Nonstabilized Azomethine Ylides in the Mannich Reaction: Synthesis of 3,3-Disubstituted Pyrrolidines, Including Oxindole Alkaloids

Article abstract of DOI:10.1021/acs.joc.7b02193

Active methylene compounds react with in situ generated nonstabilized azomethine ylides via the domino Mannich reaction-dipolar cycloaddition to form 3,3-disubstituted pyrrolidines, including oxindole alkaloids. When the starting material possesses a single activated hydrogen, the reaction terminates at the Mannich base stage. The developed methodology was applied to a short and efficient synthesis of (±)-horsfiline and N-protected (±)-coerulescine.

Full text of DOI:10.1021/acs.joc.7b02193

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Note
Nonstabilized Azomethine Ylides in the Mannich Reaction. Synthesis
of 3,3-Disubstituted Pyrrolidines, Including Oxindole Alkaloids
Evgeny M. Buev, Vladimir S. Moshkin, and Vyacheslav Y. Sosnovskikh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02193 • Publication Date (Web): 19 Oct 2017
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Nonstabilized Azomethine Ylides in the Mannich Reaction. Synthesis of 3,3ꢀ
Disubstituted Pyrrolidines, Including Oxindole Alkaloids
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Evgeny M. Buev, Vladimir S. Moshkin*, and Vyacheslav Y. Sosnovskikh
Institute of Natural Sciences and Mathematics, Ural Federal University, 620000 Ekaterinburg, Russian
Federation
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Keywords: Nonstabilized azomethine ylides; Saturated azaheterocycles; Pyrrolidines; Oxindole
alkaloids; Horsfiline; [3+2] Cycloaddition; Mannich reaction; Domino reaction.
Graphical Abstract
ABSTRACT: Active methylene compounds react with in situ generated nonstabilized
azomethine ylides via domino Mannich reaction–dipolar cycloaddition to form 3,3ꢀdisubstituted
pyrrolidines, including oxindole alkaloids. When starting material possesses a single activated
hydrogen the reaction terminates at the Mannich base stage. The developed methodology was
applied in short and efficient synthesis of (±)ꢀhorsfiline and Nꢀprotected (±)ꢀcoerulescine.
Reactions of nonstabilized azomethine ylides are one of the most convenient methods for a
synthesis of various nitrogen containing compounds. Their use in the synthesis of fiveꢀmembered
azaheterocycles by [3+2] cycloadditions to multiple bonds of dipolarophiles is attractive and
frequently utilized methodology.1 The significant advantages of this approach are the easy of in
situ generation of starting ylides, the formation of two new covalent bonds of the product by
single cycloaddition step, as well as the selectivity of this process, which allows to create few
chiral centers with a specific configuration simultaneously. All aspects mentioned above make
them an indispensable tool in the synthesis of natural and biologically active compounds. A
combination of [3+2] cycloaddition of these ylides with subsequent oneꢀtwo stage oneꢀpot
transformations of primary adducts opens especially broad prospects. Thus, methods based on
the reactions of nonstabilized azomethine ylides for the synthesis of adrenergic 2ꢀalkylaminoꢀ1ꢀ
arylethanols and 3ꢀarylpyrrolidines, containing conformationally fixed phenethylamine moiety,
tetrahydroisoquinoline alkaloids, showing antihypertensive and antidepressive effects, and
*Eꢀmail: mvslc@mail.ru (V. S. Moshkin)
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tetrahydroꢀγꢀcarbolines, structurally related to antihistamine medicinal compounds, were
developed previously by a number of research groups including ours.2
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Synthetic potential of nonstabilized azomethine ylides is not limited by the [3+2]
cycloadditions (Scheme 1). Examples of 1,5ꢀ and 1,7ꢀelectrocyclizations of conjugated
azomethine ylides are also known in the literature.3 The reactions of azomethine ylides with
various nucleophilic compounds in the presence of H+ are intensively studied by Seidel and other
authors over the last 10 years.4 In the latter case, the initially formed azomethine ylide is not
involved into pericyclic reaction, but acts as a base. Iminium cation formed by this process then
reacts with internal or external Cꢀ, Nꢀ, Oꢀ, Pꢀ or Sꢀnucleophile. This direction within the scope of
simplest symmetric nonstabilized azomethine ylides with Cꢀnucleophiles was previously little
studied.4 Whereas, in perspective it should appear to be a modification of the Mannich reaction,
and thus became the subject of the present work. To the best of our knowledge, the first example
of such process was the reaction of ethyl 6ꢀphenylcomanoate with Nꢀ(methoxymethyl)ꢀNꢀ
(trimethylsilylmethyl)benzylamine described in 1999.5a Later there was another instance of the
similar reaction of pꢀhydroxybenzaldehyde.5b However, in both cases, observed reactions were
side processes and have not been further developed.
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Scheme 1. General synthetic possibilities of azomethine ylides
For the implement of our investigation, frequently utilized methods of simple nonstabilized
azomethine ylides 1a,b generation were used (Scheme 2). They are decarboxylative
condensation of Nꢀalkylꢀαꢀamino acids 2a,b with carbonyl compounds6 and desilylation of Nꢀ
(methoxymethyl)ꢀNꢀ(trimethylsilylmethyl)benzylamine (3) in the presence of TFA or LiF.7
Moreover, recently we discovered new precursors of these ylides – spiroanthraceneoxazolidines
4a,b, which are readily available from anthraquinone 5, Nꢀsubstituted glycines 2a,b and
formaldehyde.8 These at room temperature stable oxazolidines have an unique ability to undergo
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a cycloreversion in a presence of other dipolarophiles at high temperature and previously proved
to be useful and convenient reagents for the synthesis of substituted pyrrolidines.
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Scheme 2. Useful methods for the generation of nonstabilized azomethine ylides
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As a model experiment, we carried out the reaction of diethyl malonate 6 with Nꢀ
methylazomethine ylide 1a, generated in situ from sarcosine 2a and formaldehyde at reflux for 2
h in the mixture of DMF and oꢀxylene (1:1). Remarkably, this reaction did not stop at the
formation of the Mannich base 7, as it could be initially assumed. It proceeded further through
the elimination of dimethylamine from intermediate 7 and the following [3+2] cycloaddition of
formed methylenemalonate 8 with another equivalent of starting ylide 1a (Scheme 3; Table 1,
entry 1,2). The above process led to the formation of simple diethyl 1ꢀmethylpyrrolidineꢀ3,3ꢀ
dicarboxylate (9а) previously unknown in the literature.
