Nickel(II)-Catalyzed Oxygen Transfer Reaction of N-Vinyl Nitrones to Prepare 2-(Pyridin-2-yl)ethanols

Article abstract of DOI:10.1021/acs.orglett.0c02947

A nickel(II)-catalyzed oxygen transfer reaction of dibenzylideneacetone-derived N-vinyl-α,β-unsaturated nitrones has been identified for the preparation of polysubstituted 2-(pyridin-2-yl)ethanols in good yields with high atom economy. The scope of the method is described, and mechanistic experiments are discussed. The reaction was easily performed at gram scales, and pyrido[2,3-c]carbazole was obtained in moderate yield over three steps.

Full text of DOI:10.1021/acs.orglett.0c02947

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Letter
Nickel(II)-Catalyzed Oxygen Transfer Reaction of N‑Vinyl Nitrones to
Prepare 2‑(Pyridin-2-yl)ethanols
Ning Zou, Jing-Xuan Lan, Gong-Gui Yan, Cui Liang, Gui-Fa Su,* and Dong-Liang Mo*
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ABSTRACT: A nickel(II)-catalyzed oxygen transfer reaction of
dibenzylideneacetone-derived N-vinyl-α,β-unsaturated nitrones has
been identified for the preparation of polysubstituted 2-(pyridin-2-
yl)ethanols in good yields with high atom economy. The scope of the
method is described, and mechanistic experiments are discussed. The
reaction was easily performed at gram scales, and pyrido[2,3-
c]carbazole was obtained in moderate yield over three steps.
Scheme 1. O-Transfer Reaction of N-Substituted α,β-
Unsaturated Nitrones
ransition-metal-catalyzed O-transfer reactions of easily
available compounds containing N−O bonds, such as
T
oximes, oxime ethers, hydroxylamines, isoxazoles, pyridine N-
oxides, and nitrones, provide a useful strategy to introduce an
oxygen atom into the target compounds.1 In 2013, Mo and
Anderson pioneered the development of a copper-catalyzed O-
transfer reaction of N-aryl-α,β-unsaturated nitrones to prepare
useful α,β-epoxyketimines in excellent yields, and the prepared
α,β-epoxyketimines could be easily converted to various
substituted tetrahydroquinolines by cyclization in the presence
of BF3·Et2O and sequential reduction in two steps (Scheme
1A).2 We recently reported an iron(III)-catalyst-controlled
selective cyclization of N-vinyl-α,β-unsaturated nitrones to
prepare polysubstituted pyridines and isoxazolines in good to
excellent yields (Scheme 1B).3 The formation of a pyridine
unit might be due to the use of FeCl3 as a strong Lewis acid to
facilitate the isomerization of the epoxyketimine to an
enaminone intermediate, followed by dehydration. However,
the O atom and vinyl groups connected to the N atom are
completely dropped from the nitrones, making this method
lack atom economy. To pursue an atom-economical O-transfer
reaction, during studies of N-vinyl-α,β-unsaturated nitrones in
our groups4 we surmised that if a weak Lewis acid catalyst were
used to avoid the isomerization of the epoxyketimine to the
enaminone with subsequent dehydration, then the epoxyketi-
mine would directly undergo an atom-economical O-transfer
reaction to furnish the pyridine derivative (Scheme 1C).
Secondary alcohols bearing a 2-pyridine as a substituent are
key intermediates that not only are normally used to access
chiral N-ligands but also are of great interest as synthetic
intermediates in the synthesis of agrochemicals, pharmaceut-
icals, and pyridocarbazoles, such as the H1 antagonists
carbinoxamine and bepotastin besylate as well as ellipticine
and strellidimine.5 To date, many elegant methods for the
preparation of functionalized pyridine derivatives have been
developed,6 including C−H activations, annulations, cyclo-
additions, and related transformations.7−10 Catalysts based on
Received: September 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02947
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a b
,
earth-abundant nickel have clear advantages in synthetic
chemistry because of they are inexpensive, nontoxic, water-
soluble, and environmentally benign.11 Herein we report a
nickel(II)-catalyzed oxygen transfer reaction of easily available
N-vinyl-α,β-unsaturated ketonitrones to prepare various
polysubstituted 2-(pyridin-2-yl)ethanols.
