ba-bj in ratios
ranging from 1:1 to 1:6.7 were obtained in total yields of 51-
91%. Electron-rich aromatic substituted propargylic alcohols
1ba-be and 1bj gave much higher yields than electron-
deficient aryl substituted 1bf-bh. Aryl substituted 1bk and 1bl
with strong electron-withdrawing group on the aromatic ring
could not form the desired products. In addition, some other
NFSI derivatives were used instead of NFSI to further explore
the scope of this alkyne aminoarylation reaction. For NFR1
aConditions: 1 (0.3 mmol), NFSI (1.2 equiv.), CuCN (10 mol%),
o
pyridine (1.5 equiv.), DCM (3 mL), 40 C for 24 h under nitrogen
atmosphere. Yields were determined after isolation of products by
column chromatography. The ration of isomers was determined by
1H NMR analysis. NFSI: Ar' = C6H5, NFR1: Ar' = 4-MeC6H4,
b
NFR2: Ar' = 4-tBuC6H4, NFR3: Ar' = 4-ClC6H4. The ratio of iso-
mers in parentheses.
Given tha
-amino--aryl enone 3 contains enamine
motif, we assumed that intramolecular dehydrogen cross cou-
pling between C–H and N–H bonds of 3 might provide 2,3-
disubsituted indoles (Scheme 2), a frequently encountered
moiety in various natural products that exhibit a broad spec-
trum of biological activities.17 To our delight, in the presence
of Pd(OAc)2 (10 mol%) and Cu(OAc)2 (1.0 equiv.), the reac-
tion of 3aa afforded N-phenylsulfonyl-2,3-disubstituted indole
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4a (80%), which gave N-free indole 5a through hydrolysis in
82% yield.
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4
5
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Scheme 2. Application of -Amino--aryl Enone 3aa for
Synthesizing 2,3-Disubstituted Indoles 4a and 5a
In order to expand the scope of alkynes aminoarylation, the
reaction of 3-alkyl substituted propargylic alcohol 6a (0.3
mmol) and NFSI (2.0 equiv.) was performed. Interestingly, a
aminoarylation cyclization reaction occurred, providing in-
denone product 2-amino-1H-inden-1-one 7a in 51% yield,
along with hydroamination product 8a in 30% yield (eq. 2).
Notably, aminoarylation and hydroamination showed opposite
regioselectivity. In the absence of pyridine, the reaction of 6a
and NFSI only formed hydroamination product 8a in 53%
yield. Without adding CuCl and pyridine, 8a could also be
obtained in 58% yield, albeit at a slightly higher temperature
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o
(90 C). These results might indicate that for hydroamination
reaction, OH group did not play as a directing group. As a
result, different regio-selectivity from employing OH as di-
recting group was observed in the aminoarylation cyclization
reaction. Indeones exist in a number of naturally occurring
compounds18 and synthetic materials,19 whose efficient syn-
thetic methods are highly desirable. Therefore, we paid atten-
tion to the aminoarylation cyclization reaction for their con-
struction. After scanning the reaction conditions carefully (to
see Table S2), we were pleased to find that 76% of 7a was
obtained with 1.5 equiv 4-acetylpridine and 10 mol% ZnCl2 as
additives (SI Table S2, entry 21).20
aGeneral reaction conditions: 6 (0.3 mmol), NFSI (2.0 equiv.),
CuCl (10 mol%), 4-acetyl pyridine (1.5 equiv.), ZnCl2 (10 mol%),
o
DCM (3 mL), 70 C for 24 h under nitrogen atmosphere. Yields
of isolated products. The ratio of isomerization was determined by
1H NMR analysis. b8a was isolated in 10% yield. c8c was isolated
in 11% yield.
To investigate the scope of this aminoarylation cyclization,
the reaction of NFSI with various 1-aryl-3-alkyl propargylic
alcohols were subsequently conducted. As summarized in
Table 3, the ortho- and para-substituted 1-aryl-3-alkyl propar-
gylic alcohols afforded the desired 2-amino-1H-inden-1-ones
7a-j in moderate to good yields (42-74%). For meta-
substituted substrates 6k and 6l, the isomeric mixture (ortho-
and meta-cyclization) 7k/7k’ and 7l/7l’ were obtained in a
total yields of 80% (7k:7k’=2:1) and 84% (7l:7l’=1.5:1), re-
spectively. Halo-substituted propargylic alcohols were tolerat-
ed in the aminoarylation reaction, thus affording the corre-
sponding products (7d, 7g-j, 7l and 7l’) in good yields, which
could be used for additional transformations. Other alkyl
groups at C3-position, especially tetra-butyl (6m) and cyclo-
propyl (6n) group were intact during this transformation and
the 2-amino-1H-inden-1-ones 7m and 7n were formed in 53%
and 56% yields, respectively. Recently, Rh-catalyzed amino-
arylation cyclization of alkyne has become a useful strategy
for constructing nitrogen-containing cyclic compounds.21 On
the other hand, instead of the formation of nitrogen-containing
cyclic compounds, this copper-catalyzed aminoarylation reac-
tion provides a facile access to amino-substituted indenone
derivatives.
