Mannich condensations of activated cyclic enamines

Article abstract of DOI:10.1080/00397911.2018.1484488

The synthesis of Mannich compounds starting from activated enamines, i.e., 2-nitromethylene-pyrrolidine and pyrrolidin-2-ylidene-acetic acid ethyl ester, with various amines and formaldehyde or ethyl glyoxylate are described. In order to furnish new Mannich type molecules and to improve the yields sequential reaction routes and 1,2,3-benzotriazole-substituted adducts as reactants were also tested. Additionally, the steric structure of a tricyclic spiro compound formed unexpectedly in high yield was elucidated in details by modern NMR methods.

Full text of DOI:10.1080/00397911.2018.1484488

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Mannich condensations of activated cyclic
enamines
Anna Alekszi-Kaszás, Péter Nemes, Gábor Tóth, Judit Halász & Pál Scheiber
To cite this article: Anna Alekszi-Kaszás, Péter Nemes, Gábor Tóth, Judit Halász & Pál Scheiber
(2018): Mannich condensations of activated cyclic enamines, Synthetic Communications, DOI:
10.1080/00397911.2018.1484488
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https://doi.org/10.1080/00397911.2018.1484488
Mannich condensations of activated cyclic enamines
a
a
b
c
a
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ꢀ
ꢀ
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Anna Alekszi-Kaszas , Peter Nemes , Gabor Toth , Judit Halasz , and Pal Scheiber
b
aDepartment of Chemistry, University of Veterinary Medicine, Budapest, Hungary; Department of
Inorganic and Analytical Chemistry, NMR Group, Budapest University of Technology and Economics,
c
Budapest, Hungary; Laboratory of Structural Chemistry, Egis Pharmaceuticals Plc, Budapest, Hungary
ABSTRACT
ARTICLE HISTORY
Received 9 April 2018
The synthesis of Mannich compounds starting from activated enam-
ines, i.e., 2-nitromethylene-pyrrolidine and pyrrolidin-2-ylidene-acetic
acid ethyl ester, with various amines and formaldehyde or ethyl
glyoxylate are described. In order to furnish new Mannich type
molecules and to improve the yields sequential reaction routes and
1,2,3-benzotriazole-substituted adducts as reactants were also tested.
Additionally, the steric structure of a tricyclic spiro compound
formed unexpectedly in high yield was elucidated in details by mod-
ern NMR methods.
KEYWORDS
Benzotriazole auxiliary;
Mannich reaction; one pot
reactions; push–pull
alkenes; pyrrolopyrimidines
GRAPHICAL ABSTRACT
Introduction
Push–pull enamines, enamines with an electron withdrawing group in the b-position,
such as b-enaminonitriles,[1–6] b-enaminoesters,[7–13] or nitroenamines[14–21] are reactive
intermediates in a large variety of reactions with different (ambident) electrophiles, such
as a,b-unsaturated oxo-compounds, carboxylic acid chlorides, dicarbonyls,[22–24] or with
1,3-dipoles[25–27] resulting in biologically active bridgehead N-heterocycles and natural
products, e.g., the extremely toxic marine alkaloid saxitoxin.[28,29]
The Mannich condensation is one of the most important and thoroughly studied
multi-component reaction in synthetic chemistry affording a wide spectrum of valuable
products used also in medicine. Push–pull enamines, particularly the representatives
with cyclic structure, containing an active hydrogen at the nucleophilic b-carbon atom
are suitable and often used components of these reactions.
ꢀ
CONTACT Peter Nemes
nemes.peter@univet.hu
Department of Chemistry, University of Veterinary Medicine, H-
1400 Budapest, P.O.Box 2, Hungary.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