Scheme 2. Substrate Scope of the O-Transfer Reaction
Initially, N-vinyl nitrone 1a was chosen as the model
substrate to test the O-transfer reaction. As shown in Table 1, a
a
Table 1. Optimization of the Reaction Conditions
b
entry
cat.
solvent, time
yield of 2a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
NiCl2
NiBr2
NiF2
DCE, 2 h
DCE, 2 h
DCE, 24 h
DCE, 2 h
DCE, 2 h
DCM, 2 h
toluene, 2 h
MeCN, 2 h
THF, 2 h
DMF, 12 h
DMSO, 12 h
DCE, 1 h
DCE, 5 h
DCE, 0.5 h
DCE, 1 h
33
37
<5
50
63
62
47
42
57
<5
<5
Ni(OTf)2
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
a
Reaction conditions: 1 (0.2 mmol), Ni(ClO4)2·6H2O (30 mol %), 4
b
Å MS (200 mg), DCE (2.0 mL), 100 °C. Isolated yields are shown.
c
c
70
61
45
51
Diastereomeric ratio.
d
e
products 2a−k in moderate to good yields. The reaction also
tolerated heteroaryl groups such as 2-furanyl and 2-thienyl,
furnishing products 2l and 2m in 55% and 69% yield,
respectively. In addition to the α,β-unsaturated ketone
moieties, the vinyl moieties on the nitrone N atom were also
evaluated. Linear and cyclic N-vinyl substituents delivered the
corresponding products in moderate yields (2n−v). N-Vinyl
groups with alkyl and aryl groups were tolerated (2n and 2o),
as were N-vinyl groups included in five- to seven-membered
carbon rings or a pyran ring (2p−v). Pleasingly, nitrone 1t
with an acetal group on the six-membered ring successfully
furnished 2t in 68% yield. N-Vinyl nitrones 1u with a phenyl
group and 1v with a tert-butyl group at the 4-position of the
six-membered ring afforded products 2u and 2v in 43% and
51% yield with a 1.1:1 and 1:1 diastereoselectivity, respectively.
When a 1:1 E/Z mixture of nitrone 1w with a methoxy group
was reacted under the standard conditions, product 2w was
obtained in 54% yield with a 1.3:1 ratio. However, a 1:1 E/Z
mixture of nitrone 1x with a CF3 group delivered product 2x in
59% yield with a 1:1.3 ratio. The two diastereomers of 2w and
2x were determined by their NOESY spectra. These results
suggested that N-styrenyl nitrones with an electron-donating
group facilitated the cyclization process. In all of these cases,
the yields of 2 were not very high because N-vinyl nitrones 1
partially decomposed to the corresponding dibenzylideneace-
tones in the presence of the Ni(II) catalyst.
cf
,
a
Reaction conditions: 1a (0.2 mmol), catalyst (20 mol %), solvent
(2.0 mL), 4 Å MS (200 mg), 100 °C. Isolated yields. Ni(ClO4)2·
b
c
d
e
f
6H2O (30 mol %). 80 °C. 120 °C. Without 4 Å MS.
33% yield of 2-(pyridin-2-yl)ethanol 2a was obtained when 20
mol % NiCl2 was used as the catalyst in DCE in the presence
of 4 Å MS at 100 °C for 2 h (entry 1). The structure of 2a was
determined by X-ray diffraction analysis. Further optimization
of the Ni(II) catalyst found that Ni(ClO4)2·6H2O gave a
higher yield than NiBr2, NiF2, and Ni(OTf)2 (entries 2−5).12
Then solvent screening revealed that product 2a was obtained
in moderate to good yields in DCM, toluene, MeCN, and THF
while no desired product was observed in DMF and DMSO
(entries 6−11). Increasing the loading of Ni(ClO4)2·6H2O to
30 mol % improved the yield of 2a to 70% after only 1 h (entry
12). However, the yield of 2a decreased when the reaction
temperature was lowered to 80 or 120 °C (entries 13 and 14).
