We also demonstrated the versatility of this approach by the
application of C-substituted cyanoacetic acids. Thus, difficult to
access 3-alkyl-3-cyanopyrrolidines 9j–n were obtained in
moderate to good yields via this one-step synthetic protocol.
Encouraged by previous results, we turned our attention to β-
ketoacids. Noteworthy, the latter possess the highest CH-acidity
and the least stability among all of the substrates examined
above. The reaction of benzoyl acetic acid with sarcosine,
paraformaldehyde, and pyrrolidine only led to a 46% yield of 3-
benzoylpyrrolidine 9o. This result required us to implement a
two-step approach (Table 1, entry 8) applying 37% aqueous
formaldehyde and pyrrolidine as an iminium cation source.
Pleasingly, this modification gave the desired pyrrolidine 9o in
77% yield. 3-Toluoyl- and 3-thenoylpyrrolidines 9p and 9q were
obtained in 56% and 45% yield, respectively. In addition, the
reaction of 2-acetyl hydrocinnamic acid provided a mixture of 3-
acetylpyrrolidine 9r and Mannich adduct 10 which were
separated by column chromatography.
In summary, we have developed a new approach to the
synthesis of 3-substituted N-methylpyrrolidines from monoalkyl
malonates, cyanoacetic acids or 2-ketocarboxylic acids,
sarcosine, and formaldehyde. These reactions proceed via a
double decarboxylative domino-sequence mediated by
pyrrolidine and involve β-amino acids and N-methylazomethine
ylide as intermediates. The proposed approach is of great value
owing to the operational convenience, broad substrate scope and
the rapid construction of all three C–C and one C–N bonds of the
pyrrolidine ring in one synthetic step promoted by a removable
CO2H group.
Acknowledgments
This work was financially supported by the Russian Science
Foundation (Grant 17-73-20070).
References and notes
The fact that Mannich base 10 was less reactive under the
reaction conditions indirectly provides evidence for the general
mechanism of these reactions depicted in Scheme 2. This process
therefore includes simultaneous decarboxylation and elimination
of dialkylamine from intermediate C via a six-membered
transition state. We also used the Mannich base obtained from
acetophenone, formaldehyde and pyrrolidine for the synthesis of
pyrrolidine 9o. However, only trace amounts of pyrrolidine 9o
were formed in a complex mixture of products. Thus, the
activating carboxylic acid group implements three functions in
the starting substrates 8: increases CH-acidity, promotes the
dialkylamine elimination, and ultimately leaves.
1
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NC
CH2O
MeNHCH2CO2H
pyrrolidine
CN
N
N
CO2H
PhH, reflux, 3 h
-2CO2, -2H2O
N
CN
Me
9s
11
Me
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(44%)
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N
N
B
A
Me
HO2C
HO2C
CN
CN
B
N
N
CN
-(CH2)4NH
-CO2
N
N
13
5
E
F
Scheme 3. Reaction of cyanoacetic acid. Reagents and conditions: 11 (1.0
mmol), sarcosine (1.5 mmol), (CH2O)n (4.0 mmol of CH2O), pyrrolidine (2.0
mmol), PhH, Δ, 3 h. Isolated yield based on 11 is depicted.
6
7
E.M. Buev, V.S. Moshkin, V.Y. Sosnovskikh, J. Org. Chem. 82
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