Catalytic Asymmetric Nazarov Cyclization of Heteroaryl Vinyl Ketones through a Crystallographically Defined Chiral Dinuclear Nickel Complex

Article abstract of DOI:10.1021/acs.orglett.5b02497

A Ni(NTf₂)₂ and tetradentate bisimino-bisquinoline ligand complex catalyzed the enantioselective Nazarov cyclization of heteroaryl vinyl ketones. An X-ray-quality crystal was obtained from a mixture of the Ni complex and the substrat

Full text of DOI:10.1021/acs.orglett.5b02497

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Nazarov Cyclization of Heteroaryl Vinyl
Ketones through a Crystallographically Defined Chiral Dinuclear
Nickel Complex
Takuya Takeda,† Shinji Harada,*,†,‡ and Atsushi Nishida*,†,‡
†Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
‡Molecular Chirality Research Center, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: A Ni(NTf2)2 and tetradentate bisimino-bisquinoline ligand complex catalyzed the enantioselective Nazarov
cyclization of heteroaryl vinyl ketones. An X-ray-quality crystal was obtained from a mixture of the Ni complex and the substrate,
which was the dinuclear chiral Ni complex. From information regarding the structure of the complex, the substrate was distorted
to form a helical shape, and the carbon atoms involved in bond formation were close to each other. In addition, mechanistic
studies revealed that the configuration of the olefin moiety was isomerized before bond formation.
Scheme 1. Enantioselective Nazarov Cyclization of Aryl
Vinyl Ketones
azarov cyclization is a ring-closing reaction of divinyl
Nketones via a pentadienyl cation intermediate in the
presence of a Brønsted acid or Lewis acid, which gives a
multisubstituted five-membered ring.1 The resulting five-
membered ring accepts various chemoselective transformations,
and several synthetic applications to biologically active
compounds have been demonstrated.2 After Frontier’s great
contribution to the use of polarized substrates,3 various
catalysts, including asymmetric catalysts, have been developed
to promote Nazarov cyclization under mild conditions. Thus,
this area of research has recently been in the spotlight.4
Meanwhile, the mechanism of Nazarov cyclization, especially
the stereoselectivity, has mainly been discussed through the use
of computational studies.5 The lack of information about the
transition state supported by experimental evidence6 might
limit the type of chiral catalyst in this area of research. Here, we
report the Nazarov cyclization of heteroaryl vinyl ketones
catalyzed by Ni(NTf2)2 and bisimino-bisquinoline (ImQ)7
complex and discuss the mechanism based on an X-ray
crystallographic analysis of the Ni−ImQ−substrate complex.
Aryl vinyl ketone is a subtype of Nazarov substrates (Scheme
1). However, there have been only two reports on catalytic and
enantioselective variants. Ma reported the fluorinative cycliza-
tion reaction using Cu-BOX catalyst.8 Recently, Rueping
introduced an indolyl substrate to this type of reaction, also
using Cu−BOX catalyst.9 We set compound 1 as a substrate for
Nazarov cyclization and screened catalysts using various metal
triflic imidates, since we have been focusing on the develop-
ment of reactions to construct heteroaromatic ring-fused
multicyclic chiral synthetic intermediates10 and on demonstrat-
ing the synthetic utility of metal triflic imidates (Mm(NTf2)n) as
a Lewis acid.10a When we used ImQ (2) as a chiral ligand, a
promising degree of enantioinduction was observed in
combination with various metal triflic imidates.11 Optimization
of the reaction conditions revealed that the conditions in
Scheme 2 gave the best result.
When we mixed the catalyst and compound 412 with
cyclopentyl methyl ether,13 we could isolate a red crystal. X-ray
crystallographic analysis of this crystal revealed that it was
dinuclear nickel complex [Ni2(imq)2(4)2]4+·4(NTf2)− (5)
(Figure 1B,C).14,15 Remarkably, the isolated complex 5 acted
Received: August 31, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02497
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Organic Letters
Letter
Interestingly, substrate 4 in the crystal structure was distorted
to make a helical shape.17 This P-helical configuration was
controlled by the chiral catalyst. Consequently, the two sp2
carbons, where the new bond would be formed, were placed
close to each other. Based on this observation, we proposed the
reaction mechanism shown in Scheme 4. The representative
Scheme 2. Enantioselective Nazarov Cyclization of 1
Catalyzed by Nickel Complex
a
Scheme 4. Proposed Reaction Mechanism
Figure 1. Procedure to obtain the crystal (A) and its crystallographic
characterization. ORTEP figure (B) and ChemDraw drawing (C) of
complex 5. Hydrogen atoms, water molecules, disordered atoms, and
counteranions have been omitted for clarity. Ellipsoids are drawn at
the 30% probability level.
a
The remaining half of the complex has been omitted for clarity.
as a catalyst (Scheme 3) with a similar reactivity and
stereoselectivity as the in situ catalyst system shown in Scheme
2.11 This result shows that the substrate 4 in the complex
should be exchanged with a new molecule of the substrate.
Therefore, we speculated that a dinuclear nickel complex
[Ni2(imq)2]4+·4(NTf2)− would be the active catalyst.16
substrate 1 would coordinate to the nickel catalyst to assemble
a complex 6 similar to the crystal structure. Activated substrate
formed the five-centered cationic intermediate 7 with a P-
helical topology, where the terminal molecular orbitals easily
overlapped. The resulting cyclized intermediate 8 could afford
the Nazarov adduct; however, the absolute stereochemistry of
the product should be opposite that of the actual product.
