Carbonyl-Directed Addition of N-Alkylhydroxylamines to Unactivated Alkynes: Regio- and Stereoselective Synthesis of Ketonitrones

Article abstract of DOI:10.1021/acs.orglett.8b03522

A variety of ketonitrones were synthesized in moderate to excellent yields with high chemo-, regio-, and stereoselectivity by using carbonyl-directed addition of N-alkylhydroxylamines to unactivated alkynes under mild conditions. The product diverisity could be controlled by the use of different bases, and EtN(n-Pr)₂ could promote the formation of ketonitrones while using EtONa as base led to indanone-derived nitrones. Control experiments indicated that the carbonyl group of the substrate acted as an H-bond acceptor except for an electron-withdrawing group, and conjugated enone skeleton accounted for the high selectivity.

Full text of DOI:10.1021/acs.orglett.8b03522

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Carbonyl-Directed Addition of N‑Alkylhydroxylamines to
Unactivated Alkynes: Regio- and Stereoselective Synthesis of
Ketonitrones
Yilin Liu,*,†,‡ Xiangqing Feng,‡ Yanyun Liu,† Hongwei Lin,† Yuanxiang Li,† Yingying Gong,† Lei Cao,†
and Liping Chen†
†Institute of Organic Synthesis, College of Chemistry and Materials Engineering, Huaihua University, Huaihua 418008, China
‡CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
S
* Supporting Information
ABSTRACT: A variety of ketonitrones were synthesized in
moderate to excellent yields with high chemo-, regio-, and
stereoselectivity by using carbonyl-directed addition of N-
alkylhydroxylamines to unactivated alkynes under mild
conditions. The product diverisity could be controlled by
the use of different bases, and EtN(n-Pr)2 could promote the
formation of ketonitrones while using EtONa as base led to indanone-derived nitrones. Control experiments indicated that the
carbonyl group of the substrate acted as an H-bond acceptor except for an electron-withdrawing group, and conjugated enone
skeleton accounted for the high selectivity.
Scheme 1. Overview of Synthesis of Ketonitrones from
Alkyne and Hydroxylamine
itrones, as 1,3-dipolars, have received much attention in
Nsynthetic organic chemistry, not only because they are
versatile building blocks to access N,O-containing heterocycles
and natural products through the stereoselective [3 + 2]-
cycloadditions with various dipolarophiles1 but also because
many other novel transformations involving nitrones have been
developed in recent years.2 A large number of protocols have
been intensively investigated, such as oxidation of a secondary
hydroxylamine3/amine,4 condensation of a carbonyl com-
pound with a hydroxylamine,5 and N-alkylation of an oxime
ether6 or oxime;7 these are the most common strategies for the
synthesis of nitrones. Despite the efficiencies of these methods,
most of the methodologies have been limited to aldonitrones,
and reports on ketonitrone chemistry remain scarce, owing to
general kinetic instability of ketonitrones5c unless an electron-
withdrawing group is present.8
An alternative approach to access ketonitrone is direct
nucleophilic addition of hydroxylamine to alkyne.9 However,
this strategy still remains underdeveloped.8a,b,e Winterfeldt first
described the synthesis of aspartate nitrone through
nucleophilic addition of N-alkylhydroxylamines to dialkyl
acetylenedicarboxylate (Scheme 1a),8a and then the extensive
studies of their synthesis and cycloaddition with alkenes were
reported by Padwa9f and Dujardin.8b,e With respect to
unactivated alkyne, coordination of the triple bond to a
metal is a strategy usually used to enhance the electrophilicity
of the alkyne. In 2014, both Zhang10 and Nakamura11
demonstrated an elegant synthesis of ketonitrones via intra-
molecular additions of hydroxylamine to alkyne activated by
Ag and Cu catalysts, respectively (Scheme 1b). Recently, Liu
and co-workers developed a gold-catalyzed N-attack of N-
hydroxyanilines at the alkynes to give unstable ketonitrones
that reacted instantaneously with their tethered alkenes,12a
allenes,12b and alkynes12c to afford bicyclic compounds,
Received: November 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03522
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Organic Letters
Letter
a
benzoazepin-4-ones, and pyrrole derivatives, respectively
(Scheme 1b). Although metal-free synthesis of ketonitrone
from simple alkyne and hydroxylamine has been successfully
achieved by Padwa9f and Beauchemin,9b respectively (Scheme
1c), these methods suffered from several drawbacks such as
high temperature, moderate yields, and limited substrate scope
(only for terminal arylacetylene). Therefore, developing a
metal-free, general, and efficient route to access ketonitrones
from alkyne and hydroxylamine remains challenging and
desirable. Herein, we report the first carbonyl-controlled
addition of N-alkylhydroxylamines to unactivated alkynes to
give ketonitrones and indanone-derived nitrones, respectively
(Scheme 1d).
