Epoxide-Mediated Stevens Rearrangements of α-Amino-Acid-Derived Tertiary Allylic, Propargylic, and Benzylic Amines: Convenient Access to Polysubstituted Morpholin-2-ones

Article abstract of DOI:10.1002/chem.201900635

A new strategy has been established for the synthesis of polysubstituted morpholin-2-ones through Stevens rearrangements of tertiary amines via in situ activation with epoxides. A range of α-amino acid-derived tertiary allylic, propargylic, and benzylic amines reacted with epoxides in the presence of zinc halide catalysts to afford structurally diverse allyl-, allenyl-, and benzyl-substituted morpholin-2-ones, respectively, in moderate-to-good yields with high regioselectivity. The process involves [2,3]- and [1,2]-Stevens rearrangements of quaternary ammonium ylide intermediates and constitutes a very convenient method to prepare polysubstituted morpholin-2-ones through tandem formation of C?N, C?O, and C?C bonds. Moreover, replacing epoxides with aziridines permitted the synthesis of polysubstituted piperazin-2-ones.

Full text of DOI:10.1002/chem.201900635

DOI: 10.1002/chem.201900635
Communication
&
Synthetic Methods
Epoxide-Mediated Stevens Rearrangements of a-Amino-Acid-
Derived Tertiary Allylic, Propargylic, and Benzylic Amines:
Convenient Access to Polysubstituted Morpholin-2-ones
You-Xiang Jin+,[a] Bang-Kui Yu+,[a] Si-Ping Qin,[a] and Shi-Kai Tian*[a, b]
corresponding ammonium ylides, which participate in Stevens
rearrangements to produce aniline derivatives.[3] This approach
Abstract: A new strategy has been established for the
synthesis of polysubstituted morpholin-2-ones through
Stevens rearrangements of tertiary amines via in situ acti-
vation with epoxides. A range of a-amino acid-derived ter-
tiary allylic, propargylic, and benzylic amines reacted with
epoxides in the presence of zinc halide catalysts to afford
structurally diverse allyl-, allenyl-, and benzyl-substituted
morpholin-2-ones, respectively, in moderate-to-good
yields with high regioselectivity. The process involves
[2,3]- and [1,2]-Stevens rearrangements of quaternary am-
monium ylide intermediates and constitutes a very con-
venient method to prepare polysubstituted morpholin-2-
ones through tandem formation of CÀN, CÀO, and CÀC
bonds. Moreover, replacing epoxides with aziridines per-
mitted the synthesis of polysubstituted piperazin-2-ones.
encouraged us to employ epoxides as a new type of electro-
philes to mediate the Stevens rearrangements of a-amino
acid-derived tertiary allylic, propargylic, and benzylic amines;
importantly, the resulting polysubstituted morpholin-2-ones
have a core structure that is present in some antifungal agents
and inhibitors of 17b-hydroxysteroid dehydrogenase type 3
(Figure 1).[4]
Figure 1. Representative bioactive molecules having a morpholin-2-one
moiety.
In contrast to tertiary allylic, propargylic, and benzylic amines,
the corresponding quaternary ammonium ylides are amenable
to participate in [2,3]- and [1,2]-Stevens rearrangements under
mild conditions due to charge acceleration.[1] These rearrange-
ments provide convenient access to various functionalized ter-
tiary amines that are not readily synthesized by alternative
methods. Although quaternary allylic, propargylic, and benzylic
ammonium ylides can be prepared stepwise through N-alkyl-
ation of tertiary amines followed by treatment with bases,[1] it
is more convenient to generate them in situ prior to Stevens
rearrangements. In this regard, earlier reported methods in-
clude transition-metal-catalyzed N-alkylation of tertiary amines
with diazo compounds[1] or with allylic carbonates.[2] In recent
years, arynes have emerged as electrophiles to activate tertiary
allylic, propargylic, and benzylic amines to generate in situ the
Our design of new Stevens rearrangements depends on the
generation of ammonium ylides through nucleophilic attack of
tertiary amines on epoxides,[5] which are readily accessible and
serve as versatile electrophiles for the construction of function-
alized molecules.[6] We envisioned that ring-opening of epoxide
B with a-amino acid-derived tertiary (allylic, propargylic, or
benzylic) amine A would afford zwitterion D, which would
lactonize readily to afford cyclic ammonium salt E.[7] Formation
of ammonium ylide F from ammonium salt E followed by a
[2,3]- or a [1,2]-Stevens rearrangement was expected to afford
morpholin-2-one C (Scheme 1).[1] The proposed process in-
volves tandem formation of CÀN, CÀO, and CÀC bonds, and
[a] Y.-X. Jin,+ B.-K. Yu,+ S.-P. Qin, Prof. Dr. S.-K. Tian
Hefei National Laboratory for Physical Sciences at the Microscale
Center for Excellence in Molecular Synthesis, and Department of Chemistry
University of Science and Technology of China, Hefei, Anhui 230026 (China)
E-mail: tiansk@ustc.edu.cn
[b] Prof. Dr. S.-K. Tian
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Shanghai 200032 (China)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201900635.