Scheme 3. New domino reaction leading to pyrrolidine ring
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It is noteworthy that using of malonate 6 and excess of spiroanthraceneoxazolidine 4a in a
microwave reactor at 210 °C for 45 min allowed to substantially increase the yield of product 9a
(Table 1, entry 3,4). Attempts to perform the reaction at lower temperatures (refluxing in oꢀ
xylene or toluene), including those with an addition of acid or base as potential catalysts, were
not successful (Table 1, entry 5–8). On the other hand, it was discovered that reaction with
spirooxazolidine 4a can be carried out without the microwave reactor by heating of the reagents
in Nꢀmethylpyrrolidone (NMP) at 210 °C, however, the yield of the product was only 25%
(Table 1, entry 9). Thus, we propose scalable and easy for practical implementation oneꢀpot
synthesis from readily available reagents which appears to be a new, fairly competitive method
for the synthesis of various 3,3ꢀdisubstituted pyrrolidines.
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Table 1. Optimization of the reaction conditions
entry
1
conditions
yield 9 (%)
2a (1.5 equiv.), CH2O (2.3 equiv.),
DMF/oꢀxylene (1:1), reflux, 2 h
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2a (3 equiv.), CH2O (5 equiv.),
DMF/oꢀxylene (1:1), reflux, 2 h
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4a (2.5 equiv.), oꢀxylene, MW, 210
°C, 90 min
4a (2.3 equiv.), oꢀxylene, MW, 210
°C, 45 min
a
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4a (2.3 equiv.), oꢀxylene, reflux, 2 h
4a (2.3 equiv.), oꢀxylene, reflux, 5 h
–
a
–
4a (2.3 equiv.), PhCO2H (0.1 equiv.),
b
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–
toluene, reflux, 5 h
4a (1.1 equiv.), tꢀBuOK (0.5 equiv.),
b
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toluene, reflux, 2 h
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4a (2.5 equiv.), NMP, 210 °C, 45 min
3 (2.5 equiv.), LiF (4 equiv.), DMF,
MW, 210 °C, 45 min
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aMixture of product 9a and starting oxazolidine 4a 1:1
determined by 1H NMR spectroscopy data. bAccording to 1H
NMR data, the reaction mixture was in general starting 4a. In
c
contrast to product 9a synthesis (entry 1ꢀ4,9) it was necessary to
purify product 9b by column chromatography.
We also managed to carry out this domino process using previously mentioned Nꢀ
(methoxymethyl)ꢀNꢀ(trimethylsilylmethyl)benzylamine (3) as the precursor of nonstabilized
azomethine ylide 1b (R = Bn) in a presence of LiF in the microwave reactor at 210 °C for 45
min. However, pyrrolidine 9b was formed as a mixture with side benzylamines and, unlike to 9a,
was isolated after the purification by column chromatography in 47% yield (Table 1, entry 10;
Table 2).
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Table 2. Synthesis of 3,3ꢀdisubstituted pyrrolidines 9a
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aReaction conditions: methylene active compound (1.0 mmol), 4
(2.3 mmol), oꢀxylene, MW, 210 °C, 45 min. Isolated yields of
b
chromatographically purified compounds are specified. Product
9a was obtained without chromatographic purification. cNꢀ
(MeOCH2)ꢀNꢀ(Me3SiCH2)benzylamine (3) was used. dNꢀBenzyl
substituted spiroanthraceneoxazolidine 4b was used.
In the next step of our research, we investigated the reaction of spiroanthraceneoxazolidines 4
with other active methylene compounds (Table 2). As expected, we obtained dimethyl 1ꢀ
methylpyrrolidineꢀ3,3ꢀdicarboxylate (9с) in good yield. Furthermore, ethyl benzoylacetate 10
was successfully converted into pyrrolidine 9d which was observed in a mixture with
debenzoylated product 9'd. The quantity of latter was depended on the duration of the reaction
(Scheme 4). Probably, nucleophilic dimethylamine eliminated from the Mannich base or traces
of water in the reaction mixture attacked benzoyl group of the main product 9d. Subsequent
retroꢀClaisen reaction gave 3ꢀethoxycarbonylpyrrolidine 9'd. Pure pyrrolidine 9d was isolated by
column chromatography in 52% yield.
Scheme 4. Reaction of spiroanthraceneoxazolidine 4a with ethyl benzoylacetate
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aYields of the mixture of products
5ꢀMethylꢀ2ꢀphenylpyrazolꢀ3ꢀone, containing imino moiety as a second activating group, also
reacted with oxazolidine 4a to give spiropyrrolidine 9e in moderate yield. It was possible to
carry out the reaction with benzyl phenyl ketone containing activating carbonyl and phenyl
groups that resulted in pyrrolidine 9f. Moreover, chromanꢀ4ꢀone, having only one activating
ketoꢀgroup conjugated with electronꢀdonating oxygen, also reacted with oxazolidine 4a and
allowed to isolate spiroꢀfused pyrrolidine 9g. In spite of this, reactions of 4a with methyl
phenylacetate as well as with phenylacetonitrile were not successful. Thus, substrates with
conformationally free weak activating groups are not suitable for this process.
A point of special interest was the investigation of the reaction between spirooxazolidines 4
and indolinꢀ2ꢀones that could lead to the formation of oxindole alkaloids coerulescine and
horsfiline 9h (Table 2). The latter was isolated from the plant Horsfieldia superba and has
attracted significant attention of scientific society as analgesic medicinal compound.9 We
discovered that unsubstituted indolinꢀ2ꢀone reacted with spiroanthraceneoxazolidine 4a to form
hard to purify coerulescine in low yield. The cause of this is, presumably, a competitive acidic
amide moiety. Nevertheless, 5ꢀmethoxyindolinꢀ2ꢀone reacted readily due to the presence in its
structure of one electronꢀdonating substituent in the para position relative to 1ꢀNH that,
apparently, decreases its acidity. As the result, (±)ꢀhorsfiline 9h was obtained in 57% yield.
Gratifyingly, 1ꢀsubstituted indolinꢀ2ꢀones smoothly reacted with azomethine ylides precursors
4 to give spirooxindoles 9i–l in good to high yields (60–80%). Taking into account the fact that
method for a debenzylation of 9i in high yield (83%) is known in the literature,10 such twoꢀstep
approach to the synthesis of coerulescine is pretty attractive.
Unfortunately, attempt to involve in this process such conformationally free ketone as
acetophenone was not successful. The reactions failed also with acidic compounds which are
capable to a selfꢀcondensation (acetylacetone, indanꢀ1,3ꢀdione, diethyl 3ꢀketoglutarate,
malononitrile). In general, it can be concluded that only one ketoꢀgroup in conformationally
fixed methylene active compound or two electronꢀwithdrawing groups in conformationally free
substrate are sufficient for this process. Despite these limits, it is obvious that discovered domino
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reaction could be achieved on a wide range of CH2ꢀacidic compounds. Thus, proposed
azomethine ylide methodology for the rapid construction of the spirocyclic systems in one stage
provides an efficient and straightforward access to various spiropyrrolidines, which are difficult
to synthesize by other methods.
