LiCl-promoted amination of β-methoxy amides (γ-lactones)

Article abstract of DOI:10.1039/d0ra07170f

An efficient and mild method has been developed for the amination of β-methoxy amides (γ-lactones) including natural products michelolide, costunolide and parthenolide derivatives by using lithium chloride in good yields. This reaction is applicable to a wide range of substrates with good functional group tolerance. Mechanism studies show that the reactions undergo a LiCl promoted MeOH elimination from the substrates to form the corresponding α,β-unsaturated intermediates followed by the Michael addition of amines.

Full text of DOI:10.1039/d0ra07170f

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LiCl-promoted amination of b-methoxy amides (g-
lactones)†
Cite this: RSC Adv., 2020, 10, 34938
Ru Zhao,a Bing-Lin Zeng,a Wen-Qiang Jia,a Hong-Yi Zhao,a Long-Ying Shen,a
a
ab
*
*
Xiao-Jian Wang
and Xian-Dao Pan
An efficient and mild method has been developed for the amination of b-methoxy amides (g-lactones)
including natural products michelolide, costunolide and parthenolide derivatives by using lithium
chloride in good yields. This reaction is applicable to a wide range of substrates with good functional
Received 20th August 2020
Accepted 11th September 2020
group tolerance. Mechanism studies show that the reactions undergo
a LiCl promoted MeOH
DOI: 10.1039/d0ra07170f
elimination from the substrates to form the corresponding a,b-unsaturated intermediates followed by
rsc.li/rsc-advances
the Michael addition of amines.
The formation of carbon–nitrogen bonds remains one of the amination of methoxy(hetero)arenes with the amine nucleo-
most fundamental and widely practiced reactions in organic philes (Fig. 1b).11 The t-Bu-P4 is also suitable to catalyze the
synthesis, due to the prevalence of this functionality in the amination of b-(hetero)arylethyl ethers with amines to synthe-
preparations of functional molecules in pharmaceutical chem- size b-(hetero)arylethylamines (Fig. 1c).12 Sun and coworkers
istry, biochemistry and material sciences.1 Various synthetic reported that C–S bond cleavage to access N-substituted acryl-
methodologies have been developed to form C(sp2)-N bonds, amide and b-aminopropanamide(Fig. 1d).13
including the Goldberg reaction,2 Buchwald–Hartwig reaction,3
imine reduction4 and the nucleophilic addition of carbon-
nucleophiles to imine derivatives.5 Meanwhile, the formations
of C(sp3)-N bonds can be achieved by reductive amination,
which involves the conversion of a carbonyl group to an amine
via an imine intermediate, such as Eschweiler–Clarke reaction6
and Borch reductive amination.7 Nucleophilic substitution of
alkyl(pseudo)halides with amines (amine alkylation) serves as
one direct strategy for the preparation of alkylamines, while the
necessity of pre-installation of the halogen atoms and the
production of stoichiometric inorganic salt wastes are consid-
ered as two main drawbacks for its application in large scale
industrial synthesis.8
Methoxy as the leaving group in the amination reactions has
recently attracted the attention of organic chemists. For
instance, Chiba and coworkers reported a method for the
nucleophilic amination of methoxy arenes,9 which was achieved
by using sodium hydride (NaH) in the presence of lithium
iodide (LiI) through a concerted nucleophilic aromatic substi-
tution pathway (Fig. 1a).10 Kondo and coworkers demonstrated
that the organic superbase t-Bu-P4 efficiently catalyzes the
aState Key Laboratory of Bioactive Substances and Functions of Natural Medicines,
Institute of Materia Medica, Peking Union Medical College and Chinese Academy of
Medical Sciences, Beijing 100050, China. E-mail: xdp@imm.ac.cn
bSchool of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
† Electronic supplementary information (ESI) available: Experimental details,
including procedures, syntheses and characterization of new compounds; and
1H and 13C NMR spectra. CCDC 1999852. For ESI and crystallographic data in
Fig. 1 Amination reactions of methyl ethers.
CIF or other electronic format see DOI: 10.1039/d0ra07170f
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Recently, we described the application of a CuBr–LiCl
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composite for the short-chain alkoxylation of aryl bromides.14
During that course of study, the single-shell lithium ion was
found to embrace a unique affinity for oxygen and can be used
as an additive to activate C–O bond and facilitate the nucleo-
philic reaction. On the basis of this study, we herein present the
synthesis of b-amino amides (g-lactones) via the elimination of
methoxy group followed by Michael addition of an amine, that
was promoted by LiCl in good yields under conventional
conditions.