Scheme 1. Our design of new Stevens rearrangements.
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importantly, constitutes a powerful new strategy for the con-
venient synthesis of polysubstituted morpholin-2-ones.[8]
Simply heating the mixture of N-allyl glycine ethyl ester 1a
with epoxide 2a in 1,4-dioxane at 1008C did not lead to the
formation of the desired morpholin-2-one 3a (Table 1, entry 1).
The reaction was dramatically affected by addition of Brønsted
argyl, benzyl, and ethoxycarbonylmethyl, were successfully in-
troduced as N-substituents, which were not involved in the
[2,3]-Stevens rearrangement (3b–e). Nevertheless, the desired
reaction did not occur with the introduction of an N-phenyl
group due to decreased nucleophilicity of the tertiary amine.
The reaction proceeded smoothly with the substrates having
various substituents at the a, b, and g-positions of the allyl
moiety (3 f–k). Alternatively, oxirane and a variety of substitut-
ed oxiranes served as suitable electrophiles to participate in
the reaction to afford the corresponding morpholin-2-ones
with high regioselectivity and low diastereoselectivity (if appli-
cable, 3l–q). To confirm the structure of the product, the Boc
group of product 3q was replaced with a p-toluenesulfonyl
group to afford morpholin-2-one 3r, which was subjected to
X-ray crystallography.
Table 1. Optimization of the reaction conditions.[a]
Entry
1a–f, X
Catalyst
Solvent
Yield [%][b]
It must be pointed out that the propargyl group of N-allyl-
N-propargyl glycine ethyl ester (1h) did not participate in the
1
2
3
4
5
6
7
8
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1a, OEt
1b, OBn
1c, OCMe3
1d, NH2
1e, NHMe
1 f, N(CH2CH2)2O
none
PhCO2H
TsOH
AlCl3
BiCl3
FeCl3
CuCl2
ZnCl2
ZnBr2
ZnI2
Zn(OTf)2
Zn(OAc)2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
(MeOCH2)2
diglyme
toluene
p-xylene
DMF
DMSO
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
0
trace
trace
0
trace
60
trace
80
85
89
56
42
55
45
67
60
30
trace
20
70
72
64
9
10
11
12
13
14
15
16
17
18
19[c]
20[d]
21
22
23
24
25
54
50
48
ZnI2
ZnI2
[a] Reaction conditions: 1a–f (0.20 mmol), 2a (0.30 mmol), catalyst
(25 mol%), solvent (0.50 mL), 1008C, 10 h. [b] Yield of isolated product.
[c] The reaction was performed at 808C. [d] The reaction was carried out at
1208C. Bn=benzyl, Ts=p-toluenesulfonyl, Tf=trifluoromethanesulfonyl,
Ac=acetyl, DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide.
acids and Lewis acids (25 mol%) to the mixture to activate the
epoxide (Table 1, entries 2–12), and gratifyingly, the use of ZnI2
afforded morpholin-2-one 3a in the best yield up to 89%
(Table 1, entry 10). We then examined a number of solvents
and changed the temperature, but failed to enhance the yield
(Table 1, entries 13–20). When the ethyl ester was replaced
with benzyl ester 1b and tert-butyl ester 1c, much lower yields
were obtained (Table 1, entries 21 and 22). To our surprise, the
reaction was applicable to a few N-allyl glycine amides, albeit
delivering morpholin-2-one 3a in significantly lower yields
(Table 1, entries 23–25).