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In view of the fact that probable intermediate of this domino process is unstable Mannich base
7 (Scheme 3), we decided to isolate it using substituted CHꢀacidic substrates which are unable to
eliminate dimethylamine. For this purpose, we carried out the reaction of
spiroanthraceneoxazolidine 4a with diethyl benzylmalonate 11a (Scheme 5).
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Scheme 5. Dimethylaminomethylation of 11a by spiroanthraceneoxazolidine 4a
Table 3. Optimization of the reaction conditions
yield (%)
12a
entry
conditions
4a (2.3 equiv.), oꢀxylene, MW, 210
°C, 45 min
a
1
2
3
–
4a (1.4 equiv.), oꢀxylene, MW, 210
°C, 60 min
67b
4a (1.0 equiv.), 11a (1.5 equiv.), oꢀ
xylene, MW, 210 °C, 45 min
65c
sarcosine 2a (1.5 equiv.) and
formaldehyde (2.25 equiv.),
DMF/oꢀxylene (1:1), reflux, 2 h
4
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aMixture of product 12a and starting oxazolidine 4a 2:1
1
b
(determined by H NMR spectroscopy data). Product 12a was
contaminated with difficult to separate initial oxazolidine 4a.
cIsolated yield based on the starting spiroanthraceneoxazolidine
4a.
Indeed, previously found conditions for the annulation (2.3 equiv. of spiroꢀfused oxazolidine
4a, heating at 210 °C) resulted in the insertion of azomethine ylide into C–H bond. However,
obtained product 12a was in the mixture with initial spiroanthraceneoxazolidine 4a. A simple
modification of the reaction conditions consisted in using of 1.5 equiv. excess of starting
benzylmalonate allowed us to isolate pure Mannich base 12a in 65% yield. As a side note,
nonstabilized azomethine ylide 1a, generated in situ from sarcosine and formaldehyde, also
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reacted with diethyl benzylmalonate 11a to give Mannich adduct 12a but in significantly lower
yield (Table 3, entry 4).
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In connection with these results, we examined such reaction on a number of other CHꢀacidic
compounds and successfully obtained corresponding amines 12b–d in 59–84% yields (Table 4).
Notably, this synthesis does not require chromatographic purification. Due to a simple
implementation, discovered dimethylaminomethylation reaction is an unusual modification of
Mannich reaction. Spiroꢀoxazolidine 4а can be considered as the basic analog of Eschenmoser
salt in this light.
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Table 4. Synthesis of Mannich products 12a
aReaction conditions: CHꢀacidic compound
(1.5 mmol), 4a (1.0 mmol), oꢀxylene, MW,
210 °C, 45 min. Isolated yields based on
starting spiroanthraceneoxazolidine 4a.
In summary, it could be concluded that reactions of CHꢀacidic compounds with nonstabilized
azomethine ylides possess a general nature and depending on number of reactive hydrogens
either stop on the Mannich base formation or proceed through the domino process resulted in the
formation of new pyrrolidine ring. In the first case, Nꢀalkylazomethine ylides are protonated and
act as Mannich iminium cations, while in the second one, they act as a synthetic equivalent of
formaldehyde and as 1,3ꢀdipole. The application of strained spiroanthraceneoxazolidines 4 was
especially effective in these reactions that allowed to significantly expand synthetic possibilities
of nonstabilized azomethine ylides. Discovered approach is particularly actual in view of new
perspective way to biologically active spiroꢀoxindole alkaloids and related to them 3,3ꢀ
disubstituted pyrrolidines.
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EXPERIMENTAL SECTION
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General Experimental Details. All solvents used were dried and distilled per standard
procedures. Microwave syntheses were performed in a sealed tube in Biotage Initiator+,
temperature was monitored by external surface sensor. Column chromatography was performed
with silica gel (40–63 ꢁm, ASTM). Chloroform, mixture of chloroform and ethanol (from 200/1
to 20/1), mixture of dichloromethane and ethanol (20/1) were used as eluents. NMR spectra were
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recorded on Bruker DRXꢀ400 (1H – 400 MHz and C – 101 MHz) and Bruker Avance IIIꢀ500
(1H – 500 MHz and 13C – 126 MHz) spectrometers in DMSOꢀd6, CDCl3. The chemical shifts are
reported in ppm relative to internal standard TMS (1H NMR) and to residual signals of the
solvents (13C NMR). The HRMS spectra were obtained using UHRꢀQq TOF mass spectrometer
maX is Impact HD (Bruker Daltonics) installed in the Institute of Organic Synthesis UB RAS.
Electrospray ionization with direct sample inlet (flow rate 240 ꢁL/h) was used. The mass
spectrometer was operating in positive mode in the mass range of 50–1550 Da.
General procedure for the synthesis of pyrrolidines 9aꢀl and Mannich adducts 12aꢀd. A 10
mL microwave reaction tube was charged with a stir bar, the corresponding active methylene
compound (1.0 mmol), 10Hꢀspiro[anthraceneꢀ9,5'ꢀoxazolidin]ꢀ10ꢀone 4 (2.3 mmol),8a dry oꢀ
xylene (3 mL) and was filled with an argon atmosphere, before it was sealed with a cap. After
preꢀstirring for 3 min the mixture was heated in microwave reactor at 210 °C for 45 min with
stirring. After cooling with a compressed air flow the resulting mixture was diluted with PhMe
(5 mL). The precipitate was filtered off. The solution was extracted with cold 1 M HCl (10 mL)
and aqueous phase was washed with PhMe (2 × 5 mL). The aqueous layer was basified with
NaHCO3 to pH = 8–9, extracted with PhMe (2 × 5 mL), dried over Na2SO4 and evaporated under
reduced pressure to give the desired product. The latter, if necessary, was purified by column
chromatography.
