Reaction of enamines with semicarbazone-based amidoalkylating reagents: A straightforward synthesis of annulated 1-aminopyrimidin-2-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2021.152826

An efficient synthesis of 1-arylideneamino-substituted hexahydro-1H-cyclopenta[d]pyrimidin-2-ones and octahydroquinazolin-2-ones has been developed. The synthesis involves a stereo- and regioselective cascade reaction of the corresponding 4-(tosylmethyl)semicarbazones with 1-morpholinocyclopentene or 1-morpholinocyclohexene to give predominantly bicyclic pyrimidines with an exocyclic C[dbnd]C double bond (80–97%). The later undergo rapid isomerization when heated in THF in the presence of TsOH to form bicyclic pyrimidines with a significant predominance of those with an endocyclic C[dbnd]C double bond (90–97%).

Full text of DOI:10.1016/j.tetlet.2021.152826

Tetrahedron Letters 66 (2021) 152826
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reaction of enamines with semicarbazone-based amidoalkylating
reagents: A straightforward synthesis of annulated 1-aminopyrimidin-2-
one derivatives
Anastasia A. Fesenko a,b, Anatoly D. Shutalev a,
⇑
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., 119991 Moscow, Russian Federation
A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, 31 Leninsky Ave., 119071 Moscow, Russian Federation
b
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 1-arylideneamino-substituted hexahydro-1H-cyclopenta[d]pyrimidin-2-ones
and octahydroquinazolin-2-ones has been developed. The synthesis involves a stereo- and regioselective
cascade reaction of the corresponding 4-(tosylmethyl)semicarbazones with 1-morpholinocyclopentene
or 1-morpholinocyclohexene to give predominantly bicyclic pyrimidines with an exocyclic C@C double
bond (80–97%). The later undergo rapid isomerization when heated in THF in the presence of TsOH to
form bicyclic pyrimidines with a significant predominance of those with an endocyclic C@C double bond
Received 31 October 2020
Revised 24 December 2020
Accepted 5 January 2021
Available online 23 January 2021
Keywords:
(90–97%).
4
-(Tosylmethyl)semicarbazones
Ó 2021 Elsevier Ltd. All rights reserved.
Enamines
Amidoalkylation
1
-Aminohexahydro-1H-cyclopenta[d]
pyrimidin-2-ones
-Aminooctahydroquinazolin-2-ones
Isomerization
1
The
organic chemistry that allows the formation of carbon–carbon
and carbon-heteroatom bonds at the -position to the amide nitro-
a
-amidoalkylation reaction is a powerful tool in synthetic
in the semicarbazone fragment, could undergo spontaneous hete-
rocyclization with the formation of 1-aminopyrimidin-2-one
derivatives (Scheme 2).
a
gen (Scheme 1) [1]. This reaction involves the interaction between
nucleophiles and electrophilic amidoalkylating reagents (e.g. 1 and
It is noteworthy that 1-aminopyrimidin-2-one derivatives
demonstrate a wide range of biological activities acting as compet-
itive AMPA receptor antagonists [5] HLGPa inhibitors [6] antialler-
gic and antiasthmatic agents [7] and possessing antibacterial [8]
antiepileptogenic [9] anxiolytic [10] schistosomicidal [11] and pes-
ticidal properties [12].
Among the various 1-aminopyrimidin-2-ones, heterocycle
annulated and benzoannulated representatives are the most stud-
ied. Their preparations involve N-amination [13] cyclization [14]
and recyclization [15] reactions. In contrast, only a few syntheses
of monocyclic and carbocycle annulated 1-aminopyrimidin-2-ones
have been reported [8a,b,12a,16].
Herein we report an efficient synthesis of hydrogenated bicyclic
1-(arylideneamino)pyrimidin-2-ones based on the reaction of
enamines (1-morpholinocyclopentene and 1-morpholinocyclohex-
ene) with 4-(tosylmethyl)semicarbazones. Plausible mechanisms
for the reaction as well as isomerization of the initial products
are also discussed.
2
in Scheme 1). Despite the wide variety of C-nucleophiles used,
only a few reactions with enamines have been reported including
those with acylimines 2 proceeding without a catalyst [2] and
those with amidoalkylating reagents 1 commonly catalyzed by a
Lewis acid [3]. Since the amide components for the synthesis of 1
and 2 were carboxamides and carbamates (R = alkyl, aryl, alkoxy),
the final products of these reactions after hydrolysis were the cor-
responding b-amido or b-carbamato ketones 3 (Scheme 1).
