Гетероциклізації β-алкокси-, β-діаміноалкіл- та споріднених β-функціоналізованих енонів (еналів) з NCN-бінуклеофілами
This review provides a detailed survey of the present literature data on β-alkoxyvinyl- and β-enaminocarbonyl compounds as CCC bis-electrophiles in reactions with the common NCN-binucleophiles. The focus is put mostly on the reactions leading to low-molecular-weight and functionalized pyrimidines as...
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| author | Vashchenko, Bohdan V. Grygorenko, Oleksandr O. Stepaniuk, Oleksandr O. |
| author_facet | Vashchenko, Bohdan V. Grygorenko, Oleksandr O. Stepaniuk, Oleksandr O. |
| author_institution_txt_mv | [
{
"author": "Bohdan V. Vashchenko",
"institution": "Taras Shevchenko National University of Kyїv, 60 Volodymyrska St., Kyїv, 01601, Ukraine"
},
{
"author": "Oleksandr O. Grygorenko",
"institution": "Taras Shevchenko National University of Kyїv, 60 Volodymyrska St., Kyїv, 01601, Ukraine"
},
{
"author": "Oleksandr O. Stepaniuk",
"institution": "Taras Shevchenko National University of Kyїv, 60 Volodymyrska St., Kyїv, 01601, Ukraine"
}
] |
| author_sort | Vashchenko, Bohdan V. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:52Z |
| description | This review provides a detailed survey of the present literature data on β-alkoxyvinyl- and β-enaminocarbonyl compounds as CCC bis-electrophiles in reactions with the common NCN-binucleophiles. The focus is put mostly on the reactions leading to low-molecular-weight and functionalized pyrimidines as the products that are of special interest as building blocks for drug discovery. |
| doi_str_mv | 10.15407/bioorganica2022.01.056 |
| first_indexed | 2025-07-17T12:19:24Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
UDC 547.853
DOI: https://doi.org/10.15407/bioorganica2022.01.056
56
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
REVIEW
Heterocyclizations of β-alkoxy, β-diaminoalkyl, and related
β-functionalized enones (enals) with NCN-binucleophiles
Bohdan V. Vashchenko1,2, Oleksandr O. Grygorenko1,2*, Oleksandr O. Stepaniuk1,2
1Enamine Ltd. (www.enamine.net),78 Chervonotkatska St., Kyїv, 02094, Ukraine
2Taras Shevchenko National University of Kyїv, 60 Volodymyrska St., Kyїv, 01601, Ukraine
Abstract: This review provides a detailed survey of the present literature data on β-alkoxyvinyl- and β-enaminocarbonyl compounds as
CCC bis-electrophiles in reactions with the common NCN-binucleophiles. The focus is put mostly on the reactions leading to low-
molecular-weight and functionalized pyrimidines as the products that are of special interest as building blocks for drug discovery.
Keywords: heterocycles; pyrimidines; enones; bis-electrophiles; binucleophiles.
Introduction
It is well-known that pyrimidines and their fused
derivatives are the most abundant heterocycles in marketed
drugs and natural compounds, such as nucleic acids and
numerous alkaloids [1-4]. A general approach toward their
synthesis (the so-called “principal pyrimidine synthesis”)
includes the use of 1,3-dicarbonyl compounds as CCC bis-
electrophiles in heterocyclizations with NCN binucleophiles
[5-10]. Due to the strong electrophilic nature of dicarbonyl
compounds, they sometimes possess high reactivity and
consequent limited stability. In turn, this results in problems
with chemo- and regioselectivity, lowered yields of the
products, as well as limited accessibility of some of the
target heterocycles. This is especially true for the case of the
simplest representatives bearing no additional substituents
or decorated with the smallest alkyl substituents at the azine
core.
