Co-Catalyzed Direct Regio- And Enantioselective Intermolecular γ-Amination of N-Acylpyrazoles

Article abstract of DOI:10.1021/acs.orglett.0c03522

A cobalt-catalyzed regio- and enantioselective γ-amination of β,γ-unsaturated N-acylpyrazoles that delivers the corresponding γ-amination products in good regio- and enantioselectivity has been established. Moreover, the nitrogen-containing compounds could be easily synthesized. DFT calculations have been provided to explain regio- and enantioselectivity for this γ-amination. The chiral γ-amination products were readily converted into the chiral γ-amino acid derivatives.

Full text of DOI:10.1021/acs.orglett.0c03522

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Letter
Co-Catalyzed Direct Regio- and Enantioselective Intermolecular
γ‑Amination of N‑Acylpyrazoles
Xin Fu, Yu Hao, He-Yuan Bai, Abing Duan,* and Shu-Yu Zhang*
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ABSTRACT: A cobalt-catalyzed regio- and enantioselective γ-amination of β,γ-unsaturated N-acylpyrazoles that delivers the
corresponding γ-amination products in good regio- and enantioselectivity has been established. Moreover, the nitrogen-containing
compounds could be easily synthesized. DFT calculations have been provided to explain regio- and enantioselectivity for this γ-
amination. The chiral γ-amination products were readily converted into the chiral γ-amino acid derivatives.
evelopment of direct and novel methods for the
Dstereoselective synthesis of carbon−nitrogen bonds
have been received more attention in organic chemistry due
to their importance in alkaloids, peptides, and pharmaceutical
compounds.1,2 While various approaches toward this important
goal have been developed at the α and β positions of carbonyl
compounds,3−5 the exploration of enantioselective synthesis of
remote C−N bonds remains a significant challenge. In this
field, organocatalysis was found to be effective in catalyzing
enantioselective γ-additions of carbonyl compounds to various
electrophiles,6 such as carbonyl,7 imine,8 and dialkyl
azodicarboxylates.9 However, among these enantioselective
methods, only a very limited number of γ-amination of
carbonyl compounds with dialkyl azodicarboxylates have been
reported. In 2006, the Jørgensen group disclosed the first
enantioselective γ-amination of unsaturated aldehydes through
reactive dienamine formed in situ with the chiral amine catalyst
(Scheme 1a, left).10a In 2012, the Tan group reported a
guanidine-catalyzed enantiodivergent γ-amination of β,γ-
unsaturated thioesters (Scheme 1a, right).10b In spite of
these achievements, the enantioselective γ-amination reactions
are mainly restricted to aldehydes or thioesters. However, to
date, enantioselective γ-amination of unsaturated N-acylpyr-
azoles has not been devised.
as well as the enantioselectivity.13 In 2017, the Yin group
reported the enantioselective vinylogous and bisvinylogous
mannich reaction of unsaturated N-acylpyrazoles by a copper
and chiral phosphine complex (Scheme 1b).14 Recently, the
Chen group reported the palladium(II)-catalyzed N,N-
bidentate AQ-directed enantioselective hydrocarbonfunction-
alization of β,γ-unsaturated amide (Scheme 1c).15 Indeed,
despite these successes in chiral γ−C-C bond formations,
development of the chiral Lewis acid catalyzed enantioselective
γ-amination of carbonyl compounds still remains challenging.
Herein, we report the β,γ-unsaturated N-acylpyrazole undergo
regio- and enantioselective cobalt complex catalyzed γ-
amination with azodicarboxylates using simple chiral bisoxazo-
line pyridines ligands. DFT calculations have been provided to
explain regio- and enantioselectivity for our chiral γ-amination
reaction.