Recently, we have developed a general method for the synthesis
of novel amidoalkylating reagents based on semicarbazones, 4-(to-
sylmethyl)semicarbazones 4, and studied their reactions with H-,
O-, S-, P-, N-nucleophiles, and anionic C-nucleophiles [4]. In contin-
uation of our research on synthetic applications of these reagents,
it was reasonable to explore their reactions with enamines. We
hypothesized that the initial products of these reactions, iminium
salts 5, due to the presence of the nucleophilic nitrogen atom N2
Sulfones 6a-d bearing an aryl or alkyl group at the
the amide nitrogen atom N4 and -unsubstituted sulfone 6e were
used as the starting amidoalkylating reagents. Readily available 1-
a-position to
a
⇑
Corresponding author.
E-mail address: shad@ioc.ac.ru (A.D. Shutalev).
https://doi.org/10.1016/j.tetlet.2021.152826
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0

A.A. Fesenko and A.D. Shutalev
Tetrahedron Letters 66 (2021) 152826
resulted in a decrease in the purity of the obtained pyrimidines
(
Entries 4 and 5).
2 2
Under the optimized conditions (CH Cl , rt, 24 h), mixtures of
pyrimidines 9b + 10b (80:20) and 9c + 10c (89:11) were prepared
from sulfones 6b,c and enamine 7 in good yields (Entries 6 and
8
6
). Analogous to 6a, a decrease in the reaction time with sulfone
b resulted in a decrease in the purity and yield of the obtained
product (Entry 7).
In contrast to
a-aryl substituted sulfones 6a-c, sulfone 6d
reacted with enamine 7 to give a mixture of 9d, 10d and 4-methyl-
benzaldehyde semicarbazone in a ratio of 19:24:57, respectively
(
Entry 9), and
all (Entry 10).
We found that sulfones 6a-c smoothly reacted with enamine 8
in CH Cl at room temperature for 24 h to give the corresponding
mixtures of pyrimidines 11a-c and 12a-c in 69–77% overall yield
Entries 11, 12, and 14). Shortening the reaction time to 3 h with
a-unsubstituted sulfone 6e did not react with 7 at
Scheme 1. Reported examples of the amidoalkylation of enamines.
2
2
(
compound 6b led to a decrease in the purity of the obtained pyrim-
idines 11b + 12b (Entry 13). It is noteworthy that, under the opti-
mized conditions, the reaction of compounds 6a-c with enamine
8
proceeds more selectively than with enamine 7. In the first case,
the amount of pyrimidines with the exocyclic C@C bond is 86–97%,
and in the second case, it is 80–86%.
Scheme 2. Proposed synthesis of 1-aminopyrimidin-2-one derivatives via the
reaction of enamines with 4-(tosylmethyl)semicarbazones.
It should be noted that the reaction between
a-propyl substi-
tuted sulfone 6d and enamine 8 (CH Cl , rt, 24 h) did not give
2
2
morpholinocyclopentene (7) and 1-morpholinocyclohexene (8)
were chosen as C-nucleophiles. First, we studied the reaction of
sulfone 6a with enamine 7. Taking into account the reported data
on the amidoalkylation of enamines with carboxamide and carba-
mate-based reagents 1 (see above), we carried out the reaction
between 6a and 7 using boron trifluoride etherate as a catalyst.
The reaction proceeded rapidly in CH Cl at room temperature
2 2
affording the expected heterocyclization products, which were
found to be a mixture of isomeric bicyclic pyrimidines 9a and
pyrimidines 11d, 12d, and the only isolated reaction product was
4-methylbenzaldehyde semicarbazone (27%) (Entry 15).
Scheme 4 shows a plausible pathway for the amidoalkylation of
enamines based on the experimental data. Due to their low basic-
ity, enamines cannot participate in the amidoalkylation via an
E1cB/Ad
trast to sulfones 6a-d, did not react with enamine 7 (Entry 10 vs
entries 3, 6, 8, and 9), an S 2 mechanism can be excluded. Thus,
the amidoalkylation of enamines 7 and 8 with sulfones 6a-c pro-
ceeds via an S 1 mechanism through the formation of N-acylim-
N
mechanism. Since a-unsubstituted sulfone 6e, in con-
N
1
0a in a 49:51 ratio, respectively (Scheme 3; entry 1 in Table 1).
