Intramolecular Cyclization of Brominated Oxime Ether Promoted with Ytterbium(0) to the Synthesis of Cyclic Imines

Article abstract of DOI:10.1002/ejoc.202000678

The first utility of ytterbium(0) as a mediating-metal in the intramolecular cyclization of brominated oxime ether was reported in this paper. In contrast to the prior methods, the N–O bond was used as a receptor of nucleophilic reagent, rather than as a source of N-centered radicals. Cyclic imines were obtained in this one-pot reaction with a broad scope of substrates and feasible reaction conditions.

Full text of DOI:10.1002/ejoc.202000678

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Intramolecular Cyclization of Brominated Oxime Ether Promoted
with Ytterbium(0) to the Synthesis of Cyclic Imines
Authors: Yiqiong Wang, Fei Huang, and Songlin Zhang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000678
Link to VoR: https://doi.org/10.1002/ejoc.202000678
01/2020

10.1002/ejoc.202000678
European Journal of Organic Chemistry
COMMUNICATION
Intramolecular Cyclization of Brominated Oxime Ether Promoted
with Ytterbium(0) to the Synthesis of Cyclic Imines
Yiqiong Wang,[a] Fei Huang[a] and Songlin Zhang *[a]
[a]
Y. Wang, F.Huang, Prof. Dr. S. Zhang
Key Laboratory of Organic Synthesis of Jiangsu Province,Institution of Chemical Engineering and Materials Science, College of Chemistry, Chemical
Engineering and Materials Science, Dushu Lake Campus, Soochow University,Suzhou, 215123, People’s Republic of China.
E-mail: zhangsl@suda.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: The first utility of ytterbium(0) as a mediating-metal in the
intramolecular cyclization of brominated oxime ether was reported in
this paper. In contrast to the prior methods, the N-O bond sued as a
receptor of nucleophilic reagent not as a source of N-centered
radical which represented the centrality in cyclic imine synthesis, and
cyclic imines were obtained in this one-pot reaction with abroad
scope of substrates and feasible reaction conditions.
synthetic community have been reported (N-O bond as a source
of N-active center): For example (1) transition-metal catalysis7;
(2) microwave heating8; (3) visible light promotion or UV
irradiation.9
Fig. 2
Strategy for the synthesis of imines
Cyclic imines are some of the most important heterocycles
which are ubiquitous scaffolds in functional materials, countless
natural products, and drugs.1, 2 As shown in Figure 1, MLN8237
is an Aurora-A kinases inhibitor that treats epithelial ovarian
cancer, fallopian tube cancer, and primary peritoneal cancer.
The small molecule (+)-JQ1 was developed by Dr. Saptarsi
Haldar and is an effective drug for the treatment of heart failure.
Myosmine is a natural tobacco alkaloid. E7016 is a type of
PARP inhibitor that treats a variety of cancers by targeting DNA
damage repair mechanisms. In addition, they are also important
precursors for the preparation of azole compounds.3
More recently, we developed a new generation method of N-
centered radicals from the reductive cleavage of N-O bond in γ-
bromo oxime ethers promoted with SmI2 (Scheme 1).10 The in
situ generated N-centered radical was reduced to N-centered
anion which underwent intramolecular nucleophilic addition to
afford 5-membered cyclic imines. Because the nitrogen anion
was easily hydrolized to afford the ketone by-product, this
methodology failed for the synthesis of other membered cyclic
imine compounds except for 5-membered ones. We presume if
SmI2 was replaced with an appropriate reductant, the C-Br bond
could be reduced to afford carbon anion which makes
intramolecular nucleophilic attack to the N-O bond yielding cyclic
imine without the by-product ketone.
Fig. 1 Imine structure in natural and drug molecules.