We initiated our study with the reaction of 3-methoxy-N-
phenylpropanamide 1a and piperidine 2a in the presence of
lithium salts (Table 1). It was found that the reaction performed
i
ꢀ
in PrOH at 120 C in a sealed tube proceeded smoothly in the
presence of 2.0 equiv. of LiCl, giving the desired product 3aa in
70% yield (entry 1), while using other additives, including LiBr,
LiI, LiOTf, Li2CO3 and NaCl instead, dramatically decreased the
i
yields (entries 2–6). PrOH was proved to be a better solvent,
whereas using other solvents, such as DMF or toluene, gave
poor results (entries 7 and 8). Lowering the equivalent of LiCl to
1.0 equiv. reduced the yield of 3aa to 38% (entry 9). No
conversion was observed when the reaction was performed in
the absence of LiCl (entry 10). Moreover, reducing the reaction
temperature or reaction time resulted in diminished yields
(entries 11 and 12). Therefore, 1.0 equiv. of 3-methoxy prop-
anamide, 2.0 equiv. of alkyl amine and 2.0 equiv. of LiCl in
iPrOH was chosen as the standard condition for the amination
of 3-methoxy propanamides.
With the optimized condition in hand, the substrate scope
and functional group tolerance of the transformation was then
examined (Scheme 1). It was found that the 3-methoxy-N-aryl-
propanamides without substitution or substituted with
Scheme 1 Evaluation of the substrate scope of b-methoxy amides and
amines. aReactions were carried out with 1a (1.0 equiv.), 2a (2.0 equiv.)
and LiCl (2.0 equiv.) in iPrOH (0.15 M) at 120 ꢀC for 12 h in sealed tube.
Yields of isolated products are given.
Table 1 Examination of the reaction conditionsa
electron-donating (–OMe) or electron-withdrawing (–Cl, –Br)
groups at the para-position of the N-aryl ring exhibit good
tolerance under the present conditions, giving good yields of
70–77% (3aa–3da). Moreover, the diversity of amines was
studied, including pyrrolidine, diethyl amine, dimethyl amine,
morpholine and methyl amine solution, and the amination
products were formed in moderate to good yields in all cases
(3ab–3db, 3ac–3dc, 3ad–3dd, 3ae–3de, 3af). However, when
using anilin (2g) as the starting material, no reaction took place.
Replacement of the N-phenyl substituent with a benzyl group
(1e) led to an increased yield of 83% (3ed). Remarkably, chal-
lenging 3-methoxypropanoyl piperazine derivatives also worked
well under the optimized conditions, producing the desired
products in good yields (3fa–3fe). Promoted by the successful
amination of the amide, we then extended this transformation
to b-methoxy g-lactones. It was noteworthy to nd that 3-
methoxymethyl g-lactones 4a also worked for this reaction with
the high yield of 85% 5ad.
Entry Additive (equiv.) Solvent
T (ꢀC) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
LiCl (2.0)
LiBr (2.0)
LiI (2.0)
LiOTf (2.0)
Li2CO3 (2.0)
NaCl (2.0)
LiCl (2.0)
LiCl (2.0)
LiCl (1.0)
—
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
DMF
120
120
120
120
120
120
120
12
12
12
12
12
12
12
12
12
12
12
6
70
30
43
38
6
N. R.
46
21
38
N. R.
23
Toluene 120
9
iPrOH
iPrOH
iPrOH
iPrOH
120
120
80
10c
11
12
LiCl (2.0)
LiCl (2.0)
120
49
a
Reaction conditions: 1a (0.45 mmol), 2a (0.90 mmol) and additive (2.0
b
equiv.) in solvent (3.0 mL) at 120 ꢀC in sealed tube. Yield of isolated
product. c No LiCl was used.