We used Co(OAc)2·4H2O as catalyst and began our
investigation employing β,γ-unsaturated N-acyl-3,5-dimethyl-
pyrazole 1a and di-tert-butyl azodicarboxylates 2a as model
substrates (Table 1). Base on previous reports, the steric
hindrance of metal dienolates was proposed to control
regioselectivity.14,16 Therefore, we introduced bisoxazoline
pyridines complexes as ligands in which the pyridine group
would be of value to activate the α-protons of β,γ-unsaturated
Recently, our laboratory has been interested in developing
aminations.11 Interestingly, the β,γ-unsaturated carbonyl
compounds have served as a nucleophilic source of both α-
or γ-positions on the basis of the different reaction
conditions.12 However, the transition-metal-based chiral
Lewis acid catalyzed enantioselective γ-additions of β,γ-
unsaturated carbonyl compounds have been rarely reported,
probably due to the difficulty of controlling the regioselectivity
Received: October 22, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03522
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
Scheme 1. Approaches for Enantioselective γ-Additions of
Carbonyl Compounds
Table 1. Optimization of Amination of Unsaturated N-
a
Acylpyrazole
b
d
temp
(°C)
total yield
(%)
ratio (3a/ ee of 4a
c
entry ligand
base
4a)
(%)
1
2
3
4
5
6
7
8
L5
L5
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L5
L5
L5
L5
L5
L5
L5
L5
rt
−20
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
86
42
88
93
81
81
91
74
54
44
78
86
90
80
86
71
83
88
56
61
1/10
1/14
1/11
1/29
1/1.3
1.4/1
1/6
1/1.1
1/8
1/1.4
1/1
1/1.5
1/5
1/5
1/5
1/3
87
88
34
83
75
67
87
7
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
DABCO
DIPEA
TMG
DBU
TEA
TEA
TEA
TEA
N-acyl-3,5-dimethyl-pyrazole 1a and chiral oxazoline group
would be helpful to control the enantioselectivity (entry 1).
However, the reaction conducted at −20 °C afforded the
product 4a in a significantly decreased yield with slightly high
enantioselectivity (entry 2). In our early research, we found
that organic bases promoted γ-amination of β,γ-unsaturated N-
acyl-3,5-dimethyl-pyrazole 1a to improve yield. After an initial
screening of ligands (entries 3−7), the separation of γ-
amination product 4a were 91% yield and 87% ee using 20 mol
% L5 as the ligand. Interestingly, switching the pyridines group
to phenyl group, the regio- and enantioselectivity of the
reaction is poor (entry 8). In particular, para-substituted
methoxy groups and trifluoromethyl groups on the pyridines
substituent provided product with decreased yield and
enantioselectivity (entries 9 and 10). PN-type ligand L9 and
SPDO ligand L10 were suppress ligands (entries 11 and 12).
Then we investigated some common organic bases and TEA
still gave the best result (entries 13−16). Encouraged by this
result, we lowered the temperature and found that the
enantioselectivity was promoted to 92% at −20 °C (entry
18). Reducing the quantities of catalyst, ligand and base, the
yield and enantioselectivity both dropped (entry 20).
Under optimized conditions, the substrate scope of the
enantioselective γ-amination was explored (Scheme 2). First,
we examined the scope of different azodicarboxylates as
electrophilic reagents (4b−4d). They all could give corre-
sponding amination products in good yields and enantiose-
lectivity (4a to 4d, 42−88% yield, 80−92% ee). With the
DBAD as azodicarboxylate amino source, various substituted
β,γ-unsaturated N-acyl-3,5-dimethylpyrazoles 1 were evaluated.