Therefore, we supposed that the configuration of the olefin
moiety would be isomerized while an equilibrium was being
achieved between 7 and 9.18 The isomerization to 9 could avoid
the steric hindrance between two aromatic rings of the
substrate, and this intermediate would afford 10 to give the
actual product 3.
Scheme 3. Asymmetric Nazarov Cyclization Using 5 as a
Catalyst
B
DOI: 10.1021/acs.orglett.5b02497
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Organic Letters
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To elucidate the equilibrium between 7 and 9, both (E)- and
(Z)-isomers of 11 were independently treated with the catalyst
and quenched before the reaction was complete. In both cases,
the recovered substrates became a mixture of (E)- and (Z)-
isomers (Scheme 5), and the E/Z ratios were similar. The
Table 1. Substrate Scope
Scheme 5. Asymmetric Nazarov Cyclization Using (E)- and
(Z)-Isomers of 11
products 12 also had an identical ee value: 47% ee. The
absolute configuration of the product was independent of the
configuration of the substrate. This experiment in Scheme 5
strongly supported the existence of an equilibrium.
Our nickel catalyst promoted Nazarov cyclization of various
heteroaryl vinyl ketones with good enantioselectivity (Table 1).
The substituent on the olefin moiety could be an aromatic,
heteroaromatic, or alkenyl group to give the Nazarov adduct in
good yields with moderate to good ee’s (entries 1−5). The
electron-withdrawing group could be an ester, amide, ketone,
or phosphoric ester (entries 6−11). Substrates that contained
amides were less reactive, while substrates that contained
ketones were more reactive than those that contained esters.
For the protective group on the nitrogen of the indole ring, a
tosyl group was suitable (entry 12), although both the reactivity
and enantioselectivity were decreased. Benzyl protection
slightly affected the enantioselectivity (entry 13). We
performed reactions with two substrates with methoxy or
fluorine substituents on the indole ring (entries 14 and 15).
Both substrates gave good results. Nonprotected indoles were
less reactive, but high enantioselectivity was achieved in all
cases (entries 16−18). A pyrrole derivative could be used
instead of indole in our catalytic system (entry 19).19
In conclusion, we have developed a novel nickel catalyst for
the catalytic and enantioselective Nazarov cyclization of
heteroaryl vinyl ketones. We also successfully isolated the
chiral active catalyst and the substrate complex,
[Ni2(imq)2(4)2]4+·4(NTf2)− (5). From its structure, we
proposed that carbon−carbon bond formation occurred as a
result of distortion of the substrate. We also confirmed that the
olefin moiety of the substrate was isomerized under the
reaction conditions. Information on the structure of 5 should
contribute to both the design of chiral ligands and mechanistic
studies of the general reaction using Lewis acid activated β-
ketoesters.
a
b
The reaction was carried out at 40 °C. Obtained as a mixture of the
keto form and enol form.11 The reaction was carried out at 40 °C
with 20 mol % of the catalyst. The reaction was carried out with 20
mol % of the catalyst.
c
d
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02497.
C
DOI: 10.1021/acs.orglett.5b02497
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Organic Letters
Experimental details, substrate supply, NMR and HPLC
Letter
(8) Nie, J.; Zhu, H.-W.; Cui, H.-F.; Hua, M.-Q.; Ma, J.-A. Org. Lett.
2007, 9, 3053.
(9) Raja, S.; Nakajima, M.; Rueping, M. Angew. Chem., Int. Ed. 2015,
spectra for obtained compounds, and supporting figures
(PDF)
X-ray data for compound 5 (CIF)
54, 2762.
(10) (a) Harada, S.; Morikawa, T.; Nishida, A. Org. Lett. 2013, 15,
5314. (b) Yoshida, K.; Morikawa, T.; Yokozuka, N.; Harada, S.;
Nishida, A. Tetrahedron Lett. 2014, 55, 6907.
AUTHOR INFORMATION
■
(11) For details, see the Supporting Information.
Corresponding Authors
(12) Compound 4 with 10 mol % of Ni(NTf2)2 gave Nazarov adduct
in 43% yield. For details, see the Supporting Information. Compound
4 was also used for Nazarov cyclization by Luo’s group. Xi, Z.-G.; Zhu,
L.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2013, 78, 606. The substrates
used in Table 1 were not appropriate for crystallization because the
reaction proceeded.
(13) Used as a less polar solvent to obtain the crystal. Watanabe, K.;
Yamagiwa, N.; Torisawa, Y. Org. Process Res. Dev. 2007, 11, 251.
(14) CCDC 1058249 contains the supplementary crystallographic
data. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(15) Several examples of tetradentate bisimino ligand−metal
complexes have been reported with X-ray crystallographic analysis
data. Depending on the structure of the ligand or the counterion,
several types of the complex would be formed. For a Ni complex, see:
(a) Prema, D.; Oshin, K.; Desper, J.; Levy, C. J. Dalton Trans. 2012,
*E-mail: s.harada@faculty.chiba-u.jp.
*E-mail: anishida@faculty.chiba-u.jp.
Author Contributions
All authors contributed equally to the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI (Grant Nos.
25460006 (S.H.) and 25293001 (A.N.)). We thank Dr.
Hiroyasu Sato (RIGAKU Co., Japan) for his generous help
with the X-ray crystallographic analysis of the nickel complex.
41, 4998. For a Mo complex, see: (b) Morales, D.; Per
Riera, V.; Corzo-Suarez, R.; García-Granda, S.; Miguel, D. Organo-
metallics 2002, 21, 1540. For Mn complexes, see: (c) Schoumacker, S.;
Hamelin, O.; Pecaut, J.; Fontecave, M. Inorg. Chem. 2003, 42, 8110.
(d) Yliheikkila, K.; Axenov, K.; Raisanen, M. T.; Klinga, M.; Lankinen,
́
ez, J.; Riera, L.;
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D
DOI: 10.1021/acs.orglett.5b02497
Org. Lett. XXXX, XXX, XXX−XXX