Highly Selective Synthesis of α-Aminoamide Utilizing an Umpolung Reaction and Characteristics of α-Hydrazonoester

Article abstract of DOI:10.1021/acs.orglett.1c01117

An umpolung reaction with α-hydrazonoesters was investigated, and it was found that α-N,N-dialkylaminoamides could be directly synthesized in yields up to 92% via a concomitant rearrangement of dialkylamino groups. As an application, a short synthesis of an inhibitor of glycine type-1-transporter was accomplished via subsequent functional group transformations in 28% overall yield.

Full text of DOI:10.1021/acs.orglett.1c01117

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Letter
Highly Selective Synthesis of α‑Aminoamide Utilizing an Umpolung
Reaction and Characteristics of α‑Hydrazonoester
Isao Mizota,* Yusuke Nakamura, Shunsuke Mizutani, Nanami Mizukoshi, Shunya Terasawa,
and Makoto Shimizu*
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ABSTRACT: An umpolung reaction with α-hydrazonoesters was investigated, and it was found that α-N,N-dialkylaminoamides
could be directly synthesized in yields up to 92% via a concomitant rearrangement of dialkylamino groups. As an application, a short
synthesis of an inhibitor of glycine type-1-transporter was accomplished via subsequent functional group transformations in 28%
overall yield.
ydrazones and their derivatives have received consid-
erable attention as stable and versatile imine deriva-
aminoamide synthesis using an SN2 type reaction at the
nitrogen atom followed by subsequent amide formation and
the second N-alkylation (Scheme 1b). Further extension of the
present reaction to the synthesis of an inhibitor of the glycine
type-1-transporter5 was also successfully carried out in an
efficient manner.
As an initial investigation, N,N-dimethylhydrazonoester 1a
was chosen as a model substrate for the α-N,N-dialkylamino
amide synthesis. Treatment of the hydrazonoester 1a in
toluene with an ether solution of ethylmagnesium bromide at
−78 °C gave the α-N,N-diethylaminoamide 2a along with the
monoethylated iminoester 3a. Encouraged with the initial
result, we screened the reaction conditions with respect to the
equivalent of the reagent, solvent, and temperature, and Table
1 summarizes the results.
H
tives,1,2 since their CN moieties behave as electrophiles of
moderate reactivity with the availability of their chiral versions,
e.g., (S)-1-amino-2-methoxymethylpyrrolidine (SAMP)/(R)-
1-amino-2-methoxymethylpyrrolidine (RAMP) hydrazones
and others.3 During our research into the α-iminoester,4 we
have become interested in the reactivity of oxime derivatives as
stable and useful substrates for the SN2 type reaction at the
nitrogen atom and for subsequent umpolung reactions to
introduce plural substituents at the nitrogen (Scheme 1a).4f−k
Scheme 1. Previous Work and This Work
As shown in Table 1, the reaction proceeded relatively fast in
polar solvents at −78 °C, while the intermediate α-ethyl-
iminoester 3a was solely formed in CH2Cl2 at −78 °C (entries
1−5). An increase in the the reaction temperature to 0 °C gave
the desired α-N,N-diethylamino amide 2a as the sole product
in 62% yield (entry 14). The best result was obtained when the
reaction was carried out with 2.5 equiv of ethylmagnesium
bromide in CH2Cl2 at 0 °C, and the desired product was
formed in 81% yield (entry 19).
Under the optimum conditions, a variety of substrates and
Grignard reagents were subjected to the present α-N,N-
Received: March 31, 2021
Published: May 20, 2021
During the exploration into the SN2 type reaction at the
nitrogen atom, we focused on a relatively strong N−N bond of
the hydrazone moiety and found that, once the N−N bond
was cleaved, the cleaved nitrogen moiety behaved as a good
nucleophile for the ester part to convert it to an amide. In this
Communication, we would like to describe an intriguing α-
https://doi.org/10.1021/acs.orglett.1c01117
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4168−4172
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Letter
Table 1. Screening of the Reaction Conditions for Tandem
N-Alkylation of α-Hydrazonoester
Scheme 2. Scope of Substrates and Nucleophiles
a
b
b
entry x equiv
solvent
temp (°C)
time
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
2a (%)
3a (%)
1
2
3
4
5
6
7
8
9
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.5
toluene
EtCN
THF
Et2O
CH2Cl2
EtCN
Et2O
CH2Cl2
EtCN
Et2O
CH2Cl2
EtCN
−78
−78
−78
−78
−78
−40
−40
−40
−20
−20
−20
0
0
0
30
0
0
0
0
33
47
24
45
0
25
20
33
23
52
6
7
25
1
6
15
2
3
0
c
c
51
45
34
62
51
47
39
52
62
51
37
66
80
81
c
c
10
11
12
13
14
15
16
17
18
19
c
c
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
13
0
0
0
15 min
30 min
30 min
30 min
d
d
a
Reaction conditions: 1a (0.20 mmol), solvent (2.0 mL) under argon.
b
c
Isolated yield. α-Hydrazonoester derived from the corresponding
d
methyl ester 1a′ was used. EtMgBr in THF was used.
dialkylamino amide formation, and Scheme 2 displays the
results. Regarding the substituents at the aromatic ring (R2),
both the electron-donating and electron-withdrawing groups
were tolerated to afford the corresponding products in good
yields (2a−g). Ethyl, pentyl, and 3-butenyl Grignard reagents
gave the N,N-dialkylated amides 2a, 2h, and 2i in good yields,
whereas methyl, phenyl, and sterically bulky iso-propyl and tert-
butyl counterparts were not effective for the present reaction.6
Although the yields were only moderate, bis-Grignard reagent7
and benzylmagnesium bromide gave the desired dialkylated
products 2n and 2o. In addition to dimethyl amides as the
products, piperidino and morpholino derivatives were formed