Different alkyl-substituted substrates 1e−1k were suitable, and
the amination products 4e−4k were obtained in good yields
9
86
73
6
10
11
12
13
14
15
16
17
18
19
38
84
87
22
18
88
92
90
90
1/10
1/14
1/14
1/8
−20
−30
−20
e
20
a
Conditions: 1a (0.1 mmol), DBAD (0.15 mmol), THF (1.0 mL), 24
b
c
h. Isolated yields. Determined by 1H NMR analysis of reaction
mixture. Determined by chiral HPLC analysis using the isolated
compound 4a. Co(OAc)2·4H2O (10 mol %), L5 (10 mol %), and
base (10 mol %) employed.
d
e
(74−92% yields) and excellent enantioselectivity (90−94% ee)
with high regioselectively (4a/3a > 20/1). Reaction of the
steric hindrance of substrates isopropyl group 1l and
cyclohexyl group 1m could yield products 4l and 4m in
good yields (55−76% yields) and excellent enantioselectivity
(94% ee). Interestingly, we further evaluated the effect of the
long alkyl chain substituents containing various functional
groups. Sulfur-, oxygen-, and nitrogen-containing functional
groups were both tolerated (4n to 4p). Notably, chloride
group 1q and ester group 1r could give products 4q and 4r in
good yields (70−87% yield) and enantioselectivity (90−92%
ee). In particular, the product 4r contained δ-amino acid
B
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a
Scheme 2. Scope of Azodicarboxylates and N-Acylpyrazoles
a
See the Supporting Information.
Figure 1. Computational results.
skeleton. The absolute configuration of 4j was confirmed by γ-
amino acid derivatives 5j (see the SI).
In order to uncover the factors controlling the regio- and
enantiosective γ-amination, we also carried out DFT
C
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calculations (Figure 1).17 We investigated the α- or γ-
amination of cobalt(II) dienolates. The calculated results
suggest that the γ-amination (via TS-S) proceeds preferentially
to form a nitrogen anion intermediate (Int-S). The transition
state TS-S is 1.0 kcal/mol lower in energy than TS-R, which
the (S)-cobalt(II) intermediate Int-S is generated. Finally,
intermediate Int-S is readily converted to intermediate Pro-S
through proton transfer. In this transformation, intermediates
Int-R is 5.0 kcal/mol higher than intermediates Int-S in
energy, which agrees to the experimentally observed (S)-
product in the catalytic reactions. These calculated results
agree with experiment.
Chiral γ-aminobutyric acids are a valuable class of
compounds that are frequently found in the structures of
biologically active molecules. More importantly, we demon-
strated the potential utility of this method. The intermolecular
γ-amination of 1j with di-tert-butyl azodicarboxylate (2a) gave
product 4j in good yield and excellent enantioselectivity with
high regioselectively (87% yield, 94% ee, 4j/3j > 20/1)
(Scheme 3a). The product 4j could be converted to the related
chiral γ-amino acid derivatives 5j with 57% yield and 94% ee
(Scheme 3b).18
Experimental procedures, crystal data for compound 4c,
1
and H and 13C NMR spectra (PDF)
Accession Codes
CCDC 2003847 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Shu-Yu Zhang − Key Laboratory for Thin Film and
Microfabrication Technology of Ministry of Education, School
of Chemistry and Chemical Engineering, and Shanghai Key
Laboratory for Molecular Engineering of Chiral Drugs,
Shanghai Jiao Tong University, Shanghai 200240, China;
orcid.org/0000-0002-1811-4159; Email: zhangsy16@
sjtu.edu.cn
Abing Duan − College of Environmental Science &
Technology, Hunan University, Changsha 410082, China;
Email: duanabing@hnu.edu.cn
Scheme 3. Synthetic Applications
Authors
Xin Fu − College of Environmental Science & Technology,
Hunan University, Changsha 410082, China; Key
Laboratory for Thin Film and Microfabrication Technology
of Ministry of Education, School of Chemistry and Chemical
Engineering, and Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Shanghai Jiao Tong University,
Shanghai 200240, China
Yu Hao − Key Laboratory for Thin Film and Microfabrication
Technology of Ministry of Education, School of Chemistry
and Chemical Engineering, and Shanghai Key Laboratory for
Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong
University, Shanghai 200240, China
He-Yuan Bai − Key Laboratory for Thin Film and
Microfabrication Technology of Ministry of Education, School
of Chemistry and Chemical Engineering, and Shanghai Key
Laboratory for Molecular Engineering of Chiral Drugs,
Shanghai Jiao Tong University, Shanghai 200240, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03522
Notes
The authors declare no competing financial interest.