To address the above issues, β-alkoxyvinyl- and
β-enaminocarbonyl compounds have been developed as the
synthetic equivalents of classical 1,3-dicarbonyl CCC bis-
Received:
Revised:
Accepted:
Published online:
15.03.2022
21.03.2022
12.04.2022
30.06.2022
Corresponding author. Tel.: +380-44-239-3315;
e-mail: gregor@univ.kiev.ua (O. O. Grygorenko)
ORCID: 0000-0002-6036-5859
electrophiles with a push-pull reactivity (Scheme 1). In
addition to increased stability and the possibility to
synthesize the simplest and the least substituted
functionalized heterocycles [11-15], these building blocks
provide increased chemo- and regioselectivity with
diminished side processes, as well as improved yields of the
condensation product [16-23]. The synthesis of these bis-
electrophiles can be achieved starting from 1,3-dicarbonyl
compounds [16, 24-26] or alkoxyvinyl acetylenes [27], by
reaction of ketals with acylating agents [28, 29], acylation
of vinyl ethers [29-31], the Heck-type palladium-catalyzed
carbonylation of vinyl ethers in the presence of aryl iodides
and carbon monoxide [32, 33], and other methods.
R1 R3
O
R2
O
OAlkR1
O R3
R2
N(Alk)2R1
O R3
R2
OAlkR3
O R1
R2
N(Alk)2R3
O R1
R2
[-alkoxyenones/enals] [-enaminones/enals][1,3-dicarbonyl]
N
N
R2
R3
N
H2N
R1
[binucleophiles]
NCN
[pyrimidines]
CCC bis-electrophiles
CCC
N
N
R2
R1
R3
Scheme 1. β-Alkoxyvinyl- and β-enaminocarbonyl compounds as
the synthetic equivalent of 1,3-dicarbonyl compounds.
This review provides a comprehensive analysis of
heterocyclizations of β-alkoxyvinyl- and β-enamino-
carbonyl compounds with NCN binucleophiles, focusing
mainly on the synthesis of low-molecular-weight and
functionalized heterocycles as the target products. First,
reactions of various bis-electrophile types with the classi-
© B.V. Vashchenko et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
B. V. Vashchenko, O. O. Grygorenko et al.
57
cal acyclic NCN binucleophiles (e.g. amidines, guanidines,
thiuronium salts, etc.) are discussed. Then, heterocycli-
zations with aminoheterocycles leading to fused pyrimidi-
nes are covered.
β-Alkoxy- and β-diaminoalkyl enals
Parent β-enaminal 1 was evaluated as a convenient
reagent for the preparation of 2-substituted pyrimidines 2 by
reactions with amidines bearing acetal [34], furan-2-yl [35],
or aminoalkyl moieties (Scheme 2) [36].
Scheme 2. Synthesis of 2-substituted pyrimidines 2.
Taking into account the fact that β-enamino carbonyl
compounds can generate the corresponding dicarbonyl
compounds upon alkaline hydrolysis [37], the chemical
behavior of α,β-unsaturated carbonyl compounds bearing a
leaving group at the β-position can be modelled by the
tautomerization of 2-formyl-3-oxopropanoate (3) into
3-hydroxyacrylate 4 that reacts with N,N-dimethylguanidine
to give 2,5-disubstituted pyrimidine 5 (Scheme 3). Ethyl
3-(dimethylamino)-2-formyl acrylate (6) is a stable synthe-
tic equivalent of both 3 and 4 and undergoes heterocyclic-
zation with amidines or isothiourea to give pyrimidine-5-
carboxylates 7 [25, 38].
Scheme 3. Heterocyclizations of 3-(dimethylamino)-2-formyl
acrylate 6.
Reactions of the corresponding β-alkoxyenals are
represented by α-alkyl-substituted derivatives 8, which
provided 2,5-disubstituted pyrimidines 9 by treatment with
amidines [39-42], guanidine [41], urea [43], and thiourea
[43] (Scheme 4).
Scheme 4. Heterocyclizations of α-alkyl-substituted β-alkoxyenals
8.
