Iminyl Radicals by Reductive Cleavage of N-O Bond in Oxime Ether Promoted by SmI2: A Straightforward Synthesis of Five-Membered Cyclic Imines

Article abstract of DOI:10.1021/acs.orglett.9b02740

A new generation method of N-centered radicals from the reductive cleavage of the N-O bond in oxime ether promoted by SmI₂ is reported for the first time. The in-situ-generated N-centered radicals underwent intramolecular cyclization to afford five-membered cyclic imines in two manners: N-centered radical addition and N-centered anion nucleophilic substitution. From a synthetic point of view, an efficient synthetic method of five-membered cyclic imines was developed. A mechanism of the transformation was proposed.

Full text of DOI:10.1021/acs.orglett.9b02740

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iminyl Radicals by Reductive Cleavage of N−O Bond in Oxime Ether
Promoted by SmI2: A Straightforward Synthesis of Five-Membered
Cyclic Imines
Fei Huang and Songlin Zhang*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Dushu
Lake Campus, Soochow University, Suzhou 215123, People’s Republic of China
S
* Supporting Information
ABSTRACT: A new generation method of N-centered radicals from the reductive cleavage of the N−O bond in oxime ether
promoted by SmI2 is reported for the first time. The in-situ-generated N-centered radicals underwent intramolecular cyclization
to afford five-membered cyclic imines in two manners: N-centered radical addition and N-centered anion nucleophilic
substitution. From a synthetic point of view, an efficient synthetic method of five-membered cyclic imines was developed. A
mechanism of the transformation was proposed.
lthough N-centered radicals have been attracting
At the end of the twentieth century, Kagan7 introduced SmI2
Aincreasing attention in the synthetic community for the to the stage of organic synthetic chemistry. Since then, SmI2
has become a “star” molecule, and it has played an important
role in the field of organic synthesis as a single-electron-transfer
reagent.8
construction of the C−N bond, which represents the centrality
in alkaloid synthesis, they have not received adequate attention
from synthetic chemists as compared with carbon radicals. The
N-centered radical-generating methods usually rely on the
addition of more easily accessible parent radicals to
unsaturated nitrogen-containing functional groups, the depro-
tonative oxidation of N−H-containing motifs with oxidants,
and the homolytic cleavage of weak N−X bond-containing
entities.1 Among all of the known strategies, the homolytic
cleavage of a N−O bond in hydroxy amine derivatives enables
an efficient and facile generation of N-centered radicals from
readily available starting materials.2 Therefore, many methods
for the homolytic cleavage of a N−O bond in hydroxy amine
derivatives affording N-centered radicals in the synthetic
community have been reported, such as (a) transition-metal
catalysis,3 (b) microwave heating,4 (c) visible-light promo-
tion,5 and ultraviolet irradiation.6 Whereas much progress in
this scenario has been made during the past decade, there still
remain considerable limitations, such as the need for toxic and
hazardous reagents, the narrow substrate scope, and the harsh
reaction conditions. Therefore, developing a new protocol for
the generation of N-centered radicals from readily available
bulk starting materials is desirable.
Although samarium diiodide is known to promote some N−
O reductive cleavage reactions,8d,9 to our knowledge, the
reductive cleavage of the N−O bond in oxime ethers promoted
by SmI2 has not been reported. With this in mind, we presume
that SmI2 is powerful enough to be used as a single-electron-
transfer reagent for the reductive cleavage of the N−O bond in
oxime ether to afford N-centered radicals. Because N-centered
radicals can be in situ further reduced to N-centered anions,
there will be N-centered radicals and anions available with the
new N-centered radical-generating method. Compared with
the well-documented homolytic cleavage of the N−O bond in
hydroxy amine derivatives mentioned above (N-centered
radicals only), this strategy for N-centered radical gener-
ationreductive cleavage of a N−O bondwill unarguably
meet the high demand for a general protocol for the generation
of N-activated centers from readily available bulk starting
materials that are widely applicable for the construction of
Received: August 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
complex nitrogen heterocycles. We report herein the reductive
cleavage of the N−O bond in oxime ethers with SmI2 to
generate the N-centered radicals, which undergo the intra-
molecular cyclic reaction under mild conditions in one pot,
affording cyclic imine compounds in good yield, which, to our
knowledge, has not been studied so far.
Scheme 2. Reaction of Oxime Ethers with SmI2
We chose the simple substituted methoxy oxime ether 1a,
which was easy to prepare as a starting material to explore this
reaction. We found that a five-membered cyclic imine
compound was perfectly synthesized when γ-bromo oxime
ether was treated with a solution of SmI2 in tetrahydrofuran
(THF) at room temperature (Scheme 1).