Scheme 2. Scope of Preparing Ketonitrone 3
As shown in Table 1, the reaction between α,β-unsaturated
ketone 1a and N-benzylhydroxylamine hydrochloride 2a was
a
Table 1. Optimization of the Reaction Conditions
b
entry
base (equiv)
solvent
time (h) yield (3aa/4a) (%)
1
2
3
4
5
6
7
8
9
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
THF
12
23
12
12
17
13
13
13
12
12
12
12
12
12
13
12
12
24/0
31/0
40/0
34/0
49/0
51/0
56/0
60/0
83/0
84/0
73/0
8/66
4/77
4/81
trace/24
5/67
3/83
dioxane
MeCN
toluene
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
a
All reactions were carried out with 1 (0.30 mmol), 2 (0.30 mmol),
EtN(n-Pr)2 (1.0 equiv), and DCM (3.0 mL), 12−24 h unless
b
otherwise stated; isolated yield based on 1. Reaction time was 39 h.
Et3N (1.5)
KOAc (1.5)
DABCO (1.5)
EtN(CH3)2 (1.5)
EtN(n-Pr)2 (1.5)
EtN(n-Pr)2 (1.0)
no base also proceeded smoothly to give the 3aa in 73% yield
(Table 1, entry 11). With 1.0 equiv of EtN(n-Pr)2, the reaction
yield was still very good (Table 1, entry 10); however, an
increase in the amount of 2a and EtN(n-Pr)2 or increasing the
reaction temperature to 50 °C all led to a decrease in yield. To
our surprise, a novel indanone-derived nitrone 4a was isolated
in modest yield as a major product accompanied by a lower
amount of nitrone 3aa when DBU was used (Table 1, entry
12). Compounds 3aa and 4a were easily separated by flash
chromatography. The structure was again determined by its
analogue 4k X-ray diffraction analysis, which reveals the cis
relationship between the 2-oxo-2-phenylethyl and phenyl
groups on the five-membered ring. Encouraged by the
observed switch in selectivity from ketonitrone 3aa to 4a, we
decided to further examine other stronger bases to promote
this transformation. As shown in Table 1, EtOK increased the
yield of ketonitrone 4a to 77%, while the yield was only
delivered in 24% with t-BuONa as base (Table 1, entries 13
and 15). MeONa gave the same yield as that of DBU (Table 1,
entry 16). EtONa was the choice of base for the reaction,
affording ketonitrone 4a in yield of 81% (Table 1, entry 14).
The amount of EtONa could be decreased to 1.3 equiv, and
the same yield was obtained (Table 1, entry 17). Of note is
that no indanone-derived nitrone 4a was observed when
weaker bases were used (Table 1, entries 1−10), and all of the
reactions gave single E-isomers of nitrone exclusively and that
only cis isomer of 4a was observed.
10
11
c
12
13
14
15
16
17
DBU (1.5)
EtOK (1.5)
EtONa (1.5)
t-BuONa (1.5)
MeONa (1.5)
EtONa (1.3)
a
All reactions were carried out with 1a (0.30 mmol), 2a (0.30 mmol),
b
base, and solvent (3.0 mL) unless otherwise stated. Isolated yield
based on 1a. BnNHOH instead of 2a was used.
c
investigated to optimize the reaction conditions. When a
mixture of 1a and 2a in THF was treated with 1.5 equiv of
Et3N at room temperature, a ketonitrone 3aa was obtained in
24% yield (Table 1, entry 1). The structure of 3aa was
determined by NMR spectroscopy and further confirmed by
the X-ray diffraction analysis of analogue 3ya in Scheme
2,which indicates the CN bond of ketonitrone 3 is an E-
configuration and the C−N double bond is perpendicular to
the benzene ring attached to nitrone. A screen of various
solvents revealed that DCM was the best choice for this
transformation (Table 1, entries 1−5). The base had a large
effect on the yield and chemoselectivity of the reaction. When
inorganic base KOAc was used, the reaction went smoothly to
give the desired product 3aa in 51% yield; a slightly higher
yield was observed when Et3N was replaced by other organic
bases DABCO and EtN(CH3)2 (Table 1, entries 7 and 8), and
EtN(n-Pr)2 furnished the ketonitrone 3aa in the highest yield
of 83%. The reaction of 1a and N-benzylhydroxylamine with
With the optimal reaction conditions in hand (Table 1, entry
10), the scope of this reaction was examined (Scheme 2). The
substituents on the aryl ring of ketones had little influence on
the reaction outcome (3ba−fa). Ketone 1g containing a 2-furyl
group was well tolerated for this transformation to afford the
corresponding product in 84% yield (3ga), and the reaction of
B
DOI: 10.1021/acs.orglett.8b03522
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methyl ketone 1h led to the ketonitrone in satisfactory yield
(3ha). Modest yield was obtained using unsaturated ester 1i as
substrate; in contrast, a trace amount of ketonitrone 3ja was
observed when acrylamide 1j was subjected to the optimal
conditions. Cinnamaldehyde 1k failed to yield the desired
ketonitrone but gave the aldonitrone 3ka′ in a yield of 87%,13
perhaps due to the higher electrophilicity of aldehyde
compared to the C−C triple bond in the structure of 1k. An
array of substituents (R3) were also examined, and all of the
reactions proceeded smoothly to furnish the corresponding
ketonitrones in 61−83% yields (3la−sa); it is noteworthy that
ketones bearing electron-withdrawing substituents gave slightly
higher yields than ketones with electron-donating substituents
(3la−na vs 3oa and 3pa). To our pleasure, cyclohexenyl-
substituted ketone 1q, alkyl-substituted 1r, and simple terminal
alkyne 1s were also effective substrates for this reaction to
furnish the desired products 3qa−sa in synthetically useful
yields. For ketones having various substituents R2, their
reactions successfully furnished desired products in good
yields (3ta−ya); for example, naphthalenyl nitrone 3ya was
afforded in 76% yield under optimal reaction conditions. When
nonaromatic enynone 1z was used, the reaction also went
smoothly to give the desired product 3za in moderate yield.