Taking the present experimental results together,22 and
based on our previous works,5,8,23 a possible mechanism was
proposed as depicted in Scheme 3. Initially, the oxidation of
Cu(I) with NFSI provided a copper(II)-coordinated benzene-
sulfonimide radical A. In the presence of pyridine, a Cu–O
complex intermediate B was formed, releasing HF which is
captured by pyridine. Next, the intramolecular regiospecific
addition of nitrogen radical to alkyne took place, producing
vinyl radical, whose geometry depends on the substitutent. For
substrate 1ae with aryl substituent, the in-situ generated vinyl
radical intermediate C prefered a sp like linear configuration.22
The
following
sequential
1,4-aryl
migration
/desulfonylation/1,3-hydrogen shift produced carbon radical E.
Finally, the homolysis of Cu(II)–O bond furnished -amino--
aryl enones 3ae, regenerating Cu(I) species for the next cata-
lytic cycle. For 6e, the vinyl radical F took a sp2 bent configu-
ration.24 The highly reactive σ radical F was quickly trapped
by aryl groups of substrates to construct carbon cyclic inter-
mediate G. The following oxidation/hydrogen atom ab-
stract/homolysis of Cu(II)–O bond finally provided 2-amino-
1H-inden-1-one 7e. As we can see here, engaging directing
groups could grant access to regiosepecific alkyne aminoaryla-
tion. The rare radical nature of the aminoarylation reaction of
Table 3. The Synthesis of 2-Amino-1H-Inden-1-one 7 a
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Chem. 2015, 7, 38-44.
propargylic alcohol exhibits complementary reactivity pattern
to its traditional ion type reaction.11
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(4) (a) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482-
8485. (b) Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13,
2395-2397. (c) Wang, W.; Shen, Y.; Meng, X.; Zhao, M.; Chen,
Y.; Chen, B. Org. Lett. 2011, 13, 4514-4517. (d) Zeng, J.; Tan, Y.
J.; Leow, M. L.; Liu, X.-W. Org. Lett. 2012, 14, 4386-4389. (e)
Yao, B.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2012, 51,
5170-5174. (f) Xiao, D.; Han, L.; Sun, Q.; Chen, Q.; Gong, N.;
Lv, Y.; Suzenet, F.; Guillaumet, G.; Chenga, T.; Li, R. RSC Ad-
vances, 2012, 2, 5054-5057. (g) Toh, K. K.; Sanjaya, S.;
Sahnoun, S.; Chong, S. Y.; Chiba, S. Org. Lett. 2012, 14, 2290-
2292. (h) Li, X.; Huang, L.; Chen, H.; Wu, W.; Huang H.; Jiang,
H. Chem. Sci. 2012, 3, 3463-3467. (i) Luo, Y.; Ji, K.; Li, Y.;
Zhang, L. J. Am. Chem. Soc. 2012, 134, 17412-17415. (j) Li, J.;
Neuville, L. Org. Lett. 2013, 15, 1752-1755. (k) Mohan, D. C.;
Rao, S. N.; Adimurthy, S. J. Org. Chem. 2013, 78, 1266-1272.
(5) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X. Angew. Chem. Int. Ed. 2013,
52, 6033-6037.
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Scheme 3. The Possible Mechanism of Aminoarylation
Reaction
In summary, utilizing NFSI as aminoarylation or amination
reagent, we have developed a mild, copper-catalyzed amino-
arylation reaction of various aryl/alkyl alkynes with hydroxyl
as directing group. The protocol for direct conversion of inter-
nal alkynes to tetrasubstituted simple alkenes with a versatile
enamide moiety is especially notable. With this methodology,
various-unsaturated carbonyl compounds and indenones
were efficiently constructed and the synthetic application for
indole derivatives was also provided. The aminoarylation reac-
tions operate via a regiospecific addition of copper coordinat-
ed nitrogen radical to C–C triple bond/Cvinyl–Caryl bond for-
mation followed by other series of radical processes. We antic-
ipate that this novel aminoarylation strategy of alkynes will
play an important role for designing more types of aminodi-
functionalization reaction of internal alkynes, and motivate
rapid development of radical amination reaction.