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A. ALEKSZI-KASZAS ET AL.
As many naturally occurring compounds contain a pyrimidine skeleton as a key
structural motif, in the last two decades we witnessed to a tremendous increase of
publications dealing with the synthesis of multi-functionalized dihydropyrimidines and
tetrahydropyrimidines.[30–38] In this way, some cyclic enamines, such as 2-nitromethy-
lene-pyrrolidine, -thiazolidine, -imidazolidine were already applied in Mannich reactions
with formaldehyde and different amines affording fused tetrahydropyrimidines. In one
[39]
of our previous papers
we described the Mannich reactions of 1-nitromethylenepyr-
rolidine (1) with aliphatic amines and formaldehyde. In two subsequent publica-
tions[18,30] we reported the Mannich reactions of 1 with ethyl glyoxylate and aromatic
amines. The products obtained could be cyclized with formaldehyde to fused
tetrahydropyrimidine derivatives.
In this present publication, we describe the synthesis of some new compounds
starting from 2-nitromethylene-pyrrolidine (1) through double Mannich reactions with
aromatic amines. Furthermore, we synthesized new Mannich products with pyrrolidin-
2-ylidene-acetic acic ethyl ester (2) aiming to broaden the scope of application of such
hitherto less studied enamines.
Results and discussion
Mannich reactions of enamines with formaldehyde and primary amines
In our previous work,[39] we reported the synthesis of Mannich products of 1 with dif-
ferent primary aliphatic amines and formaldehyde with good yields. In this article, we
also describe the analogous reactions using aromatic amines (Scheme 1). In ethanol at
room temperature, the reactions with anilines bearing electron-donating groups gave
pyrrolopyrimidine derivatives 3 in good yields (Table 1). On the other hand, anilines
with electron withdrawing substituent(s) exerting a strong deactivating effect did not
react, and the formations of several unidentifiable products were observed.
In a similar procedure, enaminoester 2 was subjected to Mannich reaction.[40]
Reacted with primary aliphatic amines and formaldehyde in the usual one pot protocol
under mild conditions, it gave the analogous fused pyrimidine derivatives 4 in good
yields (Scheme 1, Table 1)
Attempts to synthesize N-aryl derivatives using some selected aromatic amines were
less successful. Under the same reaction conditions, only 4-methyl- and 4-methoxy-
anilines gave the expected compounds 4j, 4k in poor yield. The numerous by-products
of the complex reaction mixtures were not analyzed.
Scheme 1. Preparation of pyrrolo-pyrimidines from enamines.

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Table 1. Compounds prepared from enamines 1 and 2 in Mannich reactions.
Entry
EWG
R
Yield (%)
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
NO2
NO2
NO2
NO2
Ph
4-MePh
4-MeOPh
2-MeOPh
CH(CH3)2
77
63
72
49
82
61
42
64
77
68
70
58
60
18
29
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
C(CH3)3
CH2Ph
2-MeOPhCH2CH2
3,4-MeOPhCH2CH2
cPentyl
cHexyl
N-Bn-piperidin-4-yl
N-Et-piperidin-3-yl
4-MePh
4-MeOPh
Reaction conditions: 1 or 2 (1.0 mmol), formaldehyde, in (2.5 – 3.0 mmol, 35%
formaline), RNH2 (1.0 mmol), in EtOH, 3–8 h stirring at ambient temperature.
Scheme 2. Mannich reaction of 1 with secondary amines.
These striking differences in reactivity of 1 and 2 can be explained with the stronger
electron withdrawing ability of the nitro group and the stronger nucleophilic character
of the aliphatic amines compared to the ethoxycarbonyl group and to the less basic
aromatic amines, respectively.
Mannich reactions of enamines with formaldehyde and secondary amines using
benzotriazole auxiliary
As we published[22,39] the nitroenamine 1 gave the expected Mannich products 5 with
secondary amines in good yield (Scheme 2). On the contrary, in a usual one pot
procedure and under same conditions the enaminoester 2 failed to furnish analogous
products. Therefore, we attempted to follow a sequential route in preparation of
Mannich products adapting the benzotriazole methodology. The benzotriazole-mediated
approach in synthesis of diverse classes of organic compounds is well documented,
particularly in the publications of the Katritzky’s group.[41] As benzotriazole, this
synthetic auxiliary, can be introduced and removed easily and can exert an activating
effect during the synthetic operations, we applied it in a two-step approach.
Benzotriazole and aldehydes react reversibly to give addition products. These hydroxy
compounds can react with amines under loss of water producing reactive species being
in equilibrium with the benzotriazolate anion and the imminium cation (Fig. 1). These
versatile intermediates in alkylation processes enable a significant extension of Mannich
reactions, as well.

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A. ALEKSZI-KASZAS ET AL.
4
Figure 1. Dissociation equilibrium of benzotriazole-adducts.
Scheme 3. Reaction of the benzotriazole adduct 5 with nitroenamine 1.
Scheme 4. Reaction of the benzotriazole adduct 5 with enaminoester 2.
According to a known procedure[42] first we prepared compound 6 that incorporates
the amine and formaldehyde components of our expected Mannich products. In the fol-
lowing step, we wanted to remove the benzotriazole auxiliary through the treatment
with an enamine to result in the target compounds. This strategy worked well with
2-nitromethylenepyrrolidine, and gave 5a in good yield as shown in Scheme 3. The
product 5a proved to be identical with the compound prepared in a one pot Mannich
reaction of 1 with formaldehyde and N-benzylmethylamine as published previously.[39]
Next the above reaction was repeated with the enamino ester 2. The desired product
analogue to 6 was not formed, but, surprisingly, the N-benzylmethylamino group was
removed to give 7 (Scheme 4).
As the above reaction reveals a strong affinity of the 1-benzotriazolylmethyl group to
the nucleophilic carbon atom of the enamino ester 2, a reversed sequence of the reac-
tion steps was tested. Thus, 1-hydroxymethyl-benzotriazole[42] 8 and the enamino-ester
2 were allowed to react, attempting to obtain 7 directly and, afterwards, to remove the
benzotriazolyl group in a treatment with an appropriate amine. This reaction, however,
led to the diastereomeric spiro compounds 9a and 9b in high yield (Scheme 5).