Specific procedures for the synthesis of pyrrolidines from diethyl malonate by action of
various nonstabilized azomethine ylide precursors. Procedure A for the synthesis of
pyrrolidines without microwave reactor. A 10 mL roundꢀbottom flask was charged with a stir
bar, diethyl malonate 6 (160 mg, 1.0 mmol), 3′ꢀmethylꢀ10Hꢀspiro[anthraceneꢀ9,5'ꢀoxazolidin]ꢀ
10ꢀone 4a (610 mg, 2.3 mmol), dry Nꢀmethylꢀ2ꢀpyrrolidone (3 mL), reflux condenser and CaCl2
tube. Mixture was heated on oil bath at 210 °C for 45 min with stirring. After cooling to room
temperature the resulting mixture was diluted with H2O (15 mL) and extracted with PhMe (2 × 5
mL). The precipitate was filtered off. The organic phase was extracted with cold 1 M HCl (10
mL). The aqueous phase was washed with PhMe (2 × 5 mL) and then it was basified with
NaHCO3 to pH = 8–9, extracted with PhMe (2 × 5 mL), dried over Na2SO4 and evaporated under
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reduced pressure to give the desired diethyl 1ꢀmethylpyrrolidineꢀ3,3ꢀdicarboxylate 9a in 25%
yield (57 mg).
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Procedure B for the synthesis of pyrrolidines using sarcosine and paraformaldehyde. A
mixture of the diethyl malonate 6 (160 mg, 1.0 mmol), finely ground sarcosine 2a (267 mg, 3.0
mmol), and paraformaldehyde (150 mg, 5.0 mmol of formaldehyde) was heated at reflux in the
mixture of dry oꢀxylene and dry DMF (1:1, 8 mL) in a 25 mL roundꢀbottom flask fitted with a
DeanꢀStark trap for 2 h on oil bath previously warmed up to 170 °C. After cooling to room
temperature the resulting mixture was washed with H2O (3 × 5 mL). The solution was extracted
with cold 1 M HCl (10 mL). The aqueous phase was washed with PhMe (2 × 5 mL) and then it
was basified with NaHCO3 to pH = 8–9, extracted with PhMe (2 × 5 mL), dried over Na2SO4
and evaporated under reduced pressure to give the desired diethyl 1ꢀmethylpyrrolidineꢀ3,3ꢀ
dicarboxylate 9a in 38% yield (87 mg).
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(trimethylsilylmethyl)benzylamine. A 10 mL microwave reaction tube was charged with a stir
bar, diethyl malonate (160 mg, 1.0 mmol), Nꢀ(methoxymethyl)ꢀNꢀ
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for the synthesis of pyrrolidines using Nꢀ(methoxymethyl)ꢀNꢀ
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(trimethylsilylmethyl)benzylamine (3) (2.5 mmol, 592 mg),7e lithium fluoride (104 mg, 4.0
mmol), dry DMF (3 mL) and was filled with an argon atmosphere, before it was sealed with a
cap. After preꢀstirring for 3 min the mixture was heated in microwave reactor at 210 °C for 45
min with stirring. After cooling with a compressed air flow the resulting mixture was diluted
with PhMe (8 mL) and was washed with H2O (3 × 5 mL). The solution was extracted with cold 1
M HCl (10 mL). The aqueous phase was washed with PhMe (2 × 5 mL) and then it was basified
with NaHCO3 to pH = 8–9, extracted with PhMe (2 × 5 mL), dried over Na2SO4 and evaporated
under reduced pressure to give the crude product. The latter was purified by column
chromatography (eluent: chloroform; Rf (chloroform/methanol, 100/2) = 0.6) to give pure diethyl
1ꢀbenzylpyrrolidineꢀ3,3ꢀdicarboxylate 9b in 47% yield (144 mg).
Diethyl 1ꢀmethylpyrrolidineꢀ3,3ꢀdicarboxylate (9а). Compound 9a was synthesized according
to the general procedure from diethyl malonate. Light brown oil, yield 147 mg (64%). 1H NMR
(400 MHz, CDCl3) δ 4.20 (q, J = 7.1 Hz, 4H, 2CO2CH2CH3), 3.03 (s, 2H, 2ꢀCH2), 2.62 (t, J =
6.8 Hz, 2H), 2.44 (t, J = 6.8 Hz, 2H), 2.35 (s, 3H, MeN), 1.25 (t, J = 7.1 Hz, 6H, 2CO2CH2CH3);
13C NMR (126 MHz, CDCl3) δ 171.4 (2C=O), 62.6 (2ꢀCH2), 61.7 (2CH2O), 59.8 (3ꢀC), 55.9 (5ꢀ
CH2), 41.8 (CH3N), 33.2 (4ꢀCH2), 14.1 (2CH3). HRMS (ESI) calcd for (C11H20NO4)+ [M+H]+:
230.1387, found: 230.1391.
Diethyl 1ꢀbenzylpyrrolidineꢀ3,3ꢀdicarboxylate (9b). Compound 9b was synthesized according
to the procedure C from diethyl malonate 6 (160 mg, 1.0 mmol) and Nꢀ(methoxymethyl)ꢀNꢀ
(trimethylsilylmethyl)benzylamine (3) (2.5 mmol, 592 mg). Crude product was purified by
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column chromatography (eluent: chloroform; Rf (chloroform/methanol, 100/2) = 0.6). Light
yellow oil, yield 144 mg (47%). 1H NMR (500 MHz, CDCl3) δ 7.34–7.28 (m, 4H, Ph), 7.26–7.22
(m, 1H, Ph), 4.19 (q, J = 7.1 Hz, 4H, 2CO2CH2CH3), 3.64 (s, 2H, PhCH2), 3.05 (s, 2H, 2ꢀCH2),
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NMR (101 MHz, CDCl3) δ 171.4 (2C=O), 138.8 (C), 128.7 (2CH), 128.4 (2CH), 127.1 (CH),
61.7 (2CH2O), 60.1, 59.54, 59.45, 53.5 (CH2), 32.7 (4ꢀCH2), 14.2 (2CH3). HRMS (ESI) calcd for
(C17H24NO4)+ [M+H]+: 306.1700, found: 306.1703.
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Dimethyl 1ꢀmethylpyrrolidineꢀ3,3ꢀdicarboxylate (9c). Compound 9c was synthesized
according to the general procedure from dimethyl malonate. Crude product was purified by
column chromatography (eluent: chloroform/ethanol, 100/1; Rf (chloroform/ethanol, 100/2) =
1
0.2). Yellow oil, yield 135 mg (67%). H NMR (500 MHz, DMSOꢀd6) δ 3.66 (s, 6H, 2CO2Me),
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2.89 (s, 2H, 2ꢀCH2), 2.48 (t, J = 6.9 Hz, 2H), 2.29 (t, J = 6.9 Hz, 2H), 2.21 (s, 3H, MeN); C
NMR (126 MHz, DMSOꢀd6) δ 171.0 (2C=O), 61.9 (2ꢀCH2), 59.1 (3ꢀC), 55.0 (5ꢀCH2), 52.8
(2CH3O), 41.1 (CH3N), 32.5 (4ꢀCH2). HRMS (ESI) calcd for (C9H16NO4)+ [M+H]+: 202.1074,
found: 202.1077.