In conclusion, we have developed a CoII−Pybox complex
can effectively catalyze the enantioselective γ-amination of β,γ-
unsaturated N-acylpyrazoles. The reaction occurs with
excellent enantioselectivity and high regioselectively. Further-
more, DFT calculations have been provided to explain regio-
and enantioselectivity for this γ-amination, which results
correspond with experiment observation. Further applications
of the catalytic system in other asymmetric reactions are
currently under investigation.
ACKNOWLEDGMENTS
■
We gratefully thank the NSFC (21672145, 51733007, and
21906049), the Science and Technology Commission of
Shanghai Municipality (17JC1403700, 19JC1430100, and
19JC1410301), and the Drug Innovation Major Project of
the Ministry of Science and Technology of China
(2018ZX09711001-005-002).
REFERENCES
■
(1) (a) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284−287.
(b) Ricci, A., Ed. Amino Group Chemistry: From Synthesis to the Life
Science; Wiley-VCH Verlag: Weinheim, 2007.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03522.
(2) For reviews of asymmetric amination of carbonyl molecules, see:
(a) Janey, J. M. Recent advances in catalytic, enantioselective α
D
https://dx.doi.org/10.1021/acs.orglett.0c03522
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Letter
aminations and α oxygenations of carbonyl compounds. Angew.
Chem., Int. Ed. 2005, 44, 4292−4300. (b) Smith, A. M. R.; Hii, K. K.
Transition metal catalyzed enantioselective α-heterofunctionalization
of carbonyl compounds. Chem. Rev. 2011, 111, 1637−1656. (c) Zhou,
F.; Liao, F.-M.; Yu, J.-S.; Zhou, J. Catalytic asymmetric electrophilic
amination reactions to form nitrogen-bearing tetrasubstituted carbon
stereocenters. Synthesis 2014, 46, 2983−3003.
(3) For reviews of α-amination of carbonyl molecules, see: (a) Erdik,
E. Electrophilic α-amination of carbonyl compounds. Tetrahedron
2004, 60, 8747−8782. (b) Greck, C.; Drouillat, B.; Thomassigny, C.
Asymmetric electrophilic α-amination of carbonyl groups. Eur. J. Org.
Chem. 2004, 2004, 1377−1385. (c) de la Torre, A.; Tona, V.;
Maulide, N. Reversing polarity: carbonyl α-aminations with nitrogen
nucleophiles. Angew. Chem., Int. Ed. 2017, 56, 12416−12423.
azodiformates via bidentate-chelation assistance. ACS Catal. 2017,
7, 2042−2046. (e) Bai, H.-Y.; Fu, X.; Pan, J.-L.; Ma, H.-Q.; Chen, Z.-
M.; Ding, T.-M.; Zhang, S.-Y. Transition metal-controlled direct
regioselective intermolecular amidation of C−H bonds with
azodicarboxylates: scope, mechanistic studies, and applications. Adv.
Synth. Catal. 2018, 360, 4205−4214. (f) Park, Y.; Kim, Y.; Chang, S.
Transition metal-catalyzed C−H amination: scope, mechanism, and
applications. Chem. Rev. 2017, 117, 9247−9301.
(6) Selected examples of electrophiles: (a) Yang, W.; Ma, D.; Zhou,
Y.; Dong, X.; Lin, Z.; Sun, J. NHC-catalyzed electrophilic
trifluoromethylation: efficient synthesis of γ-trifluoromethyl α,β-
unsaturated esters. Angew. Chem., Int. Ed. 2018, 57, 12097−12101.