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Scheme 5. The unusual reaction of 8 with enaminoester 2.
Scheme 6. Proposed mechanism for the formation of 9a,b.
Their formation can be explained with a reaction cascade as follows (Scheme 6). It is
supposed that the enamino ester 2 was N- and C-alkylated producing the intermediates
A and B probably in a nearly 1:1 ratio. The 1,3-diene C can be derived from the equi-
librium mixture B through the loss of a proton. C and A can interact in a 4 þ 2 cycliza-
tion to provide the spiro compounds 9a,b.

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A. ALEKSZI-KASZAS ET AL.
6
Figure 2. Structures of 9a and 9b.
The molecular ion [Mþ] of 9, formed by electron impact ionization, at m/z 453.2337
in its HR mass spectrum confirms the molecular formula C24H31N5O4 that is consistent
with 12 double bond equivalents resulting in five rings and seven double bonds.
In the NMR spectra of the product 9 two series of signals were observed demonstrat-
ing the formation of two diastereomers 9a and 9b in a ratio of 91:9 determined by the
signal intensities. Unfortunately, attempts to separate the diastereomers failed, after the
numerous repeated recrystallizations practically no change in the above diastereomeric
ratio was observed. The unfavorable interaction between the two bulky i.e., C(6)-
COOEt and C(5)-benzotriazolylmethylpyrrolidino groups in 9b can be considered as a
1
plausible explanation for the high diastereoselectivity. The signal assignment of their H
and 13C NMR spectra and their diastereomeric differentiation was achieved by different
NMR techniques as follows. Noteworthy that the reaction had led to racemic mixtures
of 9a and 9b, but, for the sake of simplicity only the enantiomeric forms with 6R con-
figurations are depicted in Figure 2.
The identification and NMR signal assignment of 1-benzotriazolylmethylene and the
1
two COOEt groups is trivial because there are no disturbing H signals in the corre-
sponding spectral range (see spectra in the Supporting material). The identification and
1
separated detection of the H signals of the two –CH2–CH2–CH2– spin-systems in the
five-membered spiro- and also in the condensed ring was achieved with selective one-
dimensional TOCSY experiments irradiating dHa-3 (2.91 ppm) and dHb-30 (2.24 ppm)
signals, respectively. The HMBC correlations of H2-C-1a00 hydrogen atoms with C-50
(dC ¼ 52.1 ppm) assigned the five-membered spiro ring. Irradiation of the Hb-6 signal
at 3.18 ppm (dd, J ¼ 12.8 and 5.0 Hz) marked out the H2-7 signals.
The 1-benzotriazolylmethylene moiety shows significantly different steric proximities
in the major 9a (5R6R) and the minor 9b (5S6R) diastereomer. The high value of the
J(Hb-6, Ha-7) verifies the antiperiplanar arrangement of these hydrogen atoms, indicat-
ing the highly preferred envelope like conformation of the six-membered ring, in
which the C-6 is the out of plane atom and the COOEt group occupies the a-equatorial
position. In recognition of characteristic hydrogen-hydrogen spatial proximities,
NOE experiments were particularly useful (as indicated with arrows in the Fig. 2).
Irradiation of the Hb-6 signal of 9a at 3.18 ppm resulted in strong NOE responses on
H2-C-1a00, Hb-7 and H-700 hydrogen atoms proving the suggested structure
unambiguously.