Ethyl 3ꢀbenzoylꢀ1ꢀmethylpyrrolidineꢀ3ꢀcarboxylate (9d). Compound 9d was synthesized
according to the general procedure from ethyl benzoylacetate. Crude product was purified by
column chromatography (eluent: chloroform/ethanol, 100/1; Rf (chloroform/ethanol, 100/2) =
1
0.3). Light yellow oil, yield 136 mg (52%). H NMR (500 MHz, CDCl3) δ 7.85 (dd, J = 8.4, 1.1
Hz, 2H, 2,6ꢀHPh), 7.54 (t, J = 7.4 Hz, 1H, 4ꢀHPh), 7.43 (t, J = 7.8 Hz, 2H, 3,5ꢀHPh), 4.10 (q, J =
7.1 Hz, 2H, CO2CH2CH3), 3.32 (d, J = 10.0 Hz, 1H, 2ꢀCHH), 3.09 (d, J = 10.0 Hz, 1H, 2ꢀCHH),
2.74–2.68 (m, 1H), 2.66–2.61 (m, 2H), 2.58 (dd, J = 9.3, 6.0 Hz, 1H), 2.39 (s, 3H, MeN), 1.02 (t,
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J = 7.1 Hz, 3H, CO2CH2CH3); C NMR (101 MHz, CDCl3) δ 194.3 (COPh), 173.2 (COOEt),
135.2 (C), 133.0 (CH), 129.0 (2CH), 128.7 (2CH), 63.7 (3ꢀC), 62.5 (CH2), 61.8 (CH2), 56.2
(CH2), 41.9 (CH3N), 33.8 (4ꢀCH2), 13.8 (CH3). HRMS (ESI) calcd for (C15H20NO3)+ [M+H]+:
262.1438, found: 262.1440.
4,7ꢀDimethylꢀ2ꢀphenylꢀ2,3,7ꢀtriazaspiro[4.4]nonꢀ3ꢀenꢀ1ꢀone (9e). Compound 9e was
synthesized according to the general procedure from 5ꢀmethylꢀ2ꢀphenylꢀ2,4ꢀdihydroꢀ3Hꢀ
pyrazolꢀ3ꢀone. Crude product was purified by column chromatography (eluent:
chloroform/ethanol, 100/1; Rf (chloroform/ethanol, 100/2) = 0.25). Yellow oil, yield 102 mg
(42%). 1H NMR (400 MHz, DMSOꢀd6) δ 7.83 (dd, J = 8.7, 1.1 Hz, 2H, 2,6ꢀHPh), 7.42 (app dd, J
= 8.7, 7.3 Hz, 2H, 3,5ꢀHPh), 7.18 (tt, J = 7.3, 1.1 Hz, 1H, 4ꢀHPh), 3.01 (d, J = 10.0 Hz, 1H, 6ꢀ
CHH), 2.94 (ddd, J = 8.4, 7.4, 3.8 Hz, 1H, 8ꢀCHH), 2.5–2.4 (masked, 1H, 8ꢀCHH), 2.45 (d, J =
10.0 Hz, 1H, 6ꢀCHH), 2.32 (s, 3H, 7ꢀMeN), 2.14 (s, 3H, 1ꢀMe), 2.15–2.08 (m, 1H, 9ꢀCHH), 2.04
(ddd, J = 13.1, 7.8, 3.8 Hz, 1H, 9ꢀCHH); 13C NMR (101 MHz, DMSOꢀd6) δ 175.5 (C=O), 164.6
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(C=N), 138.0 (C), 128.9 (2CH), 124.5 (CH), 118.0 (2CH), 62.3 (2ꢀCH2), 58.5 (3ꢀC), 55.8 (5ꢀ
CH2), 41.0 (CH3N), 33.4 (4ꢀCH2), 13.8 (CH3). HRMS (ESI) calcd for (C14H18N3O)+ [M+H]+:
244.1445, found: 244.1448.
(1ꢀMethylꢀ3ꢀphenylpyrrolidinꢀ3ꢀyl)(phenyl)methanone (9f). Compound 9f was synthesized
according to the general procedure from 1,2ꢀdiphenylethanꢀ1ꢀone, except that a mixture of cold
1 M HCl (10 mL) and MeOH (2 mL) was used for the extraction of corresponding pyrrolidine
from the reaction mixture instead of 1 M HCl (10 mL). Crude product was purified by column
chromatography (eluent: chloroform/ethanol from 100/1 to 100/5; Rf (chloroform/ethanol, 100/2)
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= 0.1). Light yellow oil, yield 133 mg (50%). H NMR (500 MHz, CDCl3) δ 7.64 (dd, J = 8.3,
1.1 Hz, 2H, Ph), 7.39 (t, J = 7.4 Hz, 1H, Ph), 7.34–7.29 (m, 4H, Ph), 7.26 (t, J = 7.8 Hz, 2H, Ph),
7.24–7.20 (m, 1H, Ph), 3.33 (d, J = 10.0 Hz, 1H, 2ꢀCHH), 2.98 (d, J = 10.0 Hz, 1H, 2ꢀCHH),
2.90 (ddd, J = 13.5, 7.7, 5.6 Hz, 1H, 4ꢀCHH), 2.74 (td, J = 8.2, 5.6 Hz, 1H, 5ꢀCHH), 2.65 (q, J =
7.7 Hz, 1H, 5ꢀCHH), 2.36 (s, 3H, MeN), 2.32 (ddd, J = 13.5, 7.7, 6.5 Hz, 1H, 4ꢀCHH); 13C NMR
(101 MHz, CDCl3) δ 200.1 (C=O), 144.4 (C), 135.7 (C), 132.1 (CH), 130.2 (2CH), 129.2 (2CH),
128.2 (2CH), 126.8 (CH), 125.9 (2CH), 66.4 (2ꢀCH2), 62.4 (3ꢀC), 56.6 (5ꢀCH2), 42.4 (CH3N),
37.3 (4ꢀCH2); HRMS (ESI) calcd for (C18H20NO)+ [M+H]+: 266.1540, found: 266.1536.