Scheme 2. Epoxide-mediated [2,3]-Stevens rearrangement of N-allylic glycine
esters. [a] Reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), ZnI2
(0.050 mmol), 1,4-dioxane (0.50 mL), 1008C, 10 h. [b] Yields of isolated prod-
ucts are given. [c] The diastereomeric ratio (d.r.) values were determined by
1H NMR spectroscopic analysis of the crude products. [d] The structure of
compound 3r was unambiguously confirmed by X-ray crystallography, see
Ref. [11]. Boc=tert-butoxycarbonyl; TFA=trifluoroacetic acid.
A range of N-allylic glycine esters were examined in the ZnI2-
catalyzed reaction with epoxide 2a to afford allyl-substituted
morpholin-2-ones
3a–k
in
moderate-to-good
yields
(Scheme 2). A variety of functional groups, such as allyl, prop-
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[2,3]-Stevens rearrangement under the above conditions
shown in Scheme 2. However, replacing the allyl group with a
methyl group permitted the [2,3]-Stevens rearrangement of
the propargyl group to take place, and allenyl-substituted mor-
pholin-2-one 5a (Scheme 3) was isolated in 40% yield. The
yield was enhanced to 65% by replacing ZnI2 with ZnBr2 as the
Lewis acid catalyst (Scheme 3). Furthermore, both terminal and
internal N-propargylic groups in glycine esters 4 were subject-
ed to a [2,3]-Stevens rearrangement to afford allenyl-substitut-
ed morpholin-2-ones in moderate-to-good yields (Scheme 3).
Scheme 4. Epoxide-mediated [1,2]-Stevens rearrangement of N-benzylic gly-
cine esters. [a] Reaction conditions: 6 (0.20 mmol), 2a (0.30 mmol), ZnCl2
(0.050 mmol), 1,4-dioxane (0.50 mL), 1008C, 10 h. [b] Yields of isolated prod-
ucts are given. [c] The structure of compound 7d was unambiguously con-
firmed by X-ray crystallography, see Ref. [11].
Scheme 3. Epoxide-mediated [2,3]-Stevens rearrangement of N-propargylic
glycine esters. [a] Reaction conditions: 4 (0.20 mmol), 2a (0.30 mmol), ZnBr2
(0.050 mmol), 1,4-dioxane (0.50 mL), 1008C, 10 h. [b] Yields of isolated prod-
ucts are given. [c] The structure of compound 5e was unambiguously con-
firmed by X-ray crystallography, see Ref. [11].
Although the [1,2]-Stevens rearrangement of the benzyl
group was not detected in the reaction of N-allyl-N-benzyl gly-
cine ethyl ester (1i) with epoxide 2a (Scheme 2), it was found
to take place in the corresponding reaction of N-benzyl-N-
methyl glycine ethyl ester (6a), in the absence of an N-allyl
group, under the same conditions. The yield for the formation
of benzyl-substituted morpholin-2-one 7a was slightly im-
proved from 59 to 62% by replacing ZnI2 with ZnCl2 as the
Lewis acid catalyst (Scheme 4). Moreover, both electron-donat-
ing groups and electron-withdrawing groups were successfully
introduced into the benzene ring of the desired benzyl-substi-
tuted morpholin-2-ones (7b–f). The reaction was further ex-
tended to the synthesis of 2-naphthylmethyl-, 2-thienylmethyl-,
and 2-benzo[b]thiophenylmethyl-substituted morpholin-2-ones
in moderate-to-good yields (7g–i). It is worth noting that in
these cases the Sommelet–Hauser rearrangement was not ob-
served at all.[9]
Scheme 5. Epoxide-mediated Stevens rearrangements of l-pipecolinic acid
derivatives.
Finally, we succeeded in the synthesis of polysubstituted pi-
perazin-2-ones simply by replacing epoxides with aziridines in
the above reactions under similar conditions.[10] For example,
treatment of N-allyl glycine ester 1a with aziridine 8 in the
presence of 25 mol% ZnCl2 afforded allyl-substituted pipera-
zin-2-one 9 in 66% yield (Figure 2).