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Although 13C chemical shifts of 9a and 9b are rather similar, a significant difference
is, however, observed only for the C-1a00 atom. Namely, this signal in 9a exhibits a con-
siderable diamagnetic shift of 8 ppm relative to that observed for 9b (67.9 ! 59.5 ppm).
This strong downfield shift can be interpreted by the well-known c–gauche effect
between of H-C(6) bond and the C-1a00 atom. In 9b there is no such spatial arrange-
ment around C-1a00.
Reactions of enamines with anilines and ethyl glyoxylate
In an earlier publication,[18] we described the three component reactions of nitroenamine
1 with ethyl glyoxylate and various anilines. The products could be transformed with for-
maldehyde to versatile multisubstituted pyrrolopyrimidines. To broaden the scope of this
procedure, we accomplished similar one pot reactions with enaminoester 2 (Scheme 7).
The reactions were carried out at room temperature in ethanol resulting in compounds
10a–e. The reaction times were 12–24 h, but the increase of the temperature led to a large
number unidentified by-products. The yields with the nitroenamines are usually higher
than with the enaminoester 2, which can be explained with the stronger electron with-
drawing effect of the nitro group. On the other hand, electron withdrawing substituents
at the aromatic ring increase the reaction time. The yields are summarized in Table 2.
As we described earlier[18] on the basis of the HPLC measurements, it can be estab-
lished that the three-component reaction takes place in two different ways. While elec-
tron donating substituents of the anilines facilitate the imine formation and the reaction
with the enamine affords directly the product, electron withdrawing substituents slow
down this reaction and the addition product of enamine and the aldehyde was formed
predominantly, which can undergo to a nucleophilic substitution with anilines to give
the desired products.
Scheme 7. One-pot reactions with enaminoester 2.
Table 2. Compounds 10a–e prepared in one-pot reactions.
Product
R
Yield (%)
10a
10b
10c
10d
10e
H
30
61
57
36
31
4-OMe
4-F
4-Me
3-NO2
Reaction conditions: 2 (1.56 mmol), RC6H5NH2 (1.56 mmol), ethyl glyoxylate,
(1.56 mmol, 50 w/w % toluene solution) in EtOH (4 mL), 3–8 h stirring at
ambient temperature.

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A. ALEKSZI-KASZAS ET AL.
8
Scheme 8. Sequential reactions of 2 with ethyl glyoxylate and anilines.
Scheme 9. Benzotriazole mediated synthesis of 10a,c,d,e.
Thus, we prepared the addition product 11 from enamine 2 with ethyl glyoxylate
which was then converted to the desired products 10 with aromatic amines. In this way
10a, 10c, and 10d were prepared, yields are 44, 68, and 52%, respectively (Scheme 8).
Attempts to prepare the Mannich products with aliphatic and alicyclic amines were
unsuccessful because of the formation of a large number of unidentifiable by-products
which can be explained with the lower stability of the imine intermediates.
In order to improve the yields of the three component reactions we attempted the
use of the benzotriazole methodology. Benzotriazole adducts with ethyl glyoxylate and
secondary amines were prepared several years ago by Katritzky et al. in benzene and
used in alkylation reactions with organometallic reagents.[42]
First we prepared the benzotriazole adducts with different anilines and ethyl glyoxy-
late.[43,44] The reactions took place with 61–92% yields in EtOH at room temperature.
The products 12a–d crystallized from the reaction mixtures and could be used in the
subsequent substitution without further purification. (Scheme 9, Table 3).
We hoped that enaminoester 2 will be a reactive CH-component in the nucleophilic
displacement of the benzotriazole moiety (Scheme 9). The reactions were examined in
different solvents, such as EtOH, polyethylene glycol (PEG 400), and water at room
temperature. The expected compounds were obtained in most cases in 31–59% yields.
The results summarized in Table 3 could be achieved in EtOH.
Materials and methods
General procedure for preparation of 3a–c
A solution of 1 mmol of 2-nitromethylene-pyrrolidine (1), 1 mmol of aniline or substi-
tuted aniline and 250 mg of formaline (35%, approx. 3 mmol of formaldehyde) in 3 mL
of ethanol was stirred at room temperature for 3–8 h. The reaction was followed