N
1
However, according to H NMR spectroscopic data, the estimated
purity of the isolated crude product did not exceed 72%.
inium cations A stabilized by the aryl group (Scheme 4). Reaction
of these cations with 7 or 8 gives intermediates B, which cyclize
into bicyclic pyrimidines C followed by elimination of morpholine
to afford the final products.
We found that the reaction between 6a and 7 proceeded in CH
2
-
Cl
2
at room temperature for 7 h even without addition of a catalyst,
resulting in a 71:29 mixture of pyrimidines 9a and 10a with a pur-
ity of 69% (Entry 2). However, under these conditions, the hetero-
cyclization of the initially formed amidoalkylation products was
incomplete, as evidenced by the NMR spectrum of the isolated
crude material, in which two singlet signals in the range of 9.95–
The regioselectivity of the amidoalkylation is determined by
elimination of morpholine from intermediates C via an E1 mecha-
nism (Scheme 4). It is noteworthy that the thermodynamically less
stable pyrimidines 9a-c and 11a-c (see below) formed predomi-
nately in the reaction of 6a-c with enamines 7 or 8 as a result of
kinetic control involving preferential abstraction of a proton in
1
0.45 ppm were observed, characteristic of the N2-H proton of
the semicarbazone moiety. After the reaction time was prolonged
to 24 h, an 80:20 mixture of 9a and 10a was isolated in 77% yield
with high purity (Entry 3). Use of benzene or MeCN as a solvent
2
the intermediate carbocation from the less hindered CH group.
1
Based on H NMR spectroscopic data, the major products (9a-c
or 11a-c) were formed as a single diastereomer with trans-diequa-
torial orientation of substituents at the C5 and C6 positions of the
3
pyrimidine ring ( J5-H,6-H = 10.6–10.8 Hz). According to the pro-
posed pathway, the stereochemistry of these compounds is con-
trolled by the interaction between cations A and enamines.
We found that heating the obtained 9a-c/10a-c and 11a-c/12a-
6 6
c mixtures (Table 1) in various solvents (EtOH, MeCN, THF, C H ) in
the presence of TsOH afforded mixtures of the same compounds
with a significant predominance of pyrimidines with the endo-
cyclic C@C double bond (90–97%, according to NMR data)
(Scheme 5, Table 2).
Using 9a + 10a mixtures we found that the purity of the isomer-
ization reaction dramatically depended on the solvent used
Table 2, entries 2–4, 6, and 7). The best result was obtained in
(
THF. An increase in the reaction time led to decreased purity of
the isolated pyrimidines (Entries 1–3). The isomerization also pro-
ceeded in AcOH or DMF at reflux providing pyrimidine mixtures
9
a + 10a with low purity (Entries 8 and 9). Under all tested condi-
Scheme 3. Amidoalkylation of enamines 7 and 8 with 4-(tosylmethyl)semicar-
bazones 6a-e.
tions, except the reaction at room temperature (Entry 5), pyrim-
2

A.A. Fesenko and A.D. Shutalev
Tetrahedron Letters 66 (2021) 152826
Table 1
Reactions of sulfones 6a-e with enamines 7 and 8.
Entry
Starting
R
R1
Reaction conditions
Pyrimidine
products
Pyrimidine
purityb
Yield
(%)
9/10 or
11/12 ratio
compoundsa
c
d
1
2
3
4
5
6
7
8
9
6a + 7
6a + 7
6a + 7
6a + 7
6a + 7
6b + 7
6b + 7
6c + 7
6d + 7
6e + 7
6a + 8
6b + 8
6b + 8
6c + 8
6d + 8
4-MeC
4-MeC
4-MeC
4-MeC
4-MeC
Ph
Ph
4-MeOC
Pr
H
6
6
6
6
6
H
H
H
H
H
4
4
4
4
4
4-MeC
4-MeC
4-MeC
4-MeC
4-MeC
Ph
6
6
6
6
6
H
H
H
H
H
4
4
4
4
4
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
, BF
, rt, 7 h
, rt, 24 h
3
ÁEt
2
O (0.90 equiv.), rt, 6 h
9a + 10a
9a + 10a
9a + 10a
9a + 10a
9a + 10a
9b + 10b
9b + 10b
9c + 10c
72
69
96
84
76
90
81
96
43
–
97
97
75
98
–
–
–
77
–
–
74
–
62
–
49:51
71:29
80:20
90:10
87:13
80:20
91:9
89:11
45:55
–
95:5
86:14
96:4
97:3
–
MeCN, rt, 24 h
, rt, 24 h
C
6
H
6
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
, rt, 24 h
, rt, 3 h
Ph
4-MeOC
6
H
4
6
H
4
,rt, 24 h
,rt, 24 h
,rt, 24 h
, rt, 24 h
, rt, 24 h
, rt, 3 h
e
4-MeC
4-MeC
4-MeC
Ph
6
6
6
H
H
H
4
4
4
9d + 10d
f
10
11
12
13
14
15
no reaction
11a + 12a
11b + 12b
11b + 12b
11c + 12c
–
4-MeC
Ph
6
H
4
75
69
–
77
–
Ph
4-MeOC
Pr
Ph
6
H
4
4-MeOC
4-MeC
6
H
4
, rt, 24 h
, rt, 24 h
g
6
H
4
–
a
1
.15–1.24 equiv. of enamine were used.