In summary, we have established a new strategy to execute
the [2,3]- and [1,2]-Stevens rearrangements of tertiary amines
through in situ activation with epoxides. With zinc halides as
the Lewis acid catalysts, a range of a-amino acid-derived ter-
tiary allylic, propargylic, and benzylic amines reacted with ep-
oxides to afford structurally diverse allyl-, allenyl-, and benzyl-
substituted morpholin-2-ones, respectively, in moderate-to-
We further examined optically active l-pipecolinic acid-de-
rived tertiary allylic, propargylic, and benzylic amines under the
above reaction conditions and observed significant erosion of
enantiopurity in the construction of nitrogen-substituted qua-
ternary stereocenters (Scheme 5). Clearly, the poor diastereose-
lectivity in the nucleophilic attack of the tertiary amine on ep-
oxide 2a contributes to the low efficiency of chirality transfer
(Scheme 1). Moreover, in the synthesis of morpholin-2-one 7j
the erosion of enantiopurity can also be attributable to the
nonconcerted [1,2]-Stevens rearrangement involving diradical
pairs.[1a,c–e,7]
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Keywords: amines · ammonium ylides · epoxides · morpholin-
2-ones · Stevens rearrangement
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Figure 2. Synthesis of piperazin-2-one 9.
good yields with high regioselectivity. The process involves
[2,3]- and [1,2]-Stevens rearrangements of quaternary ammoni-
um ylide intermediates and constitutes a very convenient
method to prepare polysubstituted morpholin-2-ones through
tandem formation of CÀN, CÀO, and CÀC bonds. Moreover, re-
placing epoxides with aziridines permitted the synthesis of
polysubstituted piperazin-2-ones.
Experimental Section
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General procedure for the epoxide-mediated Stevens rear-
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A mixture of tertiary amine 1 (4 or 6, 0.20 mmol), epoxide 2
(0.30 mmol), and ZnX2 (0.05 mmol) in 1,4-dioxane (0.50 mL) was
stirred at 1008C under nitrogen for 10 h, cooled to room tempera-
ture, and concentrated under reduced pressure. The residue was
purified by silica gel chromatography, using a mixture of ethyl ace-
tate and petroleum ether (1:20 to 1:2) as the eluent, to give mor-
pholin-2-one 3 (5 or 7).
Acknowledgements
[7] E. Tayama, S. Otoyama, H. Tanaka, Tetrahedron: Asymmetry 2009, 20,
2600–2608.
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (21772182) and the Strategic
Priority Research Program of the Chinese Academy of Sciences
(XDB20000000).
ˇ
[8] For a review, see: U. Trstenjak, J. Ilas, D. Kikelj, Synthesis 2012, 44,
3551–3578.
[9] For reviews on the Sommelet–Hauser rearrangement, see: a) Refs. [1d]
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[10] To our knowledge, the ring-opening of aziridines with tertiary amines
has not been reported yet.
[11] CCDC 1876818 (3r), 1876819 (5e), and 1876820 (7d) contain the sup-
plementary crystallographic data for this paper. These data are provided
free of charge by The Cambridge Crystallographic Data Centre.
Conflict of interest
The authors declare no conflict of interest.
Manuscript received: February 10, 2019
Version of record online: && &&, 0000
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Communication
COMMUNICATION
&
Synthetic Methods
Y.-X. Jin, B.-K. Yu, S.-P. Qin, S.-K. Tian*
&& – &&
Epoxide-Mediated Stevens
Rearrangements of a-Amino-Acid-
Derived Tertiary Allylic, Propargylic,
and Benzylic Amines: Convenient
Access to Polysubstituted Morpholin-
2-ones
New Stevens rearrangement: Zinc-
halide-catalyzed ring-opening of epox-
ides with a-amino acid-derived tertiary
allylic, propargylic, and benzylic amines
followed by [2,3]- and [1,2]-Stevens rear-
rangements of the resulting quaternary
ammonium ylide intermediates has
been established as a convenient
method to access polysubstituted mor-
pholin-2-ones through tandem forma-
tion of CÀN, CÀO, and CÀC bonds (see
scheme).
Chem. Eur. J. 2019, 25, 1 – 5
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