A wide range of β-enaminals bearing an α-substituent
have been reported, including compounds with alkyl 10
[40, 44, 45], cycloalkyl 11 [46], nitrile 12 [47-51], imide 13
[52], ester groups 14 [38], chorine [53], and other moieties
(Scheme 5). Formyldiene 15 was used as a versatile reagent
for the synthesis of a series of 5-vinylpyrimidines [54].
5-(Het)aryl-substituted pyrimidines could be prepared by
using aryl-substituted enones 16 [53, 55-57] or those
decorated with thiohetaryl groups [58].
On the contrary, heterocyclizations of β-aryl-substituted
alkoxyenals 17 [59] and enaminals 18 [60] have been
scarcely reported providing limited examples of 2,4-disub-
stituted pyrimidine synthesis (Scheme 6). This substitution
pattern was also represented by enaminal 19 [61-63].
Scheme 5. Heterocyclizations of α-substituted β-enaminals.
Scheme 6. Heterocyclizations of β-substituted enals 17–19.
Usual β-alkoxy- and β-diaminoalkyl enones
One more type of β-alkoxy-α,β-unsaturated carbonyl
compounds is represented by a few examples of alkyl- 20
[36] and aryl-substituted 21 β-alkoxyenones (Scheme 7)
[32]. The most well-studied compound for this category is
CF3-substituted derivative 22a [64-66], which might be due
to its chemical accessibility and the importance of the
corresponding fluorinated heterocyclic products to
medicinal chemistry. The known examples included the
reaction of 22a with guanidine [67, 68], urea [67, 69], thio-
urea [67], isothiourea [70], formamidine [69] acetamidine,
and benzamidine [71]. The variability of substituents and
heterocyclization conditions of trifluoro-4-alkoxybut-3-en-
2-ones 22 for the synthesis of 4-CF3-substituted pyrimidines
is summarized in Table 1 [29, 66-69, 72-79].
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
58
Analogous transformations included the condensation of
CHF2-substituted analog 23 with benzamidine [80] and
C2F5-substituted compound 24 – with urea [81] (Scheme 7).
Prominent examples of using 22a, 23, and β,β-dimetho-
xyenones 25 and 26 included reactions with amidine 27 for
the synthesis of 4-(di)trifluoromethylpyrimidines 28 and 29
(Scheme 8) [82]. Related 2-(ethoxymethylene)-4,4,5,5-
tetrafluoro-3-oxopentenoate 30 was used for the preparation
of tetrafluoroethylpyrimidine 31 (Scheme 9) [75, 76]. In
turn, using 5-aminotetrazole could result in either 2-amino-
pyrimidines [83] or 2-azidopyrimidines [76].
Scheme 7. Heterocyclizations of β-alkoxyenones 20-24.
Table 1. Heterocyclizations of CF3-substituted β-alko-
xyenones 37.
R1 R2 R3 R4 Conditions %
H H NH2 Et NaOH, EtOH 70 [84]
CO2Et H NH2 Et aminotetrazole
, 1,4-dioxane,
NaOAc.3H2O,
reflux, 16-18 h
38 [83]
CO2Et H NH2 Et NaOAc.3H2O,
DMF, 80 °С,
24-26 h
60 [83]
CO2Et H NMe2 Et EtONa, EtOH,
reflux, 1 h
70 [85]
H CH2N3 SMe Me Na2CO3, H2O,
rt, 3 h
75 [86]
H (CH2)2CO2Me Me Me trichloro-
isocyanuric
acid, EtOH, rt,
30 min.