(6) Zheng, G.; Li, Y.; Han, J.; Xiong, T.; Zhang, Q. Nat. Commun.
2015, 6, 7011 doi: 10.1038/ncomms8011.
(7) (a) Labinger, J. A.; Bercaw, J. E. Nature, 2002, 417, 507 -514. (b)
Godula, K.; Sames, D. Science, 2006, 312, 67-72. (c) Lyons,
T.W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147-1169.
(8) (a) Zhang, H.; Pu, W.; Xiong, T.; Li, Y.; Zhou, X.; Sun, K.; Liu,
Q.; Zhang, Q. Angew. Chem. Int. Ed. 2013, 52, 2529-2533. (b)
Zhang, H.; Song, Y.; Zhao, J.; Zhang, J.; Zhang, Q. Angew.
Chem. Int. Ed. 2014, 53, 11079-11083. (c) Zhang, G.; Xiong, T.;
Wang, Z.; Xu, G.; Wang, X.; Zhang, Q. Angew. Chem. Int. Ed.
2015, 54, 12649-12653.
(9) Suarez, A. I. O.; Lyaskovskyy, V.; Reek, J. N. H.; van der Vlugt,
J. I.; de Bruin, B. Angew. Chem. Int. Ed. 2013, 52, 12510-12529.
(10) Mo, F.; Tabor, J. R.; Dong, G. Chem. Lett. 2014, 43, 264-271.
(11) (a) Fürstner, A.; Davies, P. W. Angew. Chem. Int. Ed. 2007, 46,
3410-3449. (b) Chinchilla, R.; Carman N. Chem. Soc. Rev. 2011,
40, 5084-5121. (c) Bauer, E. B. Synthesis 2012, 1131-1151. (d)
Zhu, Y.; Sun. L.; Lu, P.; Wang, Y. ACS Catal. 2014, 4, 1911-
1925.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, spectral data
for new compounds, and crystallographic data for 3ai (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(12) (a) Liu, P.; Deng, C.-L.; Lei, X.; Lin, G.-Q. Eur. J. Org. Chem.
2011, 7308-7316. (b) Biannic, B.; Aponick, A. Eur. J. Org. Chem.
2011, 6605-6617. (c) Han, F.; Yang, L.; Li, Z.; Xia, C. Adv. Synth.
Catal. 2012, 354, 1052-1060.
*liy078@nenu.edu.cn
Notes
The authors declare no competing financial interest.
(13) Crisp, G. T.; Millan, M. J. Tetrahedron 1998, 54, 637-648.
(14) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455-3460.
(15) The crystal structure of 3ai see CCDC 1412400.
ACKNOWLEDGMENT
We acknowledge the fanancial support for this work from the
National NSF of China (21172033, 21372041 and 21302017),
Changbai Mountain Scholarship Program, and the Fundamental
Research Funds for the Central Universities (2412016KJ006).
(16) Traven, V. F.; Ivanov, I. V.; Lebedev, V. S.; Chibisova, T. A.;
Milevskii, B. G.; Soloveva, N.P.; Polshakov, V. I.; Alexandrov, G.
G.; Kazheva, O. N.; Dyachenko, O. A. Russ. Chem. Bull. 2010,
59, 1605-1611.
REFERENCES
(1) Dewick, P. M. Medicinal Natural Products; A Biosynthetic Ap-
(17) (a) Robinson, B. Chem. Rev. 1963, 63, 373-401. (b) Saxton, J. E.
Nat. Prod. Rep. 1997, 14, 559-590.
proach 3rd edn (Wiley, 2008).
(2) Rappoport, Z. The Chemistry of Enamines (Wiley: New York,
1994).
(18) Russell, M. A.; Chai, C. L. L.; Wardlaw, J. H.; Elix, J. A. J. Nat.
Prod. 2000, 63, 129-131.
(3) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079-3159. (b) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo,
F.; Tada, M. Chem. Rev. 2008, 108, 3795-3892. (c) Huang, L.;
Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Chem. Rev.
2015, 115, 2596-2697. (d) Shi, S.-L.; Buchwald, S. L. Nature
(19) Kitani, Y.; Morita, A.; Kumamoto, T.; Ishikawa, T. Helv. Chim.