For reviews, see: (b) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.;
Zanardi, F. The vinylogous Aldol and related addition reactions: ten
years of progress. Chem. Rev. 2011, 111, 3076−3154. (c) Jurberg, I.
D.; Chatterjee, I.; Tannerta, R.; Melchiorre, P. When asymmetric
aminocatalysis meets the vinylogy principle. Chem. Commun. 2013,
(4) For recent examples of asymmetric α-amination of carbonyl
molecules, see: (a) Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi,
M.; Matsunaga, S.; Shibasaki, M. Catalytic asymmetric synthesis of 3-
aminooxindoles: enantiofacial selectivity switch in bimetallic vs
monometallic schiff base catalysis. J. Am. Chem. Soc. 2010, 132,
1255−1257. (b) Zhu, C.-L.; Zhang, F.-G.; Meng, W.; Nie, J.; Cahard,
D.; Ma, J.-A. Enantioselective base-free electrophilic amination of
benzofuran-2(3H)-ones: catalysis by binol-derived P-spiro quaternary
phosphonium salts. Angew. Chem., Int. Ed. 2011, 50, 5869−5872.
(c) Shen, K.; Liu, X.; Wang, G.; Lin, L.; Feng, X. Facile and efficient
enantioselective hydroxyamination reaction: synthesis of 3-hydrox-
yamino-2-oxindoles using nitrosoarenes. Angew. Chem., Int. Ed. 2011,
50, 4684−4688. (d) Takeda, T.; Terada, M. Development of a chiral
bis(guanidino)iminophosphorane as an uncharged organosuperbase
for the enantioselective amination of ketones. J. Am. Chem. Soc. 2013,
135, 15306−15309. (e) Maji, B.; Baidyaab, M.; Yamamoto, H.
Asymmetric construction of quaternary stereocenters by magnesium
catalysed direct amination of β-ketoesters using in situ generated
nitrosocarbonyl compounds as nitrogen sources. Chem. Sci. 2014, 5,
3941−3945. (f) Xu, C.; Zhang, L.; Luo, S. Merging aerobic oxidation
and enamine catalysis in the asymmetric α-amination of β-
ketocarbonyls using N-hydroxycarbamates as nitrogen sources.
Angew. Chem., Int. Ed. 2014, 53, 4149−4153. (g) Wang, S.-G.; Yin,
Q.; Zhuo, C.-X.; You, S.-L. Asymmetric dearomatization of β-
naphthols through an amination reaction catalyzed by a chiral
phosphoric acid. Angew. Chem., Int. Ed. 2015, 54, 647−650. (h) Nan,
J.; Liu, J.; Zheng, H.; Zuo, Z.; Hou, L.; Hu, H.; Wang, Y.; Luan, X.
Direct asymmetric dearomatization of 2-naphthols by scandium-
catalyzed electrophilic amination. Angew. Chem., Int. Ed. 2015, 54,
2356−2360. (i) Yang, X.; Toste, F. D. Direct asymmetric amination of
α-branched cyclic ketones catalyzed by a chiral phosphoric acid. J. Am.
Chem. Soc. 2015, 137, 3205−3208. (j) Ohmatsu, K.; Ando, Y.;
Nakashima, T.; Ooi, T. A modular strategy for the direct catalytic
asymmetric α-amination of carbonyl compounds. Chem. 2016, 1,
802−810. (k) Guo, J.-X.; Zhou, T.; Xu, B.; Zhu, S.-F.; Zhou, Q.-L.
Enantioselective synthesis of α-alkenyl α-amino acids via N−H
insertion reactions. Chem. Sci. 2016, 7, 1104−1108. (l) Shang, M.;
Wang, X.; Koo, S. M.; Youn, J.; Chan, J.; Yao, W.; Hastings, B. T.;
Wasa, M. Frustrated Lewis acid/Brønsted base catalysts for direct
enantioselective α-amination of carbonyl compounds. J. Am. Chem.