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Table 2 Evaluation of the substrate scope of b-methoxy g-lactones of
Encouraged by the above results, our research was then
extended to perform this transformation between the natural
product michelolide derivatives 4b with b-methoxy g-lactone
subunit and various amines 2 (Scheme 2).15 Due to a high
tolerance and compatibility of function groups, this strategy can
be applied to 4b possessing both hydroxy group and carbon–
carbon double bond. Both cyclic amines (2a, 2b, 2e, 2h) and
linear amines (2d, 2i, 2f, 2j) gave the corresponding products in
moderate to excellent yields. Additionally, the structure of
product 5bb was unambiguously identied by X-ray
crystallography.
natural productsa
Entry
1
Substrate
Product
Yieldb (%)
99
2
70
Meanwhile, it is well demonstrated that amine substituted
natural products is an efficient hydrophilic modication
strategy used in medicinal chemistry.16 Therefore, this system
was then extended to the amination of other natural product
derivatives (4c–4g) containing b-methoxy g-lactone subunit
(Table 2).17 Arglabin derivative 4c underwent the amination to
give the product (5cd) in 99% yield, which is equivalent to the
commercially available antitumor agent Arglabin-DMA.16a,18
Michelolide derivative (4d and 4e) gave similarly good yields, in
which the epoxy subunit does not affect the yield under the
optimized conditions.19 The costunolide derivative 4f was con-
verted to the corresponding product 5fd in 60% yield, while the
reaction based on the parthenolide derivative 4g gave the
desired product 5gd in 48% yield.
3
4
61c
60
48
5
The investigation on the mechanism of reaction was con-
ducted by detailed control experiments as follows (Scheme 3):
a
Reactions were carried out with 4 (1.0 equiv.), 2d (2.0 equiv.) and LiCl
(2.0 equiv.) in iPrOH (0.15 M) at 120 ꢀC for 5 h in sealed tube. b Yields of
isolated products are given. c Reaction was conducted for 18 h.
rst, N-(3-methoxypropyl)aniline (6a) and 2-methoxy-N-phenyl-
acetamide (7a) were prepared and subjected to the previously
described standard condition respectively (Scheme 3a). In these
reactions, no reaction took place, suggesting that the subunit of
carbonyl b-ethers was essential for this reaction. Second, the
desired product 3aa was obtained under the standard reaction
conditions when the substrates bearing either 3-benzyloxy or 3-
phenoxyl groups were used as the starting materials (Scheme
3b). Thus, these results supported a mechanism that there
would undergo an intermediate in common. Moreover, the ex-
pected product 3aa was not observed when the reaction of 1a
without LiCl was examined (Table 1, entry 7), verifying that LiCl
also essential in this elimination process. Finally, the reaction
of 3-methoxy-N-phenylacetamide (1a) under the standard reac-
tion condition was examined in absence of amine, only trace of
eliminate product (9a) was observed (Scheme 3c). Subsequently,
when 2 equiv. of 1-methylpiperidine (2j) was added to the
reaction above, both a,b-unsaturated amide 9a and the 3-iso-
propyl substituted product 10a were isolated in 27% and 21%
yield respectively. Then the reaction of eliminate product 9a and
piperidine 2a was examined, and the desired product 3aa was
afforded in 68% yield, which indicated that elimination and
addition process would be involved in this procedure. These
experiments provided evidence that the amine 2 not only
Scheme 2 Evaluation of the substrate scope of amines with michel-
olide derivatives. aReactions were carried out with 4b (1.0 equiv.), 2 (2.0
equiv.) and LiCl (2.0 equiv.) in iPrOH (0.15 M) at 120 ꢀC for 5 h in sealed
tube. Yields of isolated products are given. bReaction was conducted
for 10 h. cReaction was conducted for 20 h. dReaction was conducted
for 15 h.
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modication route of g-lactones in medicinal chemistry, which
would proceeds through two steps, which includes the initial
formation of the a,b-unsaturated amide by the elimination of
MeOH followed by the Michael addition with amines. Further
investigation on detailed applications is currently underway.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This study was nancially supported in part by Chinese
Academy of Medical Sciences Innovation Fund for Medical
Sciences (CAMS-2017-12M-1-011), the National Drug Innovation
Major Project (2018ZX09711-001-005) and Disciplines
Construction Project (Grant 201920200802).
Notes and references
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Scheme 3 Control experiments. aReactions were carried out with 6a,
7a, 8a, 8b and 1a (1.0 equiv.), 2a and 2j (2.0 equiv.) and LiCl (2.0 equiv.)
i
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the product 3a.
In conclusion, we reported a novel strategy for the synthesis
of the b-amino amides (g-lactones). The reaction shows a broad
substrate scope for b-methoxy amides (g-lactones) and a wide
range of natural product derivatives including michelolide,
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nation reaction provides an alternative b-position hydrophilic
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Scheme 4 Tentative pathways of the reaction.
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