Scheme 1 Reaction pathway of imine cyclizing of γ-bromo oxime ether
promoted with SmI2
So, various synthetic methods have been developed for the
preparation of cyclic imines in the past few decades. Compared
with the earlier reported synthesis methods, for example, 4-
chlorobutyronitrile reacts with Grignard reagent;4 γ-Azido
ketones as substrates to synthesize cyclic imines by an
intramolecular 'aza-Wittig' reaction5 and palladium-catalyzed
aminoolefins and aminoalkynes.6 The intramolecular addition of
N-centered radical to carbon double bond represents the
centrality in cyclic imine synthesis (Fig. 2). As a consequence,
Various methods for the homolytic cleavage of a N-O bond in
hydroxy amine derivatives affording N-centered radicals in the
The rapid development of ytterbium(0) in organic synthesis
has been recently achieved due to its role as a reducing agent11
and its reactivity towards various electrophilic organic
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000678
European Journal of Organic Chemistry
COMMUNICATION
compounds.12 Especially the reaction of an ytterbium reagent
with electrophiles13 makes ytterbium(0) come into our view in the
finding of appropriate reductant to replace SmI2 in the imine
cyclizing of γ-bromo oxime ether. We report herein ytterbium
reacted with brominated oxime ether to generate ytterbium
reagent, which undergoing the intramolecular cyclic reaction with
the N-O bond as a receptor of nucleophilic reagent under mild
condition in one-pot afforded cyclic imine compounds in good
yields, which has not been studied so far.
We chose simple ɤ-brominated methoxy oxime ether 1a 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 ytterbium in THF at
60°C (Scheme 2)
Next, we studied the effect of the dosage of Yb and reaction
temperature on the yield of imine products. The results were
shown in Table 2.
Table 2
Reaction condition screeninga
Entry
1a/Yb
T (oC)
rt
Time (h)
2a (%)b
18
1
2
12
12
12
12
12
12
12
12
8
1：1
1:1.1
1:1.2
1:1.3
1:1.4
1:1.5
1:1.6
1:1.7
1:1.5
1:1.5
rt
21
3
rt
25
4
rt
35
Scheme
2
Preparation of five-membered ring by Yb mediated
5
rt
40
brominated oxime ether
6
rt
54
7
rt
49
8
rt
48
9
40
60
60
10
4
70
a To a solution of Yb (X mmol) in THF (5mL) was added oxime ether (0.5mmol)
b
in THF (2mL) under a nitrogen atmosphere then the mixture was stirred.
RESULTS AND DISCUSSSION
Isolated yield based on 1a after aluminium oxide column chromatography.
In view of the good result, we firstly conducted preliminary
experiments using ɤ-brominated oxime ether as substrate to
screen several metals.
It can be seen from Table 2 that the yield of 2a was gradually
changing higher with the increasing loading of Yb (Table 2,
entries 1-5). To our delight, the yield could be improved to 54%
when the amount of Yb was increased to 1.5 equivalents (Table
1, entry 6). More usage of Yb resulted in a little lower yield of 2a
(Table 2, entries 7, 8). Then we explored the temperature and
found that the reaction at 60°C was more conducive to the
synthesis of 2a (Table 1, entry 10). Thus, 1.5 equivalent dosage
of Yb and 60°C proved to be the optimal reaction conditions.
With the optimized reaction conditions established, the
substrate scope of the reaction was subsequently explored and
the results were summarized in Table 3. In general, the
introduction of various electron-donating or electron-withdrawing
groups on aryl rings all proceeded smoothly affording the
corresponding products in moderate to excellent yields (Table 3).
Good yields were obtained with γ-bromo oxime ethers bearing
electron-donating groups on the aryl ring, such as methyl group
(2b), methoxy group (2c), ethyl group (2d), t-butyl group (2e).
With γ-bromo oxime ether bearing electron-withdrawing group
on the aryl ring, such as fluorine atom (2f), the product could
also be synthesized in good yield. The disubstituted aryl γ-
bromo oxime ether also showed good reactivity, providing
products 2g and 2h in good yield. The heterocyclic ring and the
fused ring gave the five-membered cyclic imine in moderate
yields (2i, 2j). To broaden the scope of this reaction, the
methoxy group in oxime ether was replaced with a benzyloxy
group, and the imine compound was synthesized in a yield of
58% (2ab). At last, ɤ-chloromethoxy oxime ether as substrate
was test and afforded the five-membered cyclic imine in 60%
yield (2ac).