Soc. 2017, 139, 95−98.
́
49, 4869−4883. (d) Marcos, V.; Aleman, J. Old tricks, new dogs:
organocatalytic dienamine activation of α,β-unsaturated aldehydes.
́
Chem. Soc. Rev. 2016, 45, 6812−6832. (e) Ordonez, M.; Cativiela, C.;
Romero-Estudillo, I. An update on the stereoselective synthesis of γ-
amino acids. Tetrahedron: Asymmetry 2016, 27, 999−1055.
̃
(7) For recent selected examples, see: (a) Mo, J.; Chen, X.; Chi, Y.
R. Oxidative γ-addition of enals to trifluoromethyl ketones:
enantioselectivity control via Lewis acid/N-heterocyclic carbene
cooperative catalysis. J. Am. Chem. Soc. 2012, 134, 8810−8813.
(b) Zhu, B.; Zhang, W.; Lee, R.; Han, Z.; Yang, W.; Tan, D.; Huang,
K.; Jiang, Z. Direct asymmetric vinylogous Aldol reaction of allyl
ketones with isatins: divergent synthesis of 3-hydroxy-2-oxindole
derivatives. Angew. Chem., Int. Ed. 2013, 52, 6666−6670. (c) Li, T.-Z.;
Jiang, Y.; Guan, Y.-Q.; Sha, F.; Wu, X.-Y. Direct enantioselective
vinylogous Aldol-cyclization cascade reaction of allyl pyrazoleamides
with isatins: asymmetric construction of spirocyclic oxindole-
dihydropyranones. Chem. Commun. 2014, 50, 10790−10792.
(d) Jing, Z.; Bai, X.; Chen, W.; Zhang, G.; Zhu, B.; Jiang, Z.
Organocatalytic enantioselective vinylogous Aldol reaction of allyl aryl
ketones to activated acyclic ketones. Org. Lett. 2016, 18, 260−263.
(e) Wang, Z.-H.; Zhang, X.-Y.; Lei, C.-W.; Zhao, J.-Q.; You, Y.; Yuan,
W.-C. Highly enantioselective sequential vinylogous Aldol reaction/
transesterification of methyl-substituted olefinic butyrolactones with
isatins for the construction of chiral spirocyclic oxindole-dihydropyr-
anones. Chem. Commun. 2019, 55, 9327−9330.
(8) (a) Xu, J.; Jin, Z.; Chi, Y. R. Organocatalytic enantioselective γ-
aminoalkylation of unsaturated ester: access to pipecolic acid
derivatives. Org. Lett. 2013, 15, 5028−5031. (b) Qiao, B.; Huang,
Y.-J.; Nie, J.; Ma, J.-A. Highly regio-, diastereo-, and enantioselective
Mannich reaction of allylic ketones and cyclic ketimines: access to
chiral benzosultam. Org. Lett. 2015, 17, 4608−4611. (c) Jia, W.-Q.;
Zhang, H.-M.; Zhang, C.-L.; Gao, Z.-H.; Ye, S. N-Heterocyclic
carbene-catalyzed [4 + 2] annulation of α,β-unsaturated carboxylic
acids: enantioselective synthesis of dihydropyridinones and spirocyclic
oxindolodihydropyridinones. Org. Chem. Front. 2016, 3, 77−81.
(d) Sun, J.; Mou, C.; Liu, C.; Huang, R.; Zhang, S.; Zheng, P.; Chi, Y.
R. Enantioselective access to multi-cyclic α-amino phosphonates via
carbene-catalyzed cycloaddition reactions between enals and six-
membered cyclic imines. Org. Chem. Front. 2018, 5, 2992−2996.
(9) (a) Shen, L.-T.; Sun, L.-H.; Ye, S. Highly enantioselective γ-
amination of α,β-unsaturated acyl chlorides with azodicarboxylates:
efficient synthesis of chiral γ-amino acid derivatives. J. Am. Chem. Soc.
