Copper-catalyzed iminohalogenation of γ, δ-unsaturated oxime esters with halide salts: Synthesis of 2-halomethyl pyrrolines

Article abstract of DOI:10.1016/j.tetlet.2019.151000

A copper-catalyzed iminohalogenation of unactivated alkenes of γ, δ-unsaturated oxime esters is achieved by using readily available halide salts. Utilizing this protocol, a sequence of structurally diversiform 2-halomethyl pyrrolines are efficiently synthesized and a mechanism involving iminyl radical intermediates, which were initiated by Cu(I) species, was proposed.

Full text of DOI:10.1016/j.tetlet.2019.151000

Journal Pre-Proof
Copper-Catalyzed Iminohalogenation of γ, δ-Unsaturated Oxime Esters with
Halide Salts: Synthesis of 2-Halomethyl Pyrrolines
Chen Chen, Jie Ding, Yuebo Wang, Xiaonan Shi, Dequan Jiao, Bolin Zhu
PII:
S0040-4039(19)30757-9
DOI:
https://doi.org/10.1016/j.tetlet.2019.151000
TETL 151000
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 April 2019
21 June 2019
31 July 2019
Please cite this article as: Chen, C., Ding, J., Wang, Y., Shi, X., Jiao, D., Zhu, B., Copper-Catalyzed
Iminohalogenation of γ, δ-Unsaturated Oxime Esters with Halide Salts: Synthesis of 2-Halomethyl Pyrrolines,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151000
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JOURNAL PRE-PROOF
Tetrahedron Letters
Copper-Catalyzed Iminohalogenation of γ, δ-Unsaturated Oxime Esters with Halide
Salts: Synthesis of 2-Halomethyl Pyrrolines
Chen Chen*, Jie Ding, Yuebo Wang, Xiaonan Shi, Dequan Jiao* and Bolin Zhu*
Tianjin Key Laboratory of Structure and Performance for Functional Molecules, MOE Key Laboratory of Inorganic-Organic Hybrid Functional Material
Chemistry, College of Chemistry, Tianjin Normal University, Tianjin 300387, P. R. China. Email: hxxycc@tjnu.edu.cn, hxxyjdq@tjnu.edu.cn,
hxxyzbl@tjnu.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A copper-catalyzed iminohalogenation of unactivated alkenes of γ, δ-unsaturated oxime esters is
achieved by using readily available halide salts. Utilizing this protocol, a sequence of
structurally diversiform 2-halomethyl pyrrolines are efficiently synthesized and a mechanism
involving iminyl radical intermediates, which were initiated by Cu(I) species, was proposed.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
γ, δ-Unsaturated Oxime Esters
Iminohalogenation
Copper-Catalyzed
Pyrrolines
Organic halides are essential functional groups present in a
variety of pharmaceuticals,1 agrochemicals,2 natural products,3
and materials,4 which can easily undergo transformations to a
variety of useful functional groups.5 Furthermore, they can be
used as starting materials in transition metal catalysis due to their
facile oxidative addition to low valent metal centers.6 Traditional
routes to synthesize organic halides have commonly involved
many drawbacks, such as multiple steps, harsh reaction
conditions, and the use of toxic reagents. Therefore, the
development of efficient approaches for the formation of carbon-
halide bonds has been the topic of extensive investigation.5-9 For
Scheme 1. Transition-Metal-Catalyzed Imino-Functionalization
of γ, δ-Unsaturated Oxime Esters
The development of efficient methodologies to synthesize 2-
halomethyl pyrrolines has become a subject of great interest
during the past few years.21, 24 In 2015, Tong21 and co-workers
reported a palladium-catalyzed iminohalogenation of alkenes
with the assistance of halide salts to provide facile access to
synthetically useful 2-halomethyl pyrrolines via C-PdII-X (X = I,
Br, Cl) reductive elimination. Electron-poor phosphine ligand
was proved to be essential for promoting this process (Scheme
2a). In 2017, Leonori24 and co-workers reported a visible-light-
mediated radical cascade process for the construction of 2-
halomethyl pyrrolines by employing NCS, diethyl-bromo-
malonate and NIS as halide source, respectively. However, only
three examples were shown in moderate yields (Scheme 2b).
Despite a variety of approaches are available, seeking for cheap
and readily available reagents/catalysts as well as mild reaction
conditions for the synthesis of this type of significant molecules
still remains challenge. Inspired by previous works and as our
continued interest in the synthesis of halogen-containing
heterocycles,25 we anticipate to realize a copper-catalyzed
iminohalogenation of γ, δ-unsaturated oxime esters with halide
8
examples, Lautens5, and Tong9 provided a new concept to
construct carbon-halide bonds by highly endothermic C-PdII-X
(X = halide) reductive elimination. Cook10 and others11 developed
palladium-catalyzed atom transfer radical cyclization reactions
for the formation of carbon-halide bonds.
Pyrrolines and their derivatives are valuable structural motifs
in a large number of bioactive molecules,12 which can be facilely
obtained through transition-metal-catalyzed cyclization of γ, δ-
unsaturated oxime esters.13-24 In recent years, Narasaka,13
Bower,14 Zhu,15 Zhu,16 Selander,17 Ohe,18 Yu,19 Wang,20 Tong,21
Liang22 and our group23 realized transition-metal-catalyzed
imino-functionalization of γ, δ-unsaturated oxime esters to
synthesize various functionalized pyrrolines (Scheme 1).