Representative results were shown in Table 1. In the
experiments, a lower yield of the desired product 2a was
obtained when Sm was used (Table 1, entry 2). The other rare
earth metals such as Pr, Nd and Dy could not induce the
reaction at all (Table 1, entries 3-5). Only trace amount of the
product 2a was gained when transition metals Mg and Zn were
used (Table 1, entries 6, 7). It was clear that ytterbium was the
best choice for the reaction.
Table 1 Screening of metalsa
Yield（%）b
Entry
M
1
2
3
4
5
6
7
Yb
Sm
Pr
55
42
NR
Nd
Dy
Mg
Zn
NR
NR
Trace
Trace
a
To a solution of M (0.75mmol) in THF (5mL) was added oxime ether
(0.5mmol) in THF (2 mL) under a nitrogen atmosphere then the mixture was
stirred for 12h at rt. b Isolated yield based on 1a after aluminium oxide column
chromatography.
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000678
European Journal of Organic Chemistry
COMMUNICATION
Table 3 Scope of ɤ-brominated oxime ether substrates a
2s, 0%
a
To a solution of Yb (0.75mmol) in THF (5mL) was added oxime ether
(0.5mmol) in THF (2mL) under a nitrogen atmosphere, the mixture was stirred
for 4h at 600C; Isolated yield based on oxime ether after aluminium oxide
column chromatography. bCholoromethoxy oxime ether as substrate.
2b, 77%
2a, 70%
2c, 78%
2f, 96%b
To determine the reaction mechanism of brominated oxime
ethers, γ, δ-unsaturated oxime ether as substrate was used
under the standard reaction conditions. The experimental result
shows that ytterbium could not promote the reaction (Scheme 3).
The result illustrates the fact that the N-O bond not as a source
of N-centered radical in the reaction.
2d, 90%b
2e, 95%b
2i, 38%
2h, 68%
2g, 82%
2j, 41%
Scheme 3 γ, δ-Unsaturated oxime ether with Yb
2ac, 60%
2a b, 58%
Based on the observation to the reaction, we propose a
possible mechanism for this reaction (Scheme 4). Firstly, the
cleavage of the C–Br bond could be achieved through two single
electron transfer (SET) process, in which Yb would donate two
electrons to afford ytterbium reagent. Then an intramolecular
nucleophilic attack occurs with N-O bond as a receptor of
ytterbium reagent yielding cyclic imine. The process maybe
promoted by the coordination of Yb(II) with N-O bond. The
ytterbium reagent in some cases makes H-abstraction to afford
the by-product 4.
a
To a solution of Yb (0.75mmol) in THF (5mL) was added oxime ether
(0.5mmol) in THF (2mL) under a nitrogen atmosphere, the mixture was stirred
for 4h at 60 0C; Isolated yield based on oxime ether after aluminium oxide
column chromatography. bBromobenzyloxy oxime ether as substrate.
c
Choloromethoxy oxime ether as substrate.
Encouraged by successful synthesis of the five-membered
cyclic imines, we next use 5-, 6-, 7- and 11-bromo oxime ethers
as sbustrates to synthesize the middle as well as macrocyclic
imine products (Table 4). As shown in Table 4, under the
reaction conditions, Yb promoted 5-bromo oxime ethers to
synthesize six-membered cyclic imine (2k) in a yield of 56%.
The target compounds could be synthesized in good yield
regardless of whether electron-donating groups (2l, 2m) or
electron-donating groups (2n) were attached to the aryl rings.
Heterocyclic compound (2o) exhibit good substrate suitability
and 5-chloro oxime ether could still synthesize 2k in 49% yield.
Unfortunately, fused substrate, and substrates 6-, 7- and 11-
bromo oxime ethers did not give the desired imine products (2p,
2q, 2r. 2s).
