Cycloadditions between methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate and various tosylacetamides: Synthesis of trifluoromethylated pyroglutamates and 2-pyridones derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.01.095

Cycloaddition reactions between methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate and various 2-tosylacetamides are described. Various 2-tosylacetamides react with methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate in the presence of NaH at room temperature in one step to form trifluoromethylated pyroglutamates as single diastereomers. However, employing the same reactants using t-BuOK as base at ?78 °C results in the formation of trifluoromethylated 2-pyridones. A ring-closure mechanism is proposed for the reaction.

Full text of DOI:10.1016/j.tetlet.2018.01.095

Accepted Manuscript
Cycloadditions between methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate and
Various Tosylacetamides: Synthesis of Trifluoromethylated Pyroglutamates
and 2-Pyridones Derivatives
Hong-Hai Zhang, Wei Shen, Long Lu
PII:
S0040-4039(18)30140-0
https://doi.org/10.1016/j.tetlet.2018.01.095
TETL 49682
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 January 2018
28 January 2018
30 January 2018
Please cite this article as: Zhang, H-H., Shen, W., Lu, L., Cycloadditions between methyl (Z)-2-bromo-4,4,4-
trifluoro-2-butenoate and Various Tosylacetamides: Synthesis of Trifluoromethylated Pyroglutamates and 2-
Pyridones Derivatives, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.01.095
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Tetrahedron Letters
Cycloadditions between methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate and Various Tosylacetamides:
Synthesis of Trifluoromethylated Pyroglutamates and 2-Pyridones Derivatives
a,
b
b,
Hong-Hai Zhang *, Wei Shen and Long Lu *
a
Key Laborabory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Jiangsu National Synergistic
Innovation Center for Advanced Materials (SICAM), Nanjing Tech University (Nanjing Tech), 30 Puzhu Road, Nanjing 211816,
P.R. China
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Road, Shanghai 200032, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Cycloaddition reactions between methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate and
various 2-tosylacetamides are described. Various 2-tosylacetamides react with methyl (Z)-
2-bromo-4,4,4-trifluoro-2-butenoate in the presence of NaH at room temperature in one
step to form trifluoromethylated pyroglutamates as single diastereomers. However,
o
Available online
employing the same reactants using t-BuOK as base at -78 C results in the formation of
trifluoromethylated 2-pyridones. A ring-closure mechanism is proposed for the reaction.
Keywords:
Fluorinated building block
cycloaddition
2009 Elsevier Ltd. All rights reserved.
trifluoromethylated proglutamate
trifluoromethylated dihydropyridine
The introduction of one or more fluorine atoms into a molecule
is known to have a marked effect on its chemical, physical, and
physiological properties. Consequently, many efforts have been
a convenient route for synthesizing these two types compounds,
under mild conditions.
1
made to introduce fluorine atoms into molecules for use in
medicinal and agricultural chemistry. Although direct
Br , CCl
H
COOMe FSO CF COOMe
H
COOMe
Br
2
4
2
2
2
H
COOMe
o
70 C
o
Br
Br
CuI, DMF, 80 C
F3C
introduction of fluorine utilizing fluorinating reagents has been
1
3
well developed in recent years, the use of fluorinated building
Scheme 1.
Synthesis route for (Z)-methyl-2-bromo-4,4,4-
blocks to synthesize fluorinated organic molecules is still
attractive due to the avoidance of the harsh reaction conditions
trifluorobut-2-enoate 1
4
and special equipment needed for handling fluorinated reagents.
We have previously reported a fluorine-containing building
1
0
Furthermore, when fluorinated building blocks are employed in
cycloaddition reactions, various fluorinated heterocyclic
block 1, which is easily prepared from methyl propiolate
Scheme 1). With compound 1 in hand, we carried out the
cycloaddition reaction between compound 1 and N-benzyl-2-
(
5
compounds can be easily prepared in a single step.
1
1
Our research group is devoted to the development of new
fluorine-containing building blocks for the synthesis of
tosylacetamide 2a to furnish 3a. After a quick survey of the
reaction conditions, the best result was found in the reactant ratio
of 2a/1/NaH=1:2:3 at room temperature with 75% yield of 3a as
a single diastereomer (entry 1 in Table 1). Under this optimized
reaction condition, various 2-tosylacetamides were examined to
explore the scope and limitations of this reaction. As shown in
Table 1, compound 1 showed good reactivity to various
substrates. Products 3a-3g were all obtained in good yields as
single diastereomers (entries 1-7). Compounds 2e-2g with aryl
group attached to nitrogen atom gave better yields (entries 5-7),
due possibly to the stability of their corresponding anions.
6
fluorinated organic compounds. Because pyroglutamic acid and
2
-pyridones derivatives are prevalent scaffolds that serve as
crucial building blocks for numerous syntheses of biologically
7
active molecules and functional materials, trifluoromethylated
pyroglutamates and 2-pyridone derivatives are of special interest
and their synthesis is therefore of particular attraction. However,
8
-9
due to the difficulty of their syntheses,
only a few synthetic
methods for these two kinds of compounds have been reported
thus far. These methods have some drawbacks, such as the
limited availability of the starting materials, the use of
environmentally unfriendly transition metals, and low yields and
low stereoselectivities of the products. Indeed, it is still highly
desirable to develop an efficient and practical method for the
synthesis of trifluoromethylated pyroglutamate and 2-pyridone
derivatives in a stereoselective manner. In this paper we describe