b
Purity of the isolated pyrimidines was estimated as a ratio of the expected integral intensity of the NH and aromatic protons region (11H for 9b + 10b and 11b + 12b; 9H
1
for 9a,c + 10a,c and 11a,c + 12a,c; 5H for 9d + 10d) to the observed integral intensity in this region in the H NMR spectrum of the crude product multiplied by 100.
c
Isolated yield.
d
According to 1H NMR spectroscopy of the crude products.
e
Obtained in a mixture with 4-methylbenzaldehyde semicarbazone (57%).
9
A 83:27 mixture of 6d and 4-methylbenzaldehyde semicarbazone, respectively, was isolated.
f
7% of starting 6e was recovered.
g
c/10b,c and 11a-c/12a-c mixtures with 56–92% purity were
obtained (Entries 10–14). Isomerization of the 11c + 12c mixture
proceeded very slowly using the weak acid AcOH (Entry 15). Crys-
tallization of the 11a,b + 12a,b mixtures (Entries 12 and 13) from
EtOH gave individual pyrimidines 12a,b in 35% and 62% isolated
yield, respectively.
The described isomerization proves that pyrimidines 10a-c,
1
2a-c with the endocyclic C@C double bond are thermodynami-
cally more stable than pyrimidines 9a-c, 11a-c with the exocyclic
one. This is also confirmed by the DFT B3LYP/6–311++G(d,p) calcu-
lations for 9b, 10b and 11b, 12b in DMSO and THF solution using
the PCM solvation model. The calculations show that 10b and
1
2b (s-cis conformers relative to the NAN bond) are more stable
than the corresponding 9b and 11b ( E = 0.88–1.26, G = 1.76–
D
D
Scheme 4. Plausible pathway for the amidoalkylation of enamines 7 and 8 with 4-
1
.98 kcal/mol).
(
tosylmethyl)semicarbazones 6a-c.
In summary, the
a-amidoalkylation of enamines (1-mor-
pholinocyclopentene and -cyclohexene) with 4-(tosylmethyl)semi-
carbazones has been studied. It was demonstrated that with
aryl-substituted amidoalkylating reagents, the reaction readily
proceeds in CH Cl at room temperature without any catalyst to
a-
2
2
give derivatives of 1-arylideneamino-substituted hexahydro-1H-
cyclopenta[d]pyrimidin-2-ones or octahydroquinazolin-2-ones as
a result of a cascade process involving spontaneous heterocycliza-
tion of the initially formed amidoalkylation products followed by
elimination of morpholine. We showed that the amidoalkylation
N
step proceeds via an S 1 mechanism with complete diastereoselec-
tivity to afford the corresponding bicyclic intermediates with
trans-diequatorial orientation of the substituents at the C5 and
C6 position of the pyrimidine ring. The morpholine elimination
step is kinetically controlled and results in the predominant forma-
tion of the bicyclic pyrimidines with an exocyclic C@C double bond
(
80–97%). Short heating of the obtained products in THF in the
Scheme 5. Acid-catalyzed isomerization of 9a-c into 10a-c, and 11a-c into 12a-c.