in good yields from the corresponding starting α-hydrazo-
noesters (2p−s). Besides the aryl derivatives examined in the
present study, unfortunately, we were unable to prepare alkyl
substituted substrates in pure form to carry out their studies.
This reaction could be scaled up as shown in Scheme 3.
When α-hydrazonoester 1a′ (10 mmol) was treated with
EtMgBr under the optimal reaction conditions, the corre-
sponding N,N-dialkylated amide 2a was obtained without
affecting the yield. This result shows that the present α-
aminoamide forming reaction is highly practical.
a
b
Reaction time was 40 min. Pentamethylenebis(magnesium bro-
c
mide) was used as a nucleophile. α-Hydrazonoester derived from the
corresponding methyl ester 1a′ was used.
Scheme 3. Gram Scale Synthesis
As a straightforward application of the present tandem
alkylation/amide formation, a short synthesis of an inhibitor of
glycine type-1-transporter5 was next examined. Scheme 4
shows the results. The α-hydrazono ester 1a was treated with
3-butenylmagnesium bromide (2.5 equiv) to give the α-
bis(buten-3-yl)aminoaminde 2i in 87% yield. Metathesis using
the Grubbs second catalyst effected the formation of the
tetrahydroazepine derivative 4 in 84% yield.8 Hydroboration/
oxidation of the formed double bond of the tetrahydroazepine
ring gave the alcohol 5 in 60% yield.9 Mesylation of the
hydroxy group followed by amination with an excess amount
of 4-fluoro-3-trifluoromethylphenylmethylamine introduced
the suitably substituted benzylamino group in 72% yield.10
The final step, amide formation with 1-methyl-1H-imidazole-4-
carbonyl chloride, was readily carried out to give the target
molecule 7 in 90% yield. Thus, a short synthesis of an inhibitor
of the glycine type-1-transporter was accomplished in 28%
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Letter
Scheme 4. Transformation to an Inhibitor of Glycine Type-
1-Transporter
Scheme 5. Mechanistic Investigation
overall yield starting from a readily available α-hydrazonoester
1a.
Scheme 6. Plausible Reaction Mechanism
In order to clarify the reaction mechanism, the following
crossover and control experiments were carried out. A mixture
of an equal amount of the α-hydrazonoesters 1f and 1h was
treated with ethylmagnesium bromide (5.0 equiv) in dichloro-
methane at 0 °C for 30 min. Good yields of the α-
diethylaminoamides 2f and 2p were obtained, in which no
crossover product with respect to the amide moiety was
detected (Scheme 5a). Next, an E-isomer-rich hydrazonoester
was treated with n-pentylmagnesium bromide (2.5 equiv) to
give the α-diethylamino amide 2h in 75% yield along with a
trace amount of the α-imino amide 8 (Scheme 5b). When the
Z-α-imino amide 9 was treated with ethylmagnesium bromide
(2.5 equiv) in dichloromethane at 0 °C for 30 min, the
addition reaction did not proceed at all (Scheme 5c).
On the basis of these results as well as our previous
examination into α-alkoxyiminoesters, we propose the
following reaction mechanism (Scheme 6). First, the addition
of the Grignard reagent to the imino moiety via a chelated
intermediate A gives the magnesium enolate B. An elimination
of the dimethylamino group proceeds followed by the
amidation11,12 with the eliminated magnesium amide via the
intermediates C and D to give the α-imino amide E, which is
attacked by the second Grignard reagent to afford the α-
dialkylamino amide enolate F. Protonation furnishes the α-
dialkylamino amide 2.
synthesis of an inhibitor of glycine type-1-transporter was
readily carried out using a metathesis of the introduced
homoallylated product followed by the appropriate functional
group transformations. The present method involves a useful
amide formation by the use of an eliminated secondary amino
moiety, which contrasts the previous SN2 type reaction at the
nitrogen atom using oxime derivatives, where eliminated
moieties are just wasted.
In conclusion, we have developed a cascade reaction
including N-alkylation/amidation/N-alkylation starting from
an α-hydrazonoester to give an α-dialkylaminoamide. An
application of the present method to a straightforward
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ASSOCIATED CONTENT
* Supporting Information
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AUTHOR INFORMATION
Corresponding Authors
■
Isao Mizota − Department of Chemistry for Materials,
Graduate School of Engineering, Mie University, Tsu, Mie
514-8507, Japan; orcid.org/0000-0003-0760-677X;
Email: imizota@chem.mie-u.ac.jp
Makoto Shimizu − Department of Chemistry for Materials,
Graduate School of Engineering, Mie University, Tsu, Mie
514-8507, Japan; School of Energy Science and Engineering
College, Nanjing Tech University, Nanjing, Jiangsu 211816,
China; orcid.org/0000-0003-0467-9594;
Email: mshimizu@chem.mie-u.ac.jp
Authors
Yusuke Nakamura − Department of Chemistry for Materials,
Graduate School of Engineering, Mie University, Tsu, Mie
514-8507, Japan
Shunsuke Mizutani − Department of Chemistry for Materials,
Graduate School of Engineering, Mie University, Tsu, Mie
514-8507, Japan
Nanami Mizukoshi − Department of Chemistry for Materials,
Graduate School of Engineering, Mie University, Tsu, Mie
514-8507, Japan
Shunya Terasawa − Department of Chemistry for Materials,
Graduate School of Engineering, Mie University, Tsu, Mie
514-8507, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01117
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid for Scientific
Research (B) and on Innovative Areas “Organic Synthesis
Based on Reaction Integration. Development of New Methods
and Creation of New Substances” from JSPS and MEXT.
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