Mendeleev Commun., 2019, 29, 145–146
a successful [3+2]-cycloaddition reaction between two unstable
as the precursor of N-benzylazomethine ylide 4b. We succeeded
in expanding the conditions found to the Mannich bases obtained
from methyl(hetero)arylketones. Specifically, b-(diethylamino)-
propiophenone 3e and b-diethylamino-p-methoxypropiophenone
3f afforded 3-aroylpyrrolidines 6e and 6f in 34 and 65% yields,
respectively, while the reaction with the 2-thienyl compound 3g
gave the 3-(2-thenoyl)pyrrolidine 6g in 61% yield. One can see
that the increase in the product yield correlates with stability
of the intermediate enone formed during the thermolysis of the
Mannich base. This enone stability increases with removal of
a moiety that undergoes enolization, with incorporation of a
donor thienyl or anisyl substituent conjugated with C=O or with
involvement of a bulky tert-butyl group.
Despite the simplicity of their structures, 3-substituted pyrro-
lidines 6a–g cannot be regarded as readily available compounds,
since only the syntheses of compounds 6d and 6e were reported.6,7
At the same time, the obtained pyrrolidine derivatives are of
interest as convenient building blocks in organic and medicinal
chemistry.8
intermediates formed in situ, it is necessary for both moieties
to be formed simultaneously and in sufficient concentrations.
Further, we tested the precursors of nonstabilized azomethine
ylides, namely N-substituted spiro[anthracene-oxazolidines] 5a,b
that we reported previously.4 Refluxing the Mannich base 3a with
compound 5a in o-xylene for 4.5 h did not lead to the target
spiropyrrolidine 6a, the resulting crude mixture consisted of
contaminated starting oxazolidine 5a. However, the reaction did
occur in the same solvent at much higher temperature of 210°C
and afforded the spiropyrrolidine 6a in 31% yield. Replacement
of Mannich dimethylamino base 3a with diethylamino derivative
3b also gave the spiropyrrolidine 6a in 26% yield. The yield of
this product reached 44% with five-fold increase of the amount
of the starting compound 3b. On the other hand, both the use of
an excess of Mannich base and lowering the reaction temperature
to 190°C resulted in highly contaminated product in a poor
yield. We also attempted to involve in this reaction a widely used
precursor of N-benzylazomethine ylide 4b, i.e. N-(methoxy-
methyl)-N-(trimethylsilylmethyl)benzylamine, but the target
product was not obtained (see Table S1). Thus, of the three
methods we used to generate the azomethine ylides, only one
proved to be suitable, namely the decomposition of spiro-
[anthracene-oxazolidine] 5a at 210°C.
Thus, we were the first to find the conditions for implementing
a domino reaction between Mannich bases and spiro[anthracene-
oxazolidines]. The suggested approach expands the applicability
scope of nonstabilized azomethine ylides and allows one to
carry out their [3+2]-cycloaddition to unstable a-methylene-
ketones without the necessity to synthesize and purify the latter
compounds.
Using the conditions found,† we obtained 2-methyl-2-aza-
spiro[4.6]undecan-6-one 6b from (dimethylaminomethyl)cyclo-
heptanone 3c in 21% yield. 1-(Diethylamino)-4,4-dimethyl-
pentan-3-one 3d with a bulky tert-butyl group gave 1-methyl-
3-pivaloylpyrrolidine 6c in 76% yield. The related N-benzyl-
pyrrolidine 6d was obtained in 79% yield using oxazolidine 5b
This work was supported by the Russian Science Foundation
(grant no. 17-73-20070).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.03.008.
†
General procedure. A 10 ml microwave reaction tube was charged with
a stir bar, the Mannich base 3 (2.0 mmol),5 3'-substituted 10H-spiro-
[anthracene-9,5'-oxazolidin]-10-one 5 (2.4 mmol),4 dry o-xylene (4 ml)
and was sealed with a cap. After prestirring for 3 min, the mixture was
heated in a microwave reactor at 210°C for 45 min with stirring. After
cooling with a compressed air flow, the resulting mixture was diluted
with toluene (10 ml). The precipitate was filtered off and washed with
toluene (4 ml). The solution was extracted with cold 0.35 m HCl (20 ml)
and the aqueous phase was washed with toluene (2×12 ml). Then the
separated aqueous layer was basified with Na2CO3 to pH 9–10 and
extracted with toluene (2×10 ml). The combined organic phase was
washed with brine, dried over Na2SO4 and evaporated in vacuo to give
the product. The latter was purified by column chromatography on silica
gel with CHCl3–EtOH as eluent.
2-Methyl-2-azaspiro[4.5]decan-6-one 6a. The product was synthesized
from dimethylamino-Mannich base 3a and purified by column chromato-
graphy (eluent: CHCl3–EtOH, 100:12). Rf 0.35 (silica gel, CHCl3–EtOH,
100:15). Dark-yellow oil, yield 31%.
Pyrrolidine 6a was also synthesized from diethylamino-Mannich base
3b as a dark-yellow oil in 44% yield (10 mmol scale synthesis).
1H NMR (400 MHz, DMSO-d6) d: 1.43 (ddd, 1H, J 12.5, 7.5, 6.1 Hz),
1.6–1.8 (m, 6H), 2.17 (s, 3H, MeN), 2.23 (ddd, 1H, J 13.2, 7.6, 5.7 Hz),
2.29–2.36 (m, 4H), 2.43 (td, 1H, 3-CHH, J 8.0, 5.8 Hz), 2.74 (d, 1H,
1-CHH, J 9.4 Hz). 13C NMR (125 MHz, DMSO-d6) d: 22.2, 26.8, 33.3,
39.2, 39.4, 41.7, 55.2, 55.9, 63.7, 211.2. HRMS (ESI), m/z: 168.1385
[M+H]+ (calc. for C10H18NO+, m/z: 168.1383).
2,2-Dimethyl-1-(1-methylpyrrolidin-3-yl)propan-1-one 6c. The product
was synthesized from diethylamino-Mannich base 3d and purified by
column chromatography (eluent: CHCl3–EtOH, 100:9). Rf 0.18 (silica gel,
CHCl3–EtOH, 100:9). Dark-yellow oil, yield 76%. 1H NMR (400 MHz,
DMSO-d6) d: 1.07 (s, 9H, But), 1.73 (dddd, 1H, 4'-CHH, J 12.0, 7.9,
6.0, 4.9 Hz), 1.88 (ddt, 1H, 4'-CHH, J 12.0, 9.9, 7.2 Hz), 2.20–2.25 (m,
1H, 2'-CHH), 2.22 (s, MeN), 2.30 (q, 1H, 5'-CHH, J 7.9 Hz), 2.61 (ddd, 1H,
5'-CHH, J 8.7, 7.4, 4.9 Hz), 2.75 (t, 1H, 2'-CHH, J 8.5 Hz), 3.57 (dtd, 1H,
3'-CH, J 9.8, 7.8, 6.3 Hz). 13C NMR (125 MHz, DMSO-d6) d: 25.7, 29.5,
41.5, 43.2, 43.7, 56.0, 59.6, 216.5. HRMS (ESI), m/z: 170.1542 [M+H]+
(calc. for C10H20NO+, m/z: 170.1539).
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For characteristics of products 6b,d–g, see Online Supplementary
Materials
.
Received: 21st September 2018; Com. 18/5696
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