presence of TsOH (0.1 equiv.) led to bicyclic pyrimidines with a sig-
nificant predominance of those with an endocyclic C@C double
bond (90–97%) as a result of isomerization. The DFT B3LYP/6–
idine mixtures 9a + 10a with similar ratios were obtained, indicat-
ing that thermodynamic equilibrium was achieved rapidly. Short
heating of 9a + 10a in THF in the presence of TsOH (0.1 equiv.) until
complete dissolution (<5 min) afforded the isomerization product
with 79% purity (Entry 1). Under these optimized conditions, 9b,
3
11++G(d,p) calculations confirm that pyrimidines with the endo-
cyclic C@C double bond are thermodynamically more stable than
those with the exocyclic bond. We believe that the developed
bicyclic pyrimidine synthesis represents a flexible method to con-
struct hydrogenated 1H-cyclopenta[d]pyrimidin-2-one and quina-
3

A.A. Fesenko and A.D. Shutalev
Tetrahedron Letters 66 (2021) 152826
Table 2
Isomerization of 9a-c into 10a-c, and 11a-c into 12a-c.
Entry
Starting
compounds
R, R1
Starting
9/10 or 11/12
ratio
Reaction conditionsa
Final
Pyrimidine
purity (%)c
9/10 or 11/12
ratiob
1
2
3
4
5
6
7
8
9
9a + 10a
9a + 10a
9a + 10a
9a + 10a
9a + 10a
9a + 10a
9a + 10a
9a + 10a
9a + 10a
9b + 10b
9c + 10c
11a + 12a
11b + 12b
11c + 12c
11c + 12c
4-MeC
4-MeC
4-MeC
4-MeC
4-MeC
4-MeC
4-MeC
4-MeC
4-MeC
Ph
6
6
6
6
6
6
6
6
6
H
H
H
H
H
H
H
H
H
4
4
4
4
4
4
4
4
4
86:14
71:29
73:27
79:21
73:27
73:27
86:14
79:21
78:22
78:22
89:11
95:5
TsOH (0.1 equiv.), THF, short heating
TsOH (0.1 equiv.), THF, reflux, 0.5 h
TsOH (0.1 equiv.), THF, reflux, 1 h
TsOH (0.1 equiv.), EtOH, reflux, 1 h
TsOH (0.1 equiv.), EtOH, rt, 24 h
TsOH (0.1 equiv.), MeCN, reflux, 0.5 h
7:93
6:94
6:94
6:94
36:64
6:94
6:94
9:91
8:92
4:96
10:90
9:91
10:90
9:91
91:9
79
63
34
4
53
10
55
9
51
80
56
88
92
83
87
TsOH (0.1 equiv.), C
AcOH, reflux, 0.5 h
DMF, reflux, 1 h
6 6
H , reflux, 0.5 h
10
11
12
13
14
15
TsOH (0.1 equiv.), THF, short heating
TsOH (0.1 equiv.), THF, short heating
TsOH (0.1 equiv.), THF, short heating
TsOH (0.1 equiv.), THF, short heating
TsOH (0.1 equiv.), THF, short heating
AcOH (1.5 equiv.), THF, reflux, 3 h
4-MeOC
6
H
4
4-MeC
Ph
6
H
4
86:14
96:4
96:4
4-MeOC
4-MeOC
6
H
H
4
4
6
a
b
c
Short heating is defined as heating on a hotplate under stirring until a solution formed (<5 min).
According to 1H NMR spectroscopy of the crude products.
Purity of the isolated pyrimidines was estimated as described in Table 1.
zolin-2-one frameworks. The methods previously described in the
literature involve the reaction of 2-(R-ylidene)cycloalkanones with
urea [17] or the three-component condensation of cycloalkanones
with aromatic aldehydes and urea [18] to give bicyclic 1,2,3,4-
tetrahydropyrimidin-2-ones with an endocyclic C@C double bond.
(c) R. Attrill, H. Tye, L.R. Cox, Tetrahedron: Asymmetry 15 (2004) 1681–1684;
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[5] D. Orain, S. Ofner, M. Koller, D.A. Carcache, W. Froestl, H. Allgeier, V. Rasetti, J.
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Lingenhoehl, S. Urwyler, Bioorg. Med. Chem. Lett. 22 (2012) 996–999.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
[
6] T. Nakamura, M. Takagi, T. Kiguchi, T. Ikenogami, N. Ueda, Patent WO
2004113345 (2004); Chem. Abstr. 142 (2004) 93672.
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Ellsworth, D.Q. Nguyen, J.P. Sanchez, H.D.H. Showalter, R. Singh, M.A. Stier, T.
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Supplementary data (copies of IR, H and 13C NMR spectra of the
synthesized compounds, computational details) to this article can
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