59 [87]
Ph 62 [87]
SMe 52 [87]
H H 2-
amino-
benzo-
thiazo-
lyl
Et H2O, reflux,
24 h
65 [88]
H Me Me/
Et
75 [88]
Me H Me/
Et
88 [88]
H Ph Me 80 [88]
H p-MeOC6H4 Me 70 [88]
H p-MeC6H4 Me 60 [88]
H p-BrC6H4 Me H2O, reflux,
8 h
80 [88]
H p-FC6H4 Me 70 [88]
H thien-2-yl Me 60 [88]
Scheme 8. Synthesis of (β-D-ribofuranosyl)-4-(di)trifluorome-
thylpyrimidines.
Scheme 9. Preparation of tetrafluoroethyl-substituted pyrimidine
31.
Representative examples of β-amino-substituted α,β-un-
saturated ketones included derivatives decorated with
(cyclo)alkyl 32 [89], acetal 33 [90, 91], piperidine 34
[58, 92], and bis-1,3-dioxolane 35 [93] moieties (Scheme
10).
Scheme 10. Heterocyclizations of 4-(dimethylamino)but-3-en-2-
ones 32-35.
Table 2. Reactions of acylated β-alkoxyacrylonitriles 36.
R1 R2 X Yield, %
Me Me S N/Aa
Me Et S 50
Me n-Pr S 15
Me i-Pr S 42
Et Et S 61
Ph Ph S N/Aa
Et Et O 10
Me Et NH2 52
Et Et NH2 50
Et Et Me 56
a Yield was not given.
B. V. Vashchenko, O. O. Grygorenko et al.
59
α-Acylacrylonitriles 36 reacted with (thio)urea or
guanidine to form the corresponding tetrasubstituted
(thio)pyrimid-2-ones or 2-aminopyrimidines (Table 2) [94].
Analogous transformations have been reported for the case
of cyano-substituted enaminones 37 (Scheme 11).
Scheme 11. Heterocyclizations of α-acyl-β-(dimethylamino)-
acrylonitriles 37.
The scope of β-alkoxyenones with electron-withdrawing
substituents at the α-position also includes sulfones 38,
which reacted with benzamidine, isothiourea, and guanidi-
nes to give the corresponding 5-sulfonylpyrimidines in mo-
derate yields (Scheme 12) [95].
Scheme 12. Reactions of α-sulfonyl-β-ethoxyenones 38.
Reactions of enones bearing an additional carbonyl or
alkoxycarbonyl moiety at the α-position [6, 8, 10, 17, 96-
98] with nucleophiles typically proceeded at the more
electrophilic ketone carbonyl group. Representative examp-
les included reactions of 2-carbonyl-3-ethoxyacrylates 39
with urea, acetamidine, and trifluoroacetamidine described
Table 3. Heterocyclizations of β-alkoxyenones 39
bearing an additional carbonyl moiety at the α-position.
R1 R2 R3 R4 R5 Yield, %
CF3 OEt H Et thien-2-yl 89
CF3 OEt H Et
74
CF3 OEt H Et O(H) 45
CF3 OEt H Et Me 55
CF3 OEt H Et CF3 39
C2F5 OEt H Et O(H) 66
Ph OEt H Et O(H) 65
thien-2-yl OEt H Et O(H) 51
n-Pr OEt H Et O(H) 72
Et OEt H Et O(H) 81
Me OEt H Et O(H) 88
Me OEt H Et CF3 58
Me Me H Et pyridine-4-yl 87
Me Me H Et SMe 70
Me OEt H Et Ph (flow synthesis) 80 [101]
Me OEt H Et NH2 85 [102]
Me OEt H Et S 86 [49]
Me OEt Me Et o-MeOC6H4 73
Me OEt Me Et cyclobutyl 82
Me OMe Me Me 4-t-BuC6H4 N/A [103]
Me OMe Me Me CF3 (no base,
MeOH, acetone)
44 [104]
Table 4. Heterocyclizations of β-enaminones 40 bearing an
alkoxycarbonyl moiety at the α-position.