Scheme 4 Possible reaction mechanism
Table 4 Reaction of brominated oxime ethers with Yb a
In summary, we have documented a new strategy for the
synthesis of cyclic imines through intramolecular cyclization of
brominated oxime ether promoted with ytterbium(0) for the first
time. As a complement to the prior methods, the N-O bond used
as a receptor of nucleophilic reagent not as a source of N-
centered radical and the reaction was conveniently carried out
under mild conditions in a one-pot fashion. This strategy
provides a broad scope and moderate to good yields of cyclic
imines in a relatively short reaction time.
2l, 69%
2o, 50%
2m, 64%
2p, NR
2k, 56%
2n, 70%
2k b, 49%
2q, 0%
2r, 0%
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000678
European Journal of Organic Chemistry
COMMUNICATION
jiwara, Chem. Lett. 1995, 851-852. (d) Y. Makioka, S. Uebori, M. Tsuno,
Y. Taniguchi, K. Takaki, Y. Fujiwara, J. Org. Chem. 1996, 61, 372-375.
[13] (a) T. Fukagawa, Y. Fujiwara, H. Taniguchi, Chem. Lett. 1982, 11, 601-
602. (b) K. Yokoo, T. Fukagawa, Y. Yamanaka, H. Taniguchi, Y.
Fujiwara, J. Org. Chem. 1984, 49, 3237-3239. (c) Z. Hou, N. Mine, Y.
Fujiwara, H. Taniguchi, J. Chem. Soc. Chem. Commun. 1985, 1700-
1702. (d) X.-X. Zhang, S.-L Zheng, S.-L Zhang, RSC Adv. 2017, 7,
54254-54257. (e) X.-J. Liu, X. Li, E. Louyriac, L. Maron, X.-B. Leng, Y.-
F. Chen, J. Am. Chem. Soc. 2019, 141, 138−142.
Acknowledgements
We gratefully acknowledge A Project Funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions, The Project of Scientific and Technologic
Infrastructure of Suzhou (No. SZS201207) and the National
Natural Science Foundation of China (No. 21072143) for
financial support.
Keywords: ytterbium(0) • cyclic imines • intramolecular
cyclization • one-pot reaction • brominated oxime ether
[1]
(a) J. B. Hudson, H. Saboune, Z. Abramowshi, G. H. N. Towers, K. L. jr.
Rinehart, Phofochem. Phofobiol. 1988, 47, 377-381. (b) K. L. Jr.
Rinehart, J. Kobayashi, G. C. Harbour, J. Gilmore, M. Mascal, T. G.
Holt, L. S. Shield, F. Lafargue, J. Am. Chem. Soc. 1987, 109, 3378-
3387. (c) K. L. Jr. Rinehart, J. Kobayashi, G. C. Harbour, R. G. Jr.
Hughes, S. A. Mizsak, T. A. Scahill, C, E, K, L. Eudistomins, J. Am.
Chem. Soc. 1984, 106, 1524-1526. (d) X. T. Zhang, R. N. Wang, L.
Zhang, Y. B. Ruan, W. W. Wang, H. W. Ji, F. C. Lin, J. Liu, Rap. Com.
Mass Spe. 2018, 32, 1791-1798.
[2]
(a) Q. M. Duan, S. McMahon, P. Anand, H. Shah, S. Thomas, H. T.
Salunga, Y. Huang, R. L. Zhang, A. M. Sahadevan, E. Lemieux, J. D.
Brown, D. Srivastava, J. E. Bradner, T. A. McKinsey, S. M. Haldar, Sci.
Transl. Med. 2017, 9, 5084-5098. (b) F. chwizer, . K hler, M.
rrenberger, L. Kn rr, T. . Ward, ACS Catal. 2013, 3, 1752-1755. (c)
V. M. Robles, M. rrenberger, T. Heinisch, . Lled s, T. chirmer, T.
.Ward, J. . Mar chal, J. Am. Chem. Soc. 2014, 136, 15676-15683.
(a) S. Hussain, F. Leipold, H. Man, E. Wells, S. P. France, K. R.