The yield of 3aa decreased to 51% without the addition of 4 Å
MS, and obvious decomposition of nitrone 1a to dibenzylide-
neacetone was observed (entry 15). The added 4 Å MS might
act as a water absorbent and avoid decomposition of the N-
vinyl nitrone. Therefore, the optimal conditions for preparing
2-(2yridine-2-yl)ethanol 2a were Ni(ClO4)2·6H2O (30 mol %)
as the catalyst in DCE with 4 Å MS as an additive at 100 °C for
1 h.
To better understand the mechanism of the O-transfer
reaction, control experiments were performed (Scheme 3).
When chalcone-derived N-vinyl nitrone 1y reacted under the
standard conditions, isoxazoline 3 was obtained in 48% yield,
showing that the vinyl group on the N atom was dropped
(Scheme 3(1)). This result revealed that the formation of
pyridine involved an O-cyclization process. With the addition
of 2.5 equiv of D2O under the standard conditions, 2a was
With the optimized conditions in hand, the substrate scope
of this Ni(II)-catalyzed O-transfer reaction was studied by
testing a variety of N-vinyl-α,β-unsaturated ketonitrones. As
shown in Scheme 2, various dibenzylideneacetone-derived N-
vinyl nitrones 1a−k with electron-donating and electron-
withdrawing groups at the para, meta, and ortho positions of
the aryl ring proceeded smoothly to afford the corresponding
B
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dependence on the type of para-substituted N-vinyl α,β-
unsaturated ketonitrone had a linear correlation with the σp
values with a ρ value of −0.76 and a nonlinear correlation with
the σm values.14 These results indicated that C−O bond
formation is the slow step of the O-transfer reaction. The
negative ρ value might reveal that electron-donating groups
facilitated the C−O bond formation, which was consistent with
the results for 2w and 2x in Scheme 2.
Scheme 3. Mechanistic Studies
On the basis of the above experimental results, a possible
mechanism for the formation of 2-(pyridin-2-yl)ethanol 2a is
proposed (Scheme 4). Initially, nitrone 1a coordinates to the
Scheme 4. Proposed Mechanism
obtained in 50% yield, and the deuterated ratio of the
methylene position in 2a was 50% (Scheme 3(2)). These
results indicated that the reaction involved an intermolecular
protonation process. The NOESY spectra of compound D-2a
showed that the hydrogen in the methylene group had a cis
relationship with the hydrogen connected to the hydroxyl
group. When a 1:1 mixture of compound 4 and nitrone 1b was
subjected to the standard conditions, product 2a was not
observed, and only 2b was obtained in 68% yield (Scheme
3(3)). These results indicated that compound 4 could not be
converted to 2a during the formation of 2b. Compound 5
combined with 5.0 equiv of water also failed to result in
product 2a, showing that the formation of 2a did not proceed
via 1,4-addition to 2-vinylpyridine 5 by water in the presence
of the Ni(II) catalyst (Scheme 3(4)). These results
demonstrated that compounds 4 and 5 were not the
intermediates to form 2a.
To investigate the independence of the rate of product
formation, the electronic nature of the aryl group in the α,β-
unsaturated ketone moiety was evaluated. Competition
experiments between para-substituted N-vinyl α,β-unsaturated
ketonitrones 1b−f and 1a were used to test the C−O bond
formation step by comparison of the relative rates to σp and σm
values, respectively.13 As shown in Figure 1, the relative rate
nickel(II) catalyst and undergoes a cyclization sequence to
form intermediate A. Cleavage of the N−O bond of
intermediate A delivers epoxyketimine B, and ring opening
of the epoxide in B affords intermediate C. Oxa-1,4-addition in
C gives intermediate D, and then C−O cleavage and
aromatization result in 2a with release of the Ni(II) catalyst
to finish the catalytic cycle.15
To show the utility of this O-transfer reaction, the gram-
scale preparation of 2a was performed. As shown in Scheme
5(1), when 1.97 g of nitrone 1a was used, the product 2a was
obtained in 60% yield (1.18 g). Compound 2a was easily
converted to diketone 6 in 46% yield and chloropyridine 7 in
75% yield by oxidation and chlorination, respectively. As
shown in Scheme 5(2), removal of the acetal group in 2t under
HCl conditions afforded ketone 8 in 66% yield. Then
reduction of 8 with NaBH4 delivered diol 9 in 71% yield
Scheme 5. Gram-Scale Preparation and Transformations of
2a and Applications of 2t
Figure 1. Correlation of relative rates to Hammett σp values.