2
Tetrahedron
1
9
ratio of 3:1 as determined by F-NMR. This result also indicated
that the steric effect may control the configuration of the product
3
, since the nitrile group is much smaller than the tosyl group.
CF3
NC
O
CF3
TABLE 1.
Cycloaddition Reactions of Tosylacetamides 2a-2g with
NC
O
(Z)-methyl-2-bromo-4,4,4-trifluorobut-2-enoate,
1,
to
provide
COOMe
COOMe
N
N
Pyroglutamades, 3a-3g.
Bn
3i'
Bn
CF3
3i
O
Tos
O
H
COOMe
Br
NaH THF
r.t.
To improve the poor ratio of 3i and 3i', the reaction of 1 and
i was performed at -78 C. To our surprise, a new complex 4i
+
Tos
R
COOMe
o
N
N
2
F3C
H
R
was obtained with NaH as base, and neither 3i nor 3i' was
observed. Encouraged by this result, the reaction conditions were
re-optimized. Reagents and reaction parameters such as bases,
solvents, proportions of the starting materials and the reaction
temperature were varied. We found that, firstly, using t-BuOK as
base could lead to moderate yield of product 4i (entries 1-4 in
Table 2). Secondly, the yield of 4i was greatly dependent on the
ratio of the starting materials. When an excess of 2i was used, the
product 4i was obtained in a good yield (entry 6). However,
when an excess of 1 was used, the yield of 4i dramatically
decreased (entry 5). After a brief survey of reaction solvents,
THF was found to be the most efficient solvent (entries 6-9).
Finally, raising the temperature was harmful to the reaction, since
2
1
3
a
b
c
Entry
2
R
3
Yield (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
CH
CH(CH )
C H
6 11
2
C
6
H
3 2
5
3a
3b
3c
3d
3e
3f
75
73
76
71
82
80
86
CH
2
CH=CH
2
6 5
C H
4-CH
4-OCH
3
C
6
H
4
2g
3
C
6
H
4
3g
a
In all cases, 1 (2.0 equiv) was added to a mixture of NaH (3.0 equiv) and 2
b
o
o
(
1.0 equiv) in THF at -78 C, then raised to 25 C with stirring for about 4h.
For Entry 1, the configuration of 3a was determined by single-crystal X-ray
analysis; the others were assigned by analogy. Isolated yield.
c
o
no product 4i was observed at 25 C (entry 10). Good yield was
o
obtained still at -78 C.
Since the products 3a-3g were obtained as single
diastereomers, we next turned our attention to the identification
of their configurations. Fortunately, we obtained single crystals
of product 3a, which enabled the structure of 3a to be determined
by X-ray crystallographic diffraction analysis. The crystal
structure clearly shows that the substituent groups at C23 and
C24, C24 and C25 are trans to each other (Figure 1). The
configuration of 3a was thus identified, and the configurations of
TABLE 2. Optimizing Reaction Conditions for Synthesis of
trifluoromethylated dihydropyridine 4.
CF3
O
H
COOMe
Br
NC
HO
base
NC
Bn
+
N
F3C
solvent
H
N
O
Bn
1
2i
1
4i
other products 3b-3g were determined by comparison of their H-
NMR spectra with that of 3a. The steric effect between the
trifluoromethyl group and the tosyl group and the ester group is
possibly a reason for the trans configuration of compounds 3.
o
a
Entry
T( C)
Base
NaH
2i:1
solvent
Yield (%)
1
2
3
4
5
6
7
8
9
-78
-78
-78
-78
-78
-78
-78
-78
-78
25
1:1
1:1
1:1
1:1
1:2
2:1
2:1
2:1
2:1
2:1
THF
THF
THF
THF
THF
THF
DMF
DME
hexane
THF
30
38
27
60
25
LHMDS
t-BuONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
b
82
40
15
52
1
0
None
a 19
b
F-NMR yield Isolated yield.
To explore the scope of the reaction, N-substituted-2-
tosylacetamides 2a-2h were re-examined using this optimized
reaction condition. The results indicated good reactivity, and
gave products 4a-4h in moderate yields (entries 1-8 in Table
3
). The scope of the starting materials was then extended to
include four N-substituted-2-cyanoacetamides, 2i-2l. In all
cases, the products 4i-4l were obtained in good yields (entries
9
-12). As shown in Table 3, N-substituted-2-cyanoacetamides
gave better yields than N-substituted-2-tosylacetamides, and
with the exception of the cyclohexyl group in 4c, no obvious
2
effect on yield was observed by changing substituent R .
Figure 1. X-ray structure of compound 3a
TABLE 3. Cycloaddition reactions of acetamide 2 with (Z)-methyl-2-
bromo-4,4,4-trifluorobut-2-enoate 1 to provide 2-pyridones 4.
To further extend the scope of this reaction, N-benzyl-2-
1
0
cyanoacetamide 2i was used to react with 1. However, a
mixture of two diastereomers 3i and 3i' was obtained with the