We also examined the reactions of ketone 1d with other
hydroxylamines, N-hydroxyaniline 2d failed to give the
corresponding product 3dd, while N-alkylhydroxylamine 2b
and 2c afforded compounds 3db and 3dc in 90% and 96%
yields under the standard conditions, respectively. Therefore,
product yields in Scheme 2 can be significantly improved if a
more basic hydroxylamine like 2b or 2c is used. Generally,
most of the ketonitrones could be purified through flash
chromatography, with some nitrones being a little labile.
Indanone-derived nitrones are valuable intermediates for
constructing spiro compounds by cycloaddition reactions with
a variety of dipolarophiles. However, the method for their
synthesis has been rarely exploited. There is one example
reported by Beauchemin that uses condensation of indanone
and N-cyclohexylhydroxylamine simply upon heating in t-
BuOH at 110 °C to afford indanone-derived nitrone in 47%
yield.5c Thus, the development of new straightforward access
to these nitrone is highly desirable. We decided to expand the
scope of the reactions with 2a under the optimal conditions
identified in Table 1, entry 17. The results are summarized in
Scheme 3, and all of the reactions proceeded efficiently to give
the desired products 4b−l in 68−86% yields. In all cases, the
ketonitrone 3 was obtained with less than 5% yield, and only
the cis isomer of 4 was observed.
Scheme 3. Scope of Preparing Indanone-Derived Nitrones
4
a
a
All reactions were carried out with 1 (0.30 mmol), 2a (0.30 mmol),
EtONa (1.3 equiv), and DCM (3.0 mL), 12−22 h unless otherwise
stated; isolated yield based on 1.
Scheme 4. Transformations of Ketonitrones with DEAD
Scheme 5. Control Experiments
With the two novel types of ketonitrones 3 and 4 in hand,
subsequently, transformations of nitrone were investigated, and
ketonitrones 3ua and 4k were subjected to [3 + 2]
cycloaddition reactions with diethyl acetylenedicarboxylate
(DEAD), giving highly functionalized 2-isoxazoline 5 and
spiro-isoxazoline 6 in 85% and 90% yields, respectively
(Scheme 4). The molecular structures of compounds 5 and
6 were confirmed by X-ray diffraction.
To gain insight into the effect of the ketone structure on
nitrone formation, we performed the control experiments.
When enyne 7 reacted with 2a, no desired product 8 was
observed (Scheme 5 (1)). Furthermore, no reaction occurred
when allyl alcohol 9a, ether 9b, or allyl alcohol acetate 9c was
utilized under the standard conditions (Scheme 5 (2)),
suggesting that the carbonyl of ketone 1 is essential for the
reaction, and a possible hydrogen-bonding between carbonyl
C
DOI: 10.1021/acs.orglett.8b03522
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Letter
and hydroxylamine promoted the reaction.14 The presence and
configuration of C−C double bond in substrate were also
important for the reaction, as no reaction occurred when 11 or
13 was used (Scheme 5 (3), (4)), which may be attributed to
the fact that these compounds cannot meet the requirement of
the rigid spatial relationship necessary for the reaction with N-
alkylhydroxylamine to proceed. We found that alkynes 15
bearing an ortho electron-withdrawing group did not yield any
product, ruling out that the carbonyl of substrate 1 only acted
as an electron-withdrawing group to promote nitrone
formation (Scheme 5 (5)). Compound 3aa could be converted
to 4a in a yield of 86% under conditions similar to those in
Scheme 3 (Scheme 5 (6)).
Accession Codes
CCDC 1859249−1859250 and 1859389−1859390 contain
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 Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liuyilinhn@126.com.
ORCID
On the basis of the experimental results and existing
literature,8a,b,e,f,15 a proposed mechanism for the reaction is
illustrated in Scheme 6. Initially, the intermediate N-
Yilin Liu: 0000-0002-8491-914X
Notes
Scheme 6. Proposed Reaction Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21502065), Hunan Provincial Natural Science Founda-
tion (No. 2015JJ6089), Scientific Research Fund of Hunan
Provincial Education Department (Nos. 15B184 and 17A166),
and Opening Fund of CAS Key Laboratory of Molecular
Recognition and Function (Chinese Academy of Sciences)
(No. 2017LRMF009) for financial support.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03522.
■
S
Descriptions of experimental procedures for compounds
and analytical characterization (PDF)
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