Scheme 1. Preparation of the Five-Membered Ring by SmI2-
Mediated Brominated Oxime Ether
In view of such a good result, we first studied the effect of
the dosage of SmI2 and the reaction temperature on the yield
of imine products. The results are shown in Table 1.
a
Table 1. Optimization of the Reaction of 1a with SmI2
c
a
entry
SmI2 (equiv)
T (°C)
2a (%)
To a solution of SmI2 (1.25 mmol) in THF (10 mL) was added
oxime ether (0.5 mmol) in THF (2 mL) under a nitrogen atmosphere
at room temperature, and the mixture was stirred for 1 h. Isolated
yield is based on oxime ether after aluminum oxide column
1
2
3
4
5
6
7
8
2.0
2.1
2.2
2.4
2.5
2.6
2.5
rt
rt
rt
rt
rt
rt
0
60
69
80
83
90
85
81
72
b
chromatography. Bromobenzyloxy oxime ether as substrate.
c
Choloromethoxy oxime ether as substrate.
2, 2a−g). For oxime ethers bearing electron-withdrawing
groups on aryl rings, the products were obtained in good yield
(Scheme 2, 2h). The above results indicated that electron-
donating group on the aryl ring was favored for the reaction
compared with the electron-withdrawing group. The hetero-
cyclic ring and the fused ring also gave the five-membered
cyclic imine in moderate yield (Scheme 2, 2i,j). To broaden
the scope of this reaction, the methoxy group in oxime ether
was replaced with a benzyloxy group, and the imine compound
was unexpectedly synthesized in 92% yield (2a). At last,
chloromethoxy oxime ether as the substrate was tested and
afforded the five-membered cyclic imine in 70% yield (2a).
Encouraged by the successful synthesis of the five-membered
cyclic imines, we next use 5-, 6-,7-, and 11-bromo oxime ethers
as substrates to synthesize the middle as well as the
macrocyclic imine products (Scheme 3). As shown in Scheme
3, 5-bromo oxime ether can afford six-membered cyclic imine
(2k1) in 41% yield. Unfortunately, when 6-,7-, and 11-bromo
oxime ethers were used as substrates, the corresponding
ketones instead of the desired imine products were formed
(2l2−n2).
2.5
10
40
a
To a solution of SmI2 (x mmol) in THF (10 mL) was added
oxime ether (0.5 mmol) in THF (2 mL) under a nitrogen atmosphere
at room temperature, and the mixture was stirred for 1 h. 1a is a Z/E
mixture. Isolated yield based on 1a after aluminum oxide column
b
c
chromatography.
It can be seen from Table 1 that the yield of 2a was gradually
increasing with the increasing loading of SmI2 (Table 1, entries
1−5). To our delight, the yield could be improved to 90%
when the amount of SmI2 was increased to 2.5 equiv (Table 1,
entry 5). Then, we explored the temperature and found that
the reaction at room temperature is more conducive to the
synthesis of 2a. Thus a 2.5 equiv dosage of SmI2 at room
temperature proved to be the optimal reaction conditions. The
reaction time was able to be shortened to 1 h.
With the optimized reaction conditions in hand, the
substrate scope of the reaction of various oxime ethers with
different substituents was subsequently explored, and the
results are summarized in Scheme 2.
As shown in Scheme 2, we found that oxime ethers bearing
an electron-donating substituent gave excellent yields (Scheme
On the basis of the observation of the reaction, we propose a
possible mechanism for this reaction (Scheme 4). First, single
B
DOI: 10.1021/acs.orglett.9b02740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
can reduce the Sm(III) to Sm(II), and this cycle will promote
the reaction affording the desired product through path A.
With the insight into the reaction mechanism of 3a with
SmI2 in Scheme 5, first the loading of Sm and iodine was
examined, and the results are listed in Table 2. From the
Scheme 3. Reaction of Brominated Oxime Ethers with SmI2
a
Table 2. Reaction Condition Screening
Scheme 4. Possible Reaction Mechanism
b
entry
3a/Sm/I2 (equiv)
T (°C)
yield 4a/5a (%)
1
2
3
4
5
6
7
8
1/1.5/0.1
1/1.5/0.2
1/1.5/0.3
1/1.5/0.4
1/1.5/0.5
1/1.5/0.6
1/1.5/1.5
1/1.5/0.5
1/1.5/0.5
1/1.8/0.5
1/2/0.5
rt
rt
rt
rt
rt
rt
rt
40
60
60
60
60
60
14/5
19/8
26/9
37/12
52/18
49/19
0/86
60/19
63/20
62/18
61/16
40/10
33/8
electron transfer from SmI2 to oxime ether causes an
equivalent cleavage of the N−O bond in the oxime ether to
form a N-centered radical. The nitrogen radical changes to a
nitrogen anion after getting an electron from SmI2. Then, an
intramolecular nucleophilic attack occurs, eventually yielding a
five-membered cyclic imine. The nitrogen anion in some cases
could be hydrolyzed to afford the ketone by product 2o.