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2
salts to synthesize 2-halomethyl pyrrolines (Scheme 2c). To the
best of our knowledge, such reactions have not been explored.
entry
1
1
catalyst
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
1,4-Dioxane
PrCN
yieldb(%)
42%
45%
75%
71%
73%
76%
32%
53%
74%
65%
69%
72%
53%
81%
46%
44%
70%
42%
1a-1
1a-2
1a-3
1a-4
1a-5
1a
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu2O
2
3
4
5
6
7
1a
Scheme 2. Methods of Synthesis of 2-Halomethyl Pyrrolines
8
1a
9
1a
For this purpose, we commenced our studies by investigating
copper-catalyzed iminoiodination of γ, δ-unsaturated oxime
esters for the construction of 2-iodomethyl pyrrolines. To our
delight, O-acyl oxime 1a-1 was treated with 20 mol%
Cu(OAc)2·H2O in MeCN at 90 °C under N2 atmosphere for 2.5 h
afforded the desired iminoiodination product 2a in 42% yield
(Table 1, entry 1). In order to examine the effect of the leaving
group, other derivatives were investigated. The use of O-pivaloyl
oxime 1a-2 led to a similar yield (Table 1, entry 2). When O-
pentafluorobenzoyl oxime 1a-3 was used, the yield of 2a
increased to 75%, implying that the aryl substituent might favor
this radical cyclization reaction (Table 1, entry 3). Thus, several
O-aroyl oximes with different substituent groups on the aromatic
moiety were examined (Table 1, entries 4-6). The O-benzoyl
oxime 1a giving compound 2a in 76% yield and could be
prepared from readily available starting materials. Hence, from
the viewpoint of cost and atom economy, 1a was used for further
optimization studies. Investigation of the solvents revealed that
MeCN was superior compared to toluene, 1, 4-dioxane and
butyronitrile (Table 1, entries 7-9). Amongst the various
transition metal catalysts tested, including Cu2O, CuI, Cu(OTf)2,
FeCl2, Cu(OAc)2 was found to be the most effective, giving
product 2a in 81% yield (Table 1, entries 10-14). However,
decreasing the catalytic loading of Cu(OAc)2 to 10 mol%,
resulted in only 46% yield of 2a, with remainder being unreacted
starting materials (Table 1, entry 15). A similar effect was
10
11
12
13
14
15c
16d
17e
18f
1a
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1a
CuI
1a
Cu(OTf)2
1a
FeCl2
1a
Cu(OAc)2
1a
Cu(OAc)2
1a
Cu(OAc)2
1a
Cu(OAc)2
1a
Cu(OAc)2
a All reactions were performed with 1 (0.2 mmol), catalyst (20 mol%), KI (0.4
o
b
mmol) in solvent (2.0 mL) at 90 C under a nitrogen atmosphere for 2.5 h.
isolated yield. c 10 mol% Cu(OAc)2 was used. d the reaction temperature was
60 oC. e NaI as iodine source. f nBu4NI as iodine source.
With the optimal conditions in hand, we then examined the
scope of γ, δ-unsaturated oxime esters. As shown in Table 2. For
the aryl-substituted oxime esters with different electronic
properties at the ortho, meta, and para position performed well in
the reaction, which included methyl, methoxyl, chloro, fluoro,
affording the desired iminoiodination products 2a-2h in 58%-
91% yields. Naphthalenyl-substituted oxime ester 1i showed a
positive result, providing 2i in 78% yield. Notably, this
transformation displayed good tolerance towards heterocycle,
thiophene-substituted oxime ester 1j reacted smoothly to give the
corresponding product 2j in 63% yield. The substituent at the
alkene part (R4) was also varied using butyl, cyclohexyl, even
bulky groups, producing the corresponding products in good to
excellent yields (2k-2o). In the case of 1p bearing a single-
substituted alkene afforded 2p in 66% yield. When 1q, with
cyclohexyl at α position, was used as the substrate, 2q was
obtained in 95% yield. γ, δ-Unsaturated oxime ester without a
gem-dimethyl group was also examined, prolonged the reaction
time to 5 h, the desired product 2r was obtained in 55% yield
when Cu2O as the catalyst. It should be noted that significant
quantities of the corresponding ketone was isolated. This was
o
observed when the reaction temperature was decreased to 60 C
(Table 1, entry 16). Different iodide sources were further tested,
n
such as NaI and Bu4NI, but they did not give better results than
KI (Table 1, entries 17-18). Hence the optimal reaction
conditions are as follows: 1a (1.0 equiv), Cu(OAc)2 (20 mol%),
KI (2.0 equiv), MeCN (2.0 mL) under N2 atmosphere at 90 °C for
2.5 h.
Table 1. Optimization of the Reaction Conditionsa