R1 R2 = R3 R4 Yield %
Me Me (Et) H 50 [105]
Et Et 45 [106]
Me Me Me 85 [105]
Me Et 65 [107]
Et Et 67 [107]
n-Pr Et 62 [107]
i-Pr Et 85 [107]
n-Bu Et N/A [108]
i-Bu Et N/A [108]
CH2cyclopropyl Et N/A [108]
CH2cyclopentyl Et N/A [108]
cyclopentyl Et N/A [108]
cyclopentyl Et N/A [108]
t-Bu Et 88 [107]
CH2OMe Et 64 [107]
Ph Et 68 [107]
Bn Me 13 [107]
p-FC6H4 Et 61 [109]
(N-Ph-pyrrolid-2-on)-
4-yl
Me 50 [110]
Et Et n-Pr 87 [111]
Me Et Ph 68 [107]
80 [112]
Et Me 73 [112]
Et Et 71 [107]
n-Pr Et 80 [107]
i-Pr Et 60 [107]
t-Bu Et 75 [107]
CH2OMe Et 67 [107]
Bn Me 22 [107]
Ph Et 72 [107]
m-O2NC6H4 Et 91 [113]
p-O2NC6H4 Et 86 [113]
(N-Ph-pyrrolid-2-on)-
4-yl
Me 65 [110]
m-O2NC6H4 Et p-ClC6H4 84 [113]
p-O2NC6H4 Et 76 [113]
Et Et p-HOC6H4 86 [114]
Me Et NH2 81 [107]
Et Et 74 [107]
n-Pr Et 73 [107]
i-Pr Et 70 [107]
t-Bu Et 81 [107]
Bn Et 37 [107]
CH2OMe Et 66 [107]
Ph Et 80 [107]
(84 [109])
p-FC6H4 Et N/A [115]
m-O2NC6H4 Et 51 [113]
H Et NMe2 59 [85]
Me Et 87 [85]
CH2OMe Me 70 [85]
Et Et 85 [85]
н-Pr Et 86 [85]
i-Pr Et 82 [85]
т-Bu Et 72 [85]
Bn Me 41 [85]
Ph Et 86 [85]
CO2Et Et 41 [85]
Ph Et SMe 77 [109]
5-Me-thien-2-yl Et (Me) 50 [56]
p-FC6H4 Et p-ClC6H4CH2S 66 [109]
a Et3N, EtOH was used instead of sodium alkoxide or alkali
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
60
for the synthesis of 2,4-disubstituted 5-carboxylates or the
corresponding ketones (Table 3) [25, 94, 99, 100]. Notably,
it is possible to apply the continuous flow synthesis conditi-
ons to the reaction of enones for bezamidine [101].
A wide range of analogous enaminones 40 easily
accessible through DMFDMA-mediated condensation
reactions has been also used for the preparation of
pyrimidines (Table 4).
A promising chemotype of pyrimidine-5-carboxylates
could be obtained from 2-(alkoxymethylene)malonate 41
that was involved in reactions with formamidine [108],
acetamidine [108], benzamidine [112], and morpholine-
derived guanidine [108] (Scheme 13).
Scheme 13. Heterocyclizations of ethyl 2-(alkoxymethylene)malo-
nates (41).
One more interesting example included the reaction of
alkoxyenone 42 bearing a non-protected β-amino group,
which provided an access to 4-aminopyrimidines (Scheme
14) [116].
Scheme 14. Heterocyclization of 4-amino-4-ethoxybut-3-en-2-one
hydrochloride (42).
Also, bis-alkoxyvinyl ketone 43 was converted into the
corresponding 4,4'-bipyrimidines 44 in moderate yield via
the condensation with amidines or isothiourea (Scheme 15)
[117].
Scheme 16. Double heterocyclization into 4,4'-bipyrimidines 44
Heterocyclization of enones 45 bearing a silylated alkyne
moiety with aromatic amidines was disclosed as a good
method for the synthesis of a wide range of alkynylpyri-
midines (Scheme 17) [118]. This transformation could be
also carried out without desilylation. However, the predo-
minant formation of ethyl 2-(4-nitrophenyl)acetate (up to
50% yield) was observed upon the typical reaction condi-
tions for the case of the nitro-substituted derivatives 45.