Mulholland, G. Grogan, N. J. Turner, ChemCatChem. 2015, 7, 579-583.
(b) B. Chin, S. L. Buchwald, J. Org. Chem. 1996, 61, 5650-5651. (c) A.
A. Godwin, M. Henry, F. P. Scott, L. Friedemann, H. Shahed, T.-G.
Laura, M. Rebecca, H. Sam, T. P. Johan, G. Gideon, T. J. Nicholas,
ACS Catal. 2016, 6, 3880−3889.
[3]
[4]
[5]
L. C. Craig, H. Bulbrook, R. M. Hixon, J. Am. Chem. Soc. 1931, 53,
1831-1835.
(a) B. Jose, P. Francisco, Org. Prep. Proced. Int. 1991, 23, 1-65. (c) P.
N. D. Singh, R. F. Klima, S. Muthukrishnan, R. S. Murthy, J.
Sankaranarayanan, H. M. Stahlecker, B. Patel, A. D. Gudmundsdo´ttir,
Tetrahedron Lett. 2005, 46, 4213–4217.
[6]
[7]
(a) B. Pugin, L. M. Venanzi, J. Am. Chem. Soc. 1983, 105, 6877-6881.
(b) Y. Fukuda, S. Matsubara, K. Utimoto, J. Org. Chem. 1991, 56,
5812-5816.
(a) Y. Koganemaru, M. Kitamura, K. Narasaka, Chem. Lett. 2002, 31,
784-785. (b) H. Chen, S. Chiba, Org. Biomol. Chem. 2014, 12, 42-46.
(c) A. Faulkner, N. J. Race, J. S. Scott, J. F. Bower, Chem. Sci. 2014, 5,
2416-2421. (d) M. Bingham, C. Moutrille, S. Z. Zard, Heterocycles.
2014, 88, 953-960. (e) H.-B. Yang, N. Selander, Chem.-Eur. J. 2017, 23,
1779-1783. (f) J. Boivin, A.-M. Schiano, S. Z. Zard, H. W. Zhang,
Tetrahedron Lett. 1999, 40, 4531-4534. (g) N. J. Race, A. Faulkner, M.
H. Shaw, J. F. Bower, Chem. Sci. 2016, 7, 1508-1513. (h) H. W. Huang,
J. H. Cai, G.-J. Deng, Org. Biomol. Chem. 2016, 14, 1519-1530.
(a) P.-C. Fernando, S. S. Jackie, W. C. John, J. Org. Chem. 2008, 73,
5558–5565. (b) P.-C. Fernando, S. M. Eoin, S. S. Jackie, W. C. John,
Chem. Commun. 2008, 4189-4191.
[8]
[9]
(a) W. C. John, Acc. Chem. Res. 2014, 47, 1406-1416. (b) S.-H. Cai, J.-
H. Xie, S.-J. Song, L. Ye, C. Feng, T.-P. Loh, ACS Catal. 2016, 6,
5571−5574. (c) J. Davies, N. S. Sheikh, D. Leonori, Angew. Chem. Int.
Ed. 2017, 56, 13361-13365.
[10] F. Huang, S.-L Zhang, Org. Lett. 2019, 21, 7430-7434.
[11] (a) Z. Hou, K. Takamine, O. Aoki, H. Shiraishi, Y. Fujiwara, H.
Taniguchi, J. Org. Chem. 1988, 53, 6077-6084. (b) K. Takaki, Y.
Tsubaki, S. Tanaka, F. Beppu, Y. Fujiwara, Chem. Lett. 1990, 203-204.
[12] (a) K. Takaki, S. Tanaka, Y. Fujiwara, Chem. Lett. 1991, 493-494. (b) Z.
Hou, H. Yamazaki, Y. Fujiwara, H. Taniguchi, Organomentallics. 1992,
11, 2711-2714. (c) Y. Makioka, M. Tsuno, K. Takaki, Y. Taniguchi, Y.
4
This article is protected by copyright. All rights reserved.