C
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with 1.2:1 dr. Interestingly, compound 8 could react with
phenyloxyamine in the presence of MeSO3H to afford
condensation/1,3-rearrangement product 10 in 40% yield.
Finally, the reaction of 4-MeC6H4NHNH2 with ketone 8 in the
presence of TCT delivered pyrido[2,3-c]carbazole 11 in 81%
yield with high [3,3]-rearrangement regioselectivity. Pyrido-
carbazoles are important heteroannulated carbazoles that
occupy a pivotal position in the field of medicinal chemistry
because of their promising antitumor activity.16
In summary, we have identified a nickel(II)-catalyzed atom-
economical O-transfer reaction to prepare various polysub-
stituted 2-(pyridin-2-yl)ethanols in good yields from dibenzy-
lideneacetone-derived N-vinyl-α,β-unsaturated nitrones. Mech-
anistic studies indicated that the C−O bond formation by
initial cyclization is the slow step of the pyridine formation.
Furthermore, the prepared 2-(pyridin-2-yl)ethanols can be
converted to diverse functional scaffolds, and a new type of
pyrido[2,3-c]carbazole was easily prepared over three steps.
Gong-Gui Yan − State Key Laboratory for Chemistry and
Molecular Engineering of Medicinal Resources, Ministry of
Science and Technology of China, and School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, Guilin
541004, China
Cui Liang − State Key Laboratory for Chemistry and Molecular
Engineering of Medicinal Resources, Ministry of Science and
Technology of China, and School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, Guilin
541004, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02947
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21871062 and 22071035), the Ministry
of Education (IRT_16R15), the Student Innovation Training
Program (202010602237), the Overseas 100 Talents Program
of Guangxi Higher Education, and the One Thousand Young
and Middle-Aged College and University Backbone Teachers
Cultivation Program of Guangxi is greatly appreciated.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02947.
Detailed experimental procedures, characterization data,
and copies of NMR spectra of compounds 1−11 and D-
2a (PDF)
REFERENCES
■
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Accession Codes
CCDC 2023862 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, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
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■
Corresponding Authors
Gui-Fa Su − State Key Laboratory for Chemistry and Molecular
Engineering of Medicinal Resources, Ministry of Science and
Technology of China, and School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, Guilin
541004, China; orcid.org/0000-0003-3128-2381;
Email: gfysglgx@163.com
Dong-Liang Mo − State Key Laboratory for Chemistry and
Molecular Engineering of Medicinal Resources, Ministry of
Science and Technology of China, and School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, Guilin
541004, China; orcid.org/0000-0002-4005-2249;
Email: moeastlight@mailbox.gxnu.edu.cn
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Authors
Ning Zou − State Key Laboratory for Chemistry and Molecular
Engineering of Medicinal Resources, Ministry of Science and
Technology of China, and School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, Guilin
541004, China
Jing-Xuan Lan − State Key Laboratory for Chemistry and
Molecular Engineering of Medicinal Resources, Ministry of
Science and Technology of China, and School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, Guilin
541004, China
D
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Letter
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(12) Other metal catalysts were also tested. It was found that
AgOTf, Yb(OTf)3 and Sc(OTf)3 as catalysts delivered product 2a in
moderate yields while using Fe(OTf)3, Cu(OAc)2 and Pd(OAc)2 did
not afford product 2a. More details are provided in the Supporting
Information.
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(14) More details about the σp and σm values are provided in the
Supporting Information.
(15) Some of the intermediates in the reaction were also detected by
HRMS trace experiments. Intermediates A−D in the reaction system
were also studied by HRMS (ESI). However, it was difficult to
identify the exact intermediates because A−D have the same
molecular weight. Some possible intermediates were also detected.
More details are provided in the Supporting Information.
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