1'ꢀMethylspiro[chromaneꢀ3,3'ꢀpyrrolidin]ꢀ4ꢀone (9g). Compound 9g was synthesized
according to the general procedure using chromanꢀ4ꢀone. Crude product was purified by
column chromatography (eluent: chloroform/ethanol from 100/1.5 to 100/4; Rf
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(chloroform/ethanol, 100/3) = 0.14). Light brown oil, yield 96 mg (44%). H NMR (500 MHz,
CDCl3) δ 7.92 (dd, J = 7.9, 1.7 Hz, 1H, 5ꢀHAr), 7.48 (ddd, J = 8.3, 7.5, 1.7 Hz, 1H, 7ꢀHAr), 7.03
(t, J = 7.6 Hz, 1H, 6ꢀHAr), 6.97 (d, J = 8.3 Hz, 1H, 8ꢀHAr), 4.39 (d, J = 11.3 Hz, 1H, 2ꢀCHH),
4.27 (d, J = 11.3 Hz, 1H, 2ꢀCHH), 2.93–2.90 (m, 1H, 5'ꢀCHH), 2.90 (d, J = 9.8 Hz, 1H, 2'ꢀ
CHH), 2.59 (d, J = 9.8 Hz, 1H, 2'ꢀCHH), 2.53 (q, J = 8.3 Hz, 1H, 5'ꢀCHH), 2.39 (s, 3H, 1'ꢀ
NMe), 2.34 (ddd, J = 12.9, 7.7, 3.6 Hz, 1H, 4'ꢀCHH), 1.73 (dt, J = 12.9, 7.9 Hz, 1H, 4'ꢀCHH);
13C NMR (126 MHz, CDCl3) δ 194.8 (C=O), 161.5 (CꢀO), 136.0 (CH), 128.0 (CH), 121.6 (CH),
120.2 (C), 117.9 (CH), 73.9 (CH2O), 60.7 (2'ꢀCH2), 56.2 (5'ꢀCH2), 52.5 (3ꢀC), 41.8 (CH3N), 31.0
(4'ꢀCH2). HRMS (ESI) calcd for (C13H16NO2)+ [M+H]+: 218.1176, found: 218.1180.
Horsfiline (5ꢀmethoxyꢀ1'ꢀmethylspiro[indolineꢀ3,3'ꢀpyrrolidin]ꢀ2ꢀone) (9h). A 10 mL
microwave reaction tube was charged with a stir bar, 5ꢀmethoxyindolinꢀ2ꢀone (1.0 mmol), 3′ꢀ
methylꢀ10Hꢀspiro[anthraceneꢀ9,5'ꢀoxazolidin]ꢀ10ꢀone 4a (2.5 mmol, 663 mg), dry oꢀxylene (3
mL) and was filled with an argon atmosphere, before it was sealed with a cap. After preꢀstirring
for 3 min the mixture was heated in microwave reactor at 225 °C for 45 min with stirring. After
cooling with a compressed air flow the resulting mixture was diluted with PhMe (5 mL). The
precipitate was filtered off. The solution was extracted with cold 1 M HCl (10 mL) and aqueous
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phase was washed with PhMe (2 × 5 mL). The aqueous layer was basified with NaHCO3 to pH =
10, extracted with DCM (2 × 5 mL), dried over Na2SO4 and evaporated under reduced pressure.
The residue was dissolved in MeOH (5 mL) and 11.5 M HCl (3 mmol, 0.26 mL) was added.
Mixture was refluxed for 1.5 h, cooled to rt, basified with NaHCO3 to pH = 10, extracted with
DCM (2 × 5 mL), dried over Na2SO4 and evaporated under reduced pressure. Crude product was
purified by column chromatography (eluent: dichloromethane/ethanol, 100/5; Rf
(dichloromethane/methanol, 9/1) = 0.4) and then it was recrystallized from hexane with small
amount of acetone. Beige powder, yield 132 mg (57%), mp 153–156 °C (in ref 10 mp 154–156
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°C). H NMR (400 MHz, DMSOꢀd6) δ 6.92–6.90 (m, 1H, 4ꢀHAr), 6.8–6.7 (m, 2H, 7,6ꢀHAr),
3.70 (s, 3H, OMe), 3.01 (td, J = 7.9, 4.1 Hz, 1H, 5'ꢀCHH), 2.74 (d, J = 9.0 Hz, 1H, 2'ꢀCHH),
2.57 (d, J = 9.0 Hz, 1H, 2'ꢀCHH), 2.50–2.43 (m, 1H, 5'ꢀCHH), 2.34 (s, 3H, 1'ꢀNMe), 2.16 (ddd, J
= 12.3, 7.9, 4.1 Hz, 1H, 4'ꢀCHH), 1.90 (dt, J = 12.3, 7.9 Hz, 1H, 4'ꢀCHH); 13C NMR (126 MHz,
DMSOꢀd6) δ 180.8 (C=O), 155.1 (CꢀO), 137.9 (C), 134.4 (C), 112.1 (CH), 110.0 (CH), 109.4
(CH), 66.0 (2'ꢀCH2), 56.1 (5'ꢀCH2), 55.4 (CH3O), 53.5 (3ꢀC), 41.5 (CH3N), 37.3 (4'ꢀCH2).
HRMS (ESI) calcd for (C13H17N2O2)+ [M+H]+: 233.1285, found: 233.1287.
1ꢀBenzylꢀ1'ꢀmethylspiro[indolineꢀ3,3'ꢀpyrrolidin]ꢀ2ꢀone (9i). Compound 9i was synthesized
according to the general procedure using 1ꢀbenzylindolinꢀ2ꢀone, except that a mixture of cold 1
M HCl (10 mL) and MeOH (2 mL) was used for the extraction of corresponding pyrrolidine
from the reaction mixture instead of 1 M HCl (10 mL). Crude product was purified by column
chromatography (eluent: chloroform/ethanol, 100/0.5; Rf (DCM/ethanol, 100/2) = 0.27). Viscous
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light yellow oil, yield 213 mg (73%). H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.4 Hz, 1H, 4ꢀ
HAr), 7.34–7.23 (m, 5H), 7.15 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H, 5ꢀHAr), 6.70 (d, J =
7.7 Hz, 1H, 7ꢀHAr), 4.91 (s, 2H, 1ꢀNCH2Ph), 3.22 (br s, 1H), 3.09 (br s, 1H), 2.94 (d, J = 9.6 Hz,
1H, 2'ꢀCHH), 2.89 (q, J = 8.3 Hz, 1H, 5'ꢀCHH), 2.56 (s, 3H, 1'ꢀNMe), 2.43 (ddd, J = 12.7, 7.5,
3.7 Hz, 1H, 4'ꢀCHH), 2.28–2.18 (m, 1H, 4'ꢀCHH); 13C NMR (126 MHz, CDCl3) δ 180.5 (C=O),
142.1 (C), 136.1 (C), 135.7 (C), 128.9 (2CH), 127.8 (CH), 127.7 (CH), 127.4 (2CH), 123.3
(CH), 123.1 (CH), 108.9 (CH), 66.4 (2'ꢀCH2), 56.8 (5'ꢀCH2), 53.4 (3ꢀC), 43.9, 42.0, 38.2 (CH2).