2011, 133, 15894−15897. (b) Chen, X.-Y.; Xia, F.; Cheng, J.-T.; Ye,
S. Highly enantioselective γ-amination by N-heterocyclic carbene
catalyzed [4 + 2] annulation of oxidized enals and azodicarboxylates.
Angew. Chem., Int. Ed. 2013, 52, 10644−10647. (c) Poh, S. B.; Ong,
J.-Y.; Lu, S.; Zhao, Y. Highly regio- and stereodivergent access to 1,2-
amino alcohols or 1,4-fluoro alcohols by NHC-catalyzed ring opening
of epoxy enals. Angew. Chem., Int. Ed. 2018, 57, 1645−1649.
(5) For some recent examples of β-amination of carbonyl molecules,
see: (a) He, J.; Shigenari, T.; Yu, J.-Q. Palladium(0)/PAr3-catalyzed
intermolecular amination of C(sp3)−H bonds: synthesis of β-amino
acids. Angew. Chem., Int. Ed. 2015, 54, 6545−6549. (b) Wu, X.; Liu,
B.; Zhang, Y.; Jeret, M.; Wang, H.; Zheng, P.; Yang, S.; Song, B.-A.;
Chi, Y. R. Enantioselective nucleophilic β-carbon-atom amination of
enals: carbene-catalyzed formal [3 + 2] reactions. Angew. Chem., Int.
Ed. 2016, 55, 12280−12284. (c) Tian, J.-M.; Yuan, Y.-H.; Xie, Y.-Y.;
Zhang, S.-Y.; Ma, W.-Q.; Zhang, F.-M.; Wang, S.-H.; Zhang, X.-M.;
Tu, Y.-Q. Catalytic asymmetric cascade using spiro-pyrrolidine
organocatalyst: efficient construction of hydrophenanthridine deriv-
atives. Org. Lett. 2017, 19, 6618−6621. (d) Bai, H.-Y.; Ma, Z.-G.; Yi,
M.; Lin, J.-B.; Zhang, S.-Y. Palladium-catalyzed direct intermolecular
amination of unactivated methylene C(sp3)−H bonds with
́
(10) (a) Bertelsen, S.; Marigo, M.; Brandes, S.; Diner, P.; Jørgensen,
K. A. Dienamine catalysis: organocatalytic asymmetric γ-amination of
α,β-unsaturated aldehydes. J. Am. Chem. Soc. 2006, 128, 12973−
E
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Letter
12980. (b) Wang, J.; Chen, J.; Kee, C. W.; Tan, C.-H.
Enantiodivergent and γ-selective asymmetric allylic amination.
Angew. Chem., Int. Ed. 2012, 51, 2382−2386.
(11) (a) Fu, X.; Bai, H.-Y.; Zhu, G.-D.; Huang, Y.; Zhang, S.-Y.
Metal-controlled, regioselective, direct intermolecular α- or γ-
amination with azodicarboxylates. Org. Lett. 2018, 20, 3469−3472.
(b) Bai, H.-Y.; Tan, F.-X.; Liu, T.-Q.; Zhu, G.-D.; Tian, J.-M.; Ding,
T.-M.; Chen, Z.-M.; Zhang, S.-Y. Highly atroposelective synthesis of
nonbiaryl naphthalene-1,2-diamine N−C atropisomers through direct
enantioselective C−H amination. Nat. Commun. 2019, 10, 3063.
(12) (a) Tong, G.; Zhu, B.; Lee, R.; Yang, W.; Tan, D.; Yang, C.;
Han, Z.; Yan, L.; Huang, K.-W.; Jiang, Z. Highly enantio- and
diastereoselective allylic alkylation of Morita−Baylis−Hillman carbo-
nates with allyl ketones. J. Org. Chem. 2013, 78, 5067−5072. (b) Gu,
Y.; Wang, Y.; Yu, T.-Y.; Liang, Y.-M.; Xu, P.-F. Rationally designed
multifunctional supramolecular iminium catalysis: direct vinylogous
Michael addition of unmodified linear dienol substrates. Angew.