JOURNAL PRE-PROOF
probably due to the lack of Thorpe-Ingold effect,26 which aids
absence of Cu(OAc)2, 2a was not detected, demonstrating that
the copper salt plays an important role in N-O bond cleavage to
form an iminyl radical (Scheme 3a). Heating the MeCN solution
of Cu(OAc)2 in the presence of 2, 2’-biquinoline at 90 oC for 1 h,
gem-dimethyl substrates, thus favoring radical cyclization. We
were also pleased to find that 1s could be transformed into the
imidazoline derivative 2s, albeit in lower yield. Unfortunately,
the thiazoline derivative 2t was not obtained under our standard
conditions.
a
deep purple solution was observed, which suggested
Cu(I)/biquinoline complex formation. This result indicates that
this reaction is initiated by Cu(I) species14b, 15 (Scheme 3b). To
further confirm the presence of the iminyl radical, a control
experiment was conducted in the presence of 2, 2, 6, 6-
tetramethyl-1-piperidinyloxy (TEMPO) under optimal conditions.
Only trace amounts of 2a was detected, and the radical trapping
product 5 was obtained in 62% yield. This result clearly
demonstrated the reactions are inhibited by TEMPO and iminyl
radical might be involved in the iminoiodination process
(Scheme 3c).
Table 2. The Reaction Scope of the Iminoiodinationa
Scheme 3. Control Experiments
Base on the literature reports14a, 14b, 15, 17-19 and above results, a
plausible mechanism is proposed in Scheme 4, Initially, Cu(I)
species was formed in situ via disproportionation or reduction of
Cu(OAc)2. Subsequently, CuX was formed via the metathesis
between Cu(I) species and KX, which reductively cleaves the
N−O bond of the oxime ester 1a to form iminyl radical. It then
undergoes an intramolecular 5-exo-trig radical cyclization to
form C-centered radical intermediate B. Subsequently, B is
trapped by Cu(II)X(OBz) to produce Cu(III) intermediate C,
followed by reductive elimination to furnish the
iminohalogenation products 2a-4a and Cu(I) species (Path I).
However, alternative Path II cannot be excluded. C-centered
a All reactions were performed with 1 (0.2 mmol), Cu(OAc)2 (0.04 mmol), KI
(0.4 mmol) in MeCN (2.0 mL) at 90 oC under a nitrogen atmosphere for 2.5 h.
b Cu2O was used instead of Cu(OAc)2, 5 h.
Since we have established the iminoiodination of γ, δ-
unsaturated
oxime
esters,
we
further
investigated
iminobromination and iminochlorination. When KBr and KCl
were used as the halide source, desired bromo-substituted
pyrroline 3a and chloro-substituted pyrroline 4a were obtained in
65% and 46% yields, respectively. As shown in Table 3, the
corresponding products with various substituents were obtained
in 52%-80% yields.
radical intermediate
B can be oxidized to carbocation
intermediate D by Cu(II) species, which can react with halide
ions to afford the 2-halomethyl pyrrolines 2a-4a.
Table 3. The Reaction Scope of Iminobromination and
Iminochlorination[a]
[a]
All reactions were performed with 1 (0.2 mmol), Cu(OAc)2 (0.04 mmol),
KX (0.4 mmol) in MeCN (2.0 mL) at 120 oC under a nitrogen atmosphere for
2.5 h.
To gain insights into the mechanism of this iminohalogenation
process, several control experiments were conducted. In the

JOURNAL PRE-PROOF
4
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iminohalogenation of unactivated alkene of γ, δ-unsaturated
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and functional groups were tolerated, giving the desired 2-
halomethyl pyrrolines in moderate to good yields. A mechanism
involving iminyl radical intermediates, which was initiated by
Cu(I) species, was proposed. We have exploited subsequent
carbon-iodine bond transformations through nucleophilic attack
and click reaction, which demonstrated the synthetic potential of
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Acknowledgments
We gratefully acknowledge the Science&Technology
Development Fund of Tianjin Education Commission for Higher
Education (2018KJ159), Doctoral Program Foundation of Tianjin
Normal University (043135202-XB1703), National Natural
Science Foundation of China (21572160), the Foundation of
Development Program of Future Expert in Tianjin Normal
University (WLQR201811) and the Program for Innovative
Research Team in University of Tianjin (TD13-5074) for
generous financial support.
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JOURNAL PRE-PROOF

First copper-catalyzed iminohalogenation of γ, δ-
unsaturated oxime esters with KX (X = I, Br, Cl)
Readily available catalyst and halide source
New method for the efficient synthesis of diversiform
2-halomethyl pyrrolines



Good functional group compatibility, moderate to
excellent yields, simple operations.

JOURNAL PRE-PROOF
6
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Copper-Catalyzed Iminohalogenation of γ, δ-
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Chen Chen*, Jie Ding, Yuebo Wang, Xiaonan Shi, Dequan Jiao* and Bolin Zhu*