HRMS (ESI) calcd for (C19H21N2O)+ [M+H]+: 293.1649, found: 293.1653.
1,1'ꢀDimethylspiro[indolineꢀ3,3'ꢀpyrrolidin]ꢀ2ꢀone (9j). Compound 9j was synthesized
according to the general procedure from 1ꢀmethylindolinꢀ2ꢀone. Crude product was purified by
column chromatography (eluent: chloroform/ethanol, 100/1; Rf (chloroform/ethanol, 100/6) =
0.35). Viscous light yellow oil, yield 140 mg (65%). 1H NMR (500 MHz, DMSOꢀd6) δ 7.36 (dd,
J = 7.5, 0.6 Hz, 1H, 4ꢀHAr), 7.27 (td, J = 7.6, 0.6 Hz, 1H, 6ꢀHAr), 7.04 (t, J = 7.6 Hz, 1H, 5ꢀ
HAr), 6.98 (d, J = 7.7 Hz, 1H, 7ꢀHAr), 3.13 (s, 3H, 1ꢀNMe), 3.03 (td, J = 8.1, 4.3 Hz, 1H, 5'ꢀ
CHH), 2.72 (d, J = 9.0 Hz, 1H, 2'ꢀCHH), 2.60 (d, J = 9.0 Hz, 1H, 2'ꢀCHH), 2.52 (q, J = 8.1 Hz,
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12.5, 7.6 Hz, 1H, 4'ꢀCHH); C NMR (126 MHz, DMSOꢀd6) δ 178.9 (C=O), 142.6 (C), 135.8
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(C), 127.6 (CH), 122.6 (CH), 122.5 (CH), 108.1 (CH), 66.0 (2'ꢀCH2), 56.1 (5'ꢀCH2), 52.6 (3ꢀC),
41.5 (1'ꢀNCH3), 37.3 (4'ꢀCH2), 26.1 (1ꢀNCH3). HRMS (ESI) calcd for (C13H17N2O)+ [M+H]+:
217.1336, found: 217.1339.
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1'ꢀBenzylꢀ1ꢀmethylspiro[indolineꢀ3,3'ꢀpyrrolidin]ꢀ2ꢀone (9k). Compound 9k was synthesized
according to the general procedure using 1ꢀmethylindolinꢀ2ꢀone (1.0 mmol, 147 mg) and Nꢀ
benzylꢀ10Hꢀspiro[anthraceneꢀ9,5'ꢀoxazolidin]ꢀ10ꢀone 4b (2.5 mmol, 853 mg), except that a
mixture of cold 1 M HCl (10 mL) and MeOH (2 mL) was used for the extraction of
corresponding pyrrolidine from the reaction mixture instead of 1 M HCl (10 mL). Crude product
was purified by column chromatography (eluent: chloroform/ethanol, 100/0.5; Rf
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(chloroform/ethanol, 100/2) = 0.28). Beige solid, yield 234 mg (80%), mp 92–93 °C. H NMR
(500 MHz, DMSOꢀd6) δ 7.44 (dd, J = 7.4, 0.8 Hz, 1H, 4ꢀHAr), 7.37 (d, J = 7.3 Hz, 2H, Ph), 7.32
(t, J = 7.5 Hz, 2H, Ph), 7.27 (td, J = 7.7, 0.8 Hz, 1H, 6ꢀHAr), 7.24 (t, J = 7.6 Hz, 1H, Ph), 7.07 (t,
J = 7.6 Hz, 1H, 5ꢀHAr), 6.98 (d, J = 7.8 Hz, 1H, 7ꢀHAr), 3.72 (d, J = 13.2 Hz, 1H, 1'ꢀNCHHPh),
3.69 (d, J = 13.2 Hz, 1H, 1'ꢀNCHHPh), 3.12 (s, 3H, 1ꢀNMe), 3.08 (td, J = 8.1, 4.2 Hz, 1H, 5'ꢀ
CHH), 2.73 (d, J = 9.0 Hz, 1H, 2'ꢀCHH), 2.65 (d, J = 9.0 Hz, 1H, 2'ꢀCHH), 2.59 (q, J = 8.1 Hz,
1H, 5'ꢀCHH), 2.20 (ddd, J = 12.7, 8.3, 4.2 Hz, 1H, 4'ꢀCHH), 1.93 (dt, J = 12.7, 7.7 Hz, 1H, 4'ꢀ
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CHH); C NMR (126 MHz, DMSOꢀd6) δ 178.6 (C=O), 142.6 (C), 139.0 (C), 135.8 (C), 128.4
(2CH), 128.2 (2CH), 127.7 (CH), 126.9 (CH), 122.6 (CH), 122.5 (CH), 108.2 (CH), 63.7 (CH2),
58.7 (CH2), 53.6 (CH2), 52.0 (3ꢀC), 36.5 (4'ꢀCH2), 26.1 (1ꢀNCH3). HRMS (ESI) calcd for
(C19H21N2O)+ [M+H]+: 293.1649, found: 293.1639.
1'ꢀMethylꢀ1ꢀpentylspiro[indolineꢀ3,3'ꢀpyrrolidin]ꢀ2ꢀone (9l). Compound 9l was synthesized
according to the general procedure using 1ꢀpentylindolinꢀ2ꢀone. Crude product was purified by
column chromatography (eluent: chloroform/ethanol, 100/2; Rf (chloroform/ethanol, 100/5) =
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0.27). Viscous light yellow oil, yield 163 mg (60%). H NMR (500 MHz, CDCl3) δ 7.62–7.55
(m, 1H, 4ꢀHAr), 7.27 (td, J = 7.7, 1.0 Hz, 1H, 6ꢀHAr), 7.09 (t, J = 7.5 Hz, 1H, 5ꢀHAr), 6.83 (d, J
= 7.8 Hz, 1H, 7ꢀHAr), 3.71 (dt, J = 14.5, 7.4 Hz, 1H, 1ꢀNCHH), 3.67 (dt, J = 14.5, 7.4 Hz, 1H,
1ꢀNCHH), 3.34 (br s, 1H), 3.25 (br s, 1H), 3.00 (br s, 1H), 2.93 (d, J = 9.7 Hz, 1H, 5'ꢀCHH),
2.63 (s, 3H, 1'ꢀNMe), 2.35 (ddd, J = 12.7, 7.2, 3.2 Hz, 1H, 4'ꢀCHH), 2.30 (br s, 1H), 1.68 (quint,
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J = 7.4 Hz, 2H, CH2), 1.39–1.30 (m, 4H, 2CH2), 0.90 (t, J = 7.0 Hz, 3H, CH3); C NMR (101
MHz, CDCl3) δ 180.2 (C=O), 142.4 (C), 136.2 (C), 127.7 (CH), 123.3 (CH), 122.7 (CH), 108.1
(CH), 66.5 (2'ꢀCH2), 56.9 (5'ꢀCH2), 53.4 (3ꢀC), 42.0, 40.2, 38.1 (CH2), 29.1 (CH2), 27.2 (CH2),
22.4 (CH2), 14.1 (CH3). HRMS (ESI) calcd for (C17H25N2O)+ [M+H]+: 273.1961, found:
273.1964.