Acta. 2002, 85, 1186-1195.
(20) ZnCl2 might act as a Lewis acid to stabilize nitrogen-centered
radicals. See Kundu, S.; Farquhar, E.; Miceli, E.; Pfaff, F. F.;
Kuhlmann, U.; Hildebrandt, P.; Braun, B.; Greco, C.; Ray, K. J.
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Am. Chem. Soc. 2012, 134, 14710-14713. Also see 8(b).
Zhang, J.; Liu, Q. Angew. Chem. Int. Ed. 2012, 51, 1244-1247.
(b) Zhang, Q.; Lv,Y.; Li, Y.; Xiong, T.; Zhang, Q. Acta Chim.
Sinica. 2014, 72, 1139-1143. (c) Sun, K., Li, Y.; Zhang, Q. Sci.
China Chem. 2015, 58, 1354-1358.
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(21) (a) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651-
3678. (b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281-295.
(22) When radical scavengers (1.5 equiv. of TEMPO (2,2,4,4-
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tetramethyl-1-piperidinyloxy),
BHT
(2,6-di-tert-butyl-4-
(24) Galli, C.; Rappoport Z. Acc. Chem. Res. 2003, 36, 580-587.
methylphenol) or DPE (1,1-diphenylethylene)) were added to
the reaction, no desired aminoarylation products. The details,
please see SI.
(23) (a) Ni, Z.; Zhang, Q.; Xiong, T.; Zheng, Y.; Li, Y.; Zhang, H.;
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Copper-Catalyzed Hydroxyl-Directed Aminoarylation of Alkynes
Jiaqiong Sun, Guangfan Zheng, Tao Xiong, Qiao Zhang, Jinbo Zhao, Yan Li* and Qian Zhang
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Scheme 1. Metal Catalyzed Aminoarylation of Alkynes
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Table 1. Optimization of Reaction Conditions of 1aa with NFSIa
Entry Catalyst Additive Solvent
2aa (%) 3aa (%)
1b
2b
3
CuCN
CuCN
CuCN
CuCN
CuCN
None
None
Py
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
DCE
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28
0
0
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0
Py
4
Et3N
DBU
Py
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0
0
6
0
0
7
CuCl
Py
0
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0
8
CuOTf
CuCN
CuCN
CuCN
CuCN
Py
0
9
Py
0
10
11
12c
Py
0
Py
CH3CN
DCM
0
Py
0
83
aGeneral reaction conditions: 1aa (0.3 mmol), NFSI (1.2 equiv.), catalyst (10 mol%), additive (1.5 equiv.), solvent (3 mL), 40 oC for 24 h
b
under nitrogen atmosphere. Yields were determined after isolation of products by column chromatography. The reaction was conducted
under air. c0.3 g 4Å Molecular sieves were used.
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Table 2. The Synthesis of -Amino--aryl Unsaturated Carbonyl Compounds 3a
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aConditions: 1 (0.3 mmol), NFSI (1.2 equiv.), CuCN (10 mol%),
pyridine (1.5 equiv.), DCM (3 mL), 40 C for 24 h under nitrogen
o
atmosphere. Yields were determined after isolation of products by
column chromatography. The ration of isomers was determined by
1H NMR analysis. NFSI: Ar' = C6H5, NFR1: Ar' = 4-MeC6H4,
b
NFR2: Ar' = 4-tBuC6H4, NFR3: Ar' = 4-ClC6H4. The ratio of iso-
mers in parentheses.
Scheme 2. Application of -Amino--aryl Enone 3aa for Synthesizing 2,3-Disubstituted Indoles 4a and 5a
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Table 3. The Synthesis of 2-Amino-1H-Inden-1-one 7 a
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aGeneral reaction conditions: 6 (0.3 mmol), NFSI (2.0 equiv.), CuCl (10 mol%), 4-acetyl pyridine (1.5 equiv.), ZnCl2 (10 mol%), DCM (3
mL), 70 oC for 24 h under nitrogen atmosphere. Yields of isolated products. The ratio of isomerization was determined by 1H NMR analy-
sis. b8a was isolated in 10% yield. c8c was isolated in 11% yield.
Scheme 3. The Possible Mechanism of Aminoarylation Reaction
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Copper-Catalyzed Hydroxyl-Directed Aminoarylation of Alkynes
Jiaqiong Sun, Guangfan Zheng, Tao Xiong, Qiao Zhang, Jinbo Zhao, Yan Li* and Qian Zhang
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