Chem., Int. Ed. 2014, 53, 14128−14131. (c) Zhan, G.; He, Q.; Yuan,
X.; Chen, Y.-C. Asymmetric direct vinylogous Michael additions of
allyl alkyl ketones to maleimides through dienamine catalysis. Org.
Lett. 2014, 16, 6000−6003.
(13) (a) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L.
Catalytic, enantioselective, vinylogous Aldol reactions. Angew. Chem.,
Int. Ed. 2005, 44, 4682−4698. (b) Ratjen, L.; García-García, P.; Lay,
F.; Beck, M. E.; List, B. Disulfonimide-catalyzed asymmetric
vinylogous and bisvinylogous Mukaiyama Aldol reactions. Angew.
Chem., Int. Ed. 2011, 50, 754−758. (c) Trost, B. M.; Gnanamani, E.;
Tracy, J. S.; Kalnmals, C. A. Zn-ProPhenol catalyzed enantio- and
diastereoselective direct vinylogous Mannich reactions between α,β-
and β,γ-butenolides and aldimines. J. Am. Chem. Soc. 2017, 139,
18198−18201.
(14) (a) Zhang, H.-J.; Shi, C.-Y.; Zhong, F.; Yin, L. Direct
asymmetric vinylogous and bisvinylogous Mannich-type reaction
catalyzed by a copper(I) complex. J. Am. Chem. Soc. 2017, 139, 2196−
2199. (b) Zhong, F.; Yue, W.-J.; Zhang, H.-J.; Zhang, C.-Y.; Yin, L.
Catalytic asymmetric construction of halogenated stereogenic carbon
centers by direct vinylogous Mannich-Type reaction. J. Am. Chem. Soc.
2018, 140, 15170−15175.
(15) (a) Wang, H.; Bai, Z.; Jiao, T.; Deng, Z.; Tong, H.; He, G.;
Peng, Q.; Chen, G. Palladium-catalyzed amide-directed enantiose-
lective hydrocarbofunctionalization of unactivated alkenes using a
chiral monodentate oxazoline ligand. J. Am. Chem. Soc. 2018, 140,
3542−3546. (b) Bai, Z.; Zheng, S.; Bai, Z.; Song, F.; Wang, H.; Peng,
Q.; Chen, G.; He, G. Palladium-catalyzed amide-directed enantiose-
lective carboboration of unactivated alkenes using a chiral
monodentate oxazoline ligand. ACS Catal. 2019, 9, 6502−6509.
(16) (a) Kawatsura, M.; Komatsu, Y.; Yamamoto, M.; Hayase, S.;
Itoh, T. Asymmetric conjugate addition of thiols to (E)-3-
crotonoyloxazolidin-2-one by iron or cobalt/pybox catalyst. Tetrahe-
dron 2008, 64, 3488−3493. (b) Hosokawa, S.; Ito, J.; Nishiyama, H.
NCN-pincer cobalt complexes containing bis(oxazolinyl)phenyl
ligands. Organometallics 2013, 32, 3980−3985. (c) Pellissier, H.;
Clavier, H. Enantioselective cobalt-catalyzed transformations. Chem.
Rev. 2014, 114, 2775−2823. (d) Yang, G.; Zhang, W. Renaissance of
pyridine-oxazolines as chiral ligands for asymmetric catalysis. Chem.
Soc. Rev. 2018, 47, 1783−1810.
(17) Lin, S.; Lin, Z. DFT studies on metal-controlled regioselective
amination of N-acylpyrazoles with azodicarboxylates. J. Org. Chem.
2019, 84, 12399−12407.
(18) See the Supporting Information for more details.
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https://dx.doi.org/10.1021/acs.orglett.0c03522
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