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Table 3. Compounds prepared via 12a–d benzotriazolyl intermediates in EtOH.
Entry
R
Product
Yield (%)
Product
Yield (%)
1
2
3
4
H
4-F
4-Me
3-NO2
12a
12c
12b
12d
61
75
71
92
10a
10c
10d
10e
59
57
51
31
Reaction conditions: for preparation of 12a,b,c,d: RC6H5NH2 (16.8 mmol), ethyl
glyoxylate (16.8 mmol, 50 w/w % toluene solution), benzotriazole (16.8 mmol), in
EtOH (20 mL), 3–8 h stirring at ambient temperature for preparation of 10a,c,d,e:
12 (1.5 mmol),
2 (1.5 mmol), in EtOH (5 mL), 8–12 h stirring at ambient
temperature.
by TLC. After completion the reaction mixture was cooled, and the crystalline product
was filtered or evaporated and purified by column chromatography.
General procedure for preparation of 4a–k
A solution of 1 mmol of pyrrolidin-2-ylidene-acetic acid ethyl ester (2), 1 mmol of a
primary amine, and 280 mg of formaline (35%, approx. 2.8 mmol of formaldehyde) in 3 mL
of ethanol was stirred at room temperature for 3–8 h. The reaction was followed by TLC.
After completion the solvent was removed at reduced pressure and the residue was purified
with column chromatography on silica gel using hexane/tert-butylmethylether/i-propyl
amine (50:45:5) as eluent.
Preparation of 5a
Benzotriazol-1-ylmethyl-benzyl-methyl-amine (5) (252 mg, 1.00 mmol), 2-nitromethyle-
nepyrrolidine (1) (128 mg, 1.00 mmol), potassium tert-butoxide (112 mg, 1.00 mmol) in
EtOH (2 mL) was stirred for 5 h. After evaporation the orange red residue was mixed
with water (2 mL) and extracted with EtOAc (2 ꢀ 2 mL). The EtOAc solution was dried
(Na2SO4) and concentrated to yield a yellow viscous oil, that solidified upon standing
(226 mg, 87%).
Preparation of 7
A mixture of 1-benztriazolylmethyl-benzyl-methylamine (504 mg, 2 mmol), enami-
noester 2 (310 mg, 2 mmol) in acetonitrile (3 mL) was stirred at room temperature for
6 h. After removal of the solvent the yellow residue was crystallized from diiso-
propyl ether.
Preparation of 9
The dense white suspension of 1-hydroxymethyl-benztriazol (8) (273 mg, 1.83 mmol)
and the enaminoester 2 (284 mg, 1.83 mmol) in acetonitrile (4 mL) was stirred at ambi-
ent temperature. After 2 h a colorless homogenous solution was obtained. Removal of
the solvent gave a pale yellow oil that solidified upon cooling. Treatment with diiso-
propyl ether led to the formation of a white solid

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A. ALEKSZI-KASZAS ET AL.
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General procedure for the synthesis of 10a–e with one pot reactions
The solution of ethyl glyoxalate (50% w/w toluene solution, 0.32 ml, 1.56 mmol), enam-
ine 2 (242 mg, 1.56 mmol) and the corresponding aromatic amine (1.56 mmol) were dis-
solved in EtOH (4 mL) and stirred at room temperature until the starting materials
were consumed. The solution was concentrated under reduced pressure and purified by
column chromatography on silica gel using cyclohexane/ethyl acetate (2:1) as eluent.
Preparation of 11
The solution of ethyl glyoxalate (50% w/w toluene solution, 0.61 ml, 3.0 mmol) and 2
(282 mg, 3.0 mmol) were dissolved in EtOAc (10.0 mL) and stirred at room temperature
for 2 h. The solution was evaporated at reduced pressure, and the residue was crystal-
lized from cyclohexane upon cooling.
General procedure for the synthesis of 10a, 10c, and 10d starting from 11
11 (232 mg, 1.5 mmol) and the corresponding aromatic amine were dissolved in EtOH
(5 mL) and the solution was stirred for 8 h at room temperature. After completion of
the reaction the solution was evaporated at reduced pressure and the residue was puri-
fied on silica gel using cyclohexane/ethyl acetate (2:1) as eluent. 10a, 10c, and 10d were
prepared, with 44, 68, and 52% yields, respectively.
General procedure for the preparation of 12a–d
The solution of ethyl glyoxalate (50% w/w toluene solution, 3.42 ml, 16.8 mmol), benzo-
triazole (2.0 g, 16.8 mmol) and amine (16.8 mmol) were dissolved in EtOH (20 mL), and
stirred at room temperature until the starting materials were consumed. Upon cooling
the product crystallizes from the solution.
General procedure for the synthesis of 10a, 10c, 10d, and 10e starting
from 12a–d
12 (1.5 mmol) and 2 (1.5 mmol) were dissolved in EtOH (5 mL) and the solution was
stirred for 8–12 h at room temperature. After completion of the reaction the solution
was evaporated at reduced pressure and the residue was purified on silica gel using
cyclohexane/ethyl acetate (2:1) as eluent.
Acknowledgments
ꢀ
ꢀ
The PhD scholarship from Szent Istvan University to A. Alekszi-Kaszas is gratefully acknowl-
ꢀ ꢀ
edged. We are grateful to Dr M. Dekany, Gedeon Richter Plc., Spectroscopic Research
Department, for the high-resolution MS measurements.

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