CF3
R1
O
H
COOMe
Br
t-BuOK
R1
R2
+
N
o
F3C
THF -78 C
H
HO
N
R2
O
2
a
1
4
1
2
b
Entry
R
R
Yield (%)
1
2
-Tos
-Tos
4a(63)
2
a
4b(64)
2
b
2
3
4
5
-Tos
-Tos
-Tos
4c(40)
4d(68)
4e(54)
2
c
d
2
e
6
-Tos
Me
4f(68)
2f
7
8
-Tos
-Tos
OMe
4g(55)
4h(67)
2g
2
h
9
-CN
-CN
4i(81)
4j(71)
2
i
1
0
2
j
1
1
1
2
-CN
-CN
4k(67)
4l(76)
2
k
2l
a
In all cases, 1 (1.0 equiv) was added to a mixture of NaH (3.0 equiv) and 2
2.0 equiv) in THF at -78 C, followed by stirring for about 30min. Isolated
o
b
(
Scheme 2. Proposed mechanism for the reaction between compound 1
and N-benzyl-2-tosylacetamide 2a.
yield.
To account for the remarkable regioselectivity and
In summary, we have disclosed a convenient, one-pot
procedure for synthesis of various trifluoromethylated
pyroglutamates and 2-pyridone derivatives via the reaction
between acetamides 2 and an easily prepared fluorine-containing
building block (Z)-methyl-2-bromo-4,4,4- trifluorobut-2-enoate
diastereoselectivity of these cycloaddition reactions, we propose
a reaction mechanism as shown in Scheme 2. Treatment of 2a
with sodium hydride gives Z-form enolate 5 with two bulky
groups trans to each other. A subsequent 1-4 addition reaction of
and 5 via a more stable chair transition state 6 forms the enolate
, which rapidly turns to 8a and 8b by an intramolecular syn-
1
7
1
, under mild conditions. Employing this fluorinated building
block to react with other dinucleophiles can lead to the formation
of new fluorinated heterocyclic compounds. Research in this
field continues in our laboratories.
proton abstraction. If the nitrogen anion of 8a attacks the carbon
bromine bond from the back side via an intramolecular SN2
reaction, 9 is formed with two bulky group CF and COOMe
3
trans to each other. To avoid the severely eclipsed interaction of
the Tos and CF groups, protonation of 9 in the work up process
3
Supplementary Material
yields 3a stereoselectively, but in the case where 2i is employed
as the starting material, a weaker eclipsing interaction of CN and
CF3 results in a mixture of two diastereomers 3i and 3i’.
Otherwise, the nitrogen anion of 8a attacking the ester leads to
the formation of complex 10. Under the condition of excess base,
compound 10 rapidly losses one equivalent of hydrogen bromine
to furnish 4a.
Supplementary material associated with this article can be
found, in the online version, at
Acknowledgments
We thank the National Natural Science Foundation of China
(Grant Numbers 21704041 and 29825104) and the Chinese
Academy of Science for the financial support.
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3
(
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7
5

Highlights:
Trifluoromethylated pyroglutamates and 2-
pyridones have been synthesized.
Trifluoromethylated pyroglutamate was obtained
as a single diastereomer.
A ring-closure mechanism is proposed for the
reaction.
•
•
•

6
Tetrahedron
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Cycloadditions between methyl (Z)-2-bromo-4,4,4-trifluoro Leave this area blank for abstract info.
2-butenoate and Various Tosylacetamides: Synthesis of
-
Trifluoromethylated Pyroglutamates and 2-Pyridones Derivatives
Honghai Zhang*, Wei Shen, and Long Lu*
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