In view of the easy addition of the N-centered radical to
carbon double bond, we designed the unsaturated oxime ether
3a, which is expected to undergo path A in Scheme 5 to
9
10
11
12
13
1/1.4/0.5
1/1.3/0.5
a
Under a nitrogen atmosphere, Sm (X mmol), 5 mL of THF, 1 (0.5
mmol) in THF (2 mL), and I2 (Y mmol) were added to the flask, and
the mixture was stirred for 4 h. Isolated yield based on 1-phenyl-4-
en-1-one O-methyl oxime after aluminum oxide column chromatog-
b
raphy.
Scheme 5. Regulation and Control of the Reaction Pathway
by the Concentration of SmI2
results, we can see that the reaction was dramatically
influenced by the dosage of I2 (Table 2, entries 1−7). When
the amount of I2 in the system was gradually increased to 0.5
equiv, the yield of 4a was increased to 52% (Table 2, entry 5).
More than 0.5 equiv of I2 results in lowering the yield of 4a
and increasing the yield of 5a (Table 2, entries 6 and 7). Next,
the effect of temperature on the reaction was investigated. To
our delight, when the temperature reached 60 °C, the yield of
4a increased to 63% (Table 2, entries 8 and 9). Finally, we
tried to increase and reduce the amount of Sm, but it could be
seen that increasing the amount of Sm did not lead to a higher
yield of imine (Table 2, entries 10 and 11), and reducing the
amount of Sm lead to a decrease in the yield of imine (Table 2,
entries 12 and 13). Thus a 1/1.5/0.5 molar ratio of
unsaturated oxime ether/Sm/I2 at 60 °C proved to be the
optimal reaction conditions. The reaction time was able to be
shortened to 4 h.
The scope of the above process was further investigated by
extending the substrate to other γ,δ-unsaturated oxime ethers.
As summarized in Scheme 6, an array of γ,δ-unsaturated oxime
ethers was suitable for this imine formation process. We found
that oxime ethers bearing electron-donating substituents gave
high yields, such as the methoxy group (4b), t-butyl group
(4c), phenyl group (4d), and methyl group (4e). For oxime
ethers bearing electron-withdrawing groups on the aryl ring,
such as 2-fluoro-(4g), 4-bromo-(4h), and 4-chloro-(4i) oxime
ether, the products were obtained in moderate yield. The
above results indicated that electron-donating groups on the
aryl ring were favored for the reaction compared with electron-
withdrawing groups. Aliphatic, heterocycle, and fused-ring
synthesize 4a. However, in the course of the experiment, we
found that the unsaturated oxime ether was subjected to path
B in Scheme 5 to produce 5a mediated by SmI2. With rational
analysis of the two paths A and B, we can draw a conclusion
that with a high concentration of SmI2, the nitrogen radical
generated could easily get one electron from SmI2 and rapidly
convert to a nitrogen anion, causing the reaction through path
B. If SmI2 is controlled at a lower concentration (by reducing
the dosage of I2 during the formation of SmI2), then the rate of
conversion of nitrogen radical to nitrogen anion will be slower,
which will facilitate the reaction through path A to afford the
cyclic imine product. If there is enough Sm(0) in the system, it
C
DOI: 10.1021/acs.orglett.9b02740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Scope of γ,δ-Unsaturated Oxime Ether
Substrates
Scheme 7. Reaction of Unsaturated Oxime Ether with SmI2
a b
,
In summary, a new generation method of N-centered
radicals from the reductive cleavage of N−O band in the
brominated and unsaturated oxime ether promoted by SmI2
was achieved for the first time. The in-situ-generated N-
centered radicals underwent intramolecular cyclization to
afford cyclic imine compounds. It is a new way to generate
N-centered radicals compared with the homolytic cleavage of a
N−O bond that represents the centrality in generating N-
centered radicals and a general, efficient, and experimentally
simple one-pot method for the preparation of five-membered
cyclic imines. Further investigation of the application of this
new generation method of N-centered radicals demonstrated
in this Letter is in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02740.
Detailed experimental procedures, characterization data,
and copies of nuclear magnetic resonance spectra of all
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhangsl@suda.edu.cn.
ORCID
Songlin Zhang: 0000-0003-4696-633X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge A Project Funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions and the National Natural Science Foundation of
China (No. 21072143) for financial support.
a
Under a nitrogen atmosphere, Sm (0.75 mmol), 5 mL of THF, γ,δ-
unsaturated oxime ether (0.5 mmol) in THF (2 mL), and I2 (0.25
mmol) were added to the flask, and the mixture was stirred at 60 °C
b
for 4 h. Isolated yield based on γ,δ-unsaturated oxime ether.
c
Substrate is 1-phenylpent-4-en-1-one O-benzyl oxime.
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