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Diethyl 2ꢀbenzylꢀ2ꢀ((dimethylamino)methyl)malonate (12a). Compound 12a was synthesized
according to the general procedure using Nꢀmethylꢀ10Hꢀspiro[anthraceneꢀ9,5'ꢀoxazolidin]ꢀ10ꢀ
one 4a (1.0 mmol, 265 mg) and diethyl 2ꢀbenzylmalonate 11a (1.5 mmol, 375 mg) without
additional purification. Product decomposes on silicaꢀgel (column chromatography eluent –
chloroform) with the formation of starting compound probably by retroꢀMannich reaction. Light
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yellow oil, yield 200 mg (65% based on starting oxazolidine 4a). H NMR (500 MHz, DMSOꢀ
d6) δ 7.27 (t, J = 7.3 Hz, 2H, 3,5ꢀHPh), 7.22 (t, J = 7.3 Hz, 1H, 4ꢀHPh), 7.12 (d, J = 7.3 Hz, 2H,
2,6ꢀHPh), 4.10 (app q, J = 7.1 Hz, 4H, 2CO2CH2CH3), 3.24 (s, 2H, PhCH2), 2.60 (s, 2H, NCH2),
2.16 (s, 6H, NMe2), 1.16 (t, J = 7.1 Hz, 6H, 2CO2CH2CH3); 13C NMR (126 MHz, DMSOꢀd6) δ
170.1 (2C=O), 136.1 (C), 129.9 (2CH), 128.1 (2CH), 126.8 (CH), 61.0 (2CH2O), 59.7 (CH2N),
58.6 (C), 46.3 ((CH3)2N), 36.2 (CH2Ph), 13.8 (2CH3). HRMS (ESI) calcd for (C17H26NO4)+
[M+H]+: 308.1857, found: 308.1856.
Diethyl 2ꢀ((dimethylamino)methyl)ꢀ2ꢀethylmalonate (12b). Compound 12b was synthesized
according to the general procedure using Nꢀmethylꢀ10Hꢀspiro[anthraceneꢀ9,5'ꢀoxazolidin]ꢀ10ꢀ
one 4a (1.0 mmol, 265 mg) and diethyl 2ꢀethylmalonate (1.5 mmol, 282 mg) without additional
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purification. Light yellow oil, yield 200 mg (82% based on starting oxazolidine 4a). H NMR
(400 MHz, DMSOꢀd6) δ 4.10 (q, J = 7.1 Hz, 4H, 2CO2CH2CH3), 2.77 (s, 2H, NCH2), 2.13 (s,
6H, NMe2), 1.92 (q, J = 7.5 Hz, 2H, CH2CH3), 1.16 (t, J = 7.1 Hz, 6H, 2CO2CH2CH3), 0.75 (t, J
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= 7.5 Hz, 3H, CH2CH3); C NMR (101 MHz, DMSOꢀd6) δ 170.4 (2C=O), 60.6 (2CH2O), 59.4
(CH2N), 58.1 (C), 46.9 ((CH3)2N), 23.8 (CH2), 13.9 (2CH3), 8.3 (CH3). HRMS (ESI) calcd for
(C12H24NO4)+ [M+H]+: 246.1700, found: 246.1697.
Diethyl 2ꢀ((dimethylamino)methyl)ꢀ2ꢀpropylmalonate (12c). Compound 12c was synthesized
according to the general procedure using Nꢀmethylꢀ10Hꢀspiro[anthraceneꢀ9,5'ꢀoxazolidin]ꢀ10ꢀ
one 4a (1.0 mmol, 265 mg) and diethyl 2ꢀpropylmalonate (1.5 mmol, 303 mg) without additional
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purification. Light yellow oil, yield 153 mg (59% based on starting oxazolidine 4a). H NMR
(400 MHz, DMSOꢀd6) δ 4.10 (q, J = 7.1 Hz, 4H, 2CO2CH2CH3), 2.77 (s, 2H, NCH2), 2.13 (s,
6H, NMe2), 1.87–1.82 (m, 2H, CH2CH2CH3), 1.15 (t, J = 7.1 Hz, 6H, 2CO2CH2CH3), 1.13–1.07
(m, 2H, CH2CH2CH3), 0.88 (t, J = 7.2 Hz, 3H, CH2CH2CH3); 13C NMR (101 MHz, DMSOꢀd6) δ
170.5 (2C=O), 60.7 (2CH2O), 60.0 (CH2N), 57.7 (C), 46.9 ((CH3)2N), 33.1 (CH2), 16.9 (CH2),
14.3 (CH3), 13.8 (2CH3). HRMS (ESI) calcd for (C13H26NO4)+ [M+H]+: 260.1857, found:
260.1857.
3ꢀ(Dimethylamino)ꢀ2,2ꢀdiphenylpropanenitrile (12d). Compound 12d was synthesized
according to the general procedure using Nꢀmethylꢀ10Hꢀspiro[anthraceneꢀ9,5'ꢀoxazolidin]ꢀ10ꢀ
one 4a (1.0 mmol, 265 mg) and 2,2ꢀdiphenylacetonitrile (1.5 mmol, 289 mg) without additional
purification. Brown viscous oil, yield 210 mg (84% based on starting oxazolidine 4a), it was
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previously known in ref 11. 1H NMR (400 MHz, DMSOꢀd6) δ 7.45–7.37 (m, 8H, Ph), 7.35–7.30
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(m, 2H, Ph), 3.40 (s, 2H, NCH2), 2.16 (s, 6H, NMe2); C NMR (101 MHz, DMSOꢀd6) δ 139.4
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(2C), 128.8 (4CH), 127.8 (2CH), 126.9 (4CH), 122.5 (C≡N), 66.0 (CH2N), 52.7 (C), 46.8
((CH3)2N). HRMS (ESI) calcd for (C17H19N2)+ [M+H]+: 251.1543, found: 251.1540.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
NMR Spectra (PDF).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: mvslc@mail.ru
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by the Russian Science Foundation (Grant 17ꢀ73ꢀ20070).
We also thank Sergey Usachev for his remarks.
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