Scheme 17. Heterocyclizations of 5-(trimethylsilyl)penten-4-yn-3-
ones 45.
Aside from the common dialkylamino moiety, screening
of a range of azolyl and N-tosyl enones 46 and 47,
respectively, in the model reaction with guanidine for the
preparation of pyrimidines 48 revealed that the best-leaving
groups is imidazolyl moiety (Scheme 18) [119]. The
reaction of a series of imidazole-1-yl enones 46d with NCN
nucleophiles was suitable to give pyrimidines in good to
excellent yields.
Scheme 18. Reaction of azolyl and N-tosyl enones 46 and 47.
β-Alkoxyvinyl- and β-enamino α-ketoesters
Using β-alkoxyvinyl α-ketoesters (synthetic equivalents
of acyl pyruvates) as the CCC bis-electrophiles was studied
as a multipurpose method for the preparation of the simplest
pyrimidine-4-carboxylates. The presence of the ester
functional group at the low-molecular-weight pyrimidine
core provides an entry towards readily accessible building
blocks relevant to medicinal chemistry. Despite the wide
synthetic potential and stability of β-alkoxyvinyl α-keto-
esters, their use in the known literature procedures had long
been limited by non-optimized reactions of 49 with
S-methyl- and S-benzyl thiouronium salts [28], acetamide,
2-methylbenzimidamide, and guanine, leading to the
formation of di- and trisubstituted pyridine-4-carboxylates
[120-123] (Table 5). However, good to high yields of
products were obtained with β-aryl-substituted enones 49,
while reactions of simplest derivative 49a and β-methylated
derivative 49c typically provided pyrimidines in low yields.
Screening for the optimal conditions of the hetero-
cyclization reaction was initially performed for the
synthesis of ethyl 2,6-diphenylpyrimidine-4-carboxylate
(R1 = R2 = Ph): the highest yield was achieved using
Na2CO3 as a base [28]. These reaction conditions were
extended to synthesize a series of 2-methylthiopyrimidines
50 (Scheme 19). When the reactions were carried out in the
presence of NaOH, hydrolysis of oxobutenoate 49 was
observed.
The reactivity of β-alkoxyvinyl α-ketoesters 49a-c as
CCC bis-electrophiles in condensation reactions with 15
representative amidines, S-methylthiuronium salt, and
guanidines was recently disclosed by our group (Scheme
20) [13]. A typical procedure relied on heating reagents in
MeCN at 70 °C in the presence of K2CO3 for 2 h (Method
A), which was suitable only for the most reactive
β-methylated enone 49c. The corresponding pyrimidines
were synthesized in good to high yields. In turn, heating of
B. V. Vashchenko, O. O. Grygorenko et al.
61
the starting compounds in the presence of Et3N in
1,4-dioxane at 100 °C for 48 h (Method B) worked well for
the parent enone 49a and the least reactive derivative 49b,
as well as for methyl, cyclopropyl, and p-chlorophenyl-
substituted amidines with low reactivity, and provided
higher yields of the corresponding pyrimidines. However,
method B proved to be ineffective in all experiments with
formamidine acetate and could not be used for chlorome-
thyl-substituted amidine due to the side alkylation of Et3N.
Table 5. Heterocyclizations of β-alkoxyvinyl α-ketoes-
ters 49.
R1 R2 R3 Conditions Yield %
Me SMe Me 1 M Na2CO3,
EtOH, H2O (5:1, v/v)
reflux, 1 h.
Ratio
CCC / NCN / base =
1 : 2 : 2
63 [28]
Ph 76 [28]
p-MeC6H4 58 [28]
p-MeOC6H4 52 [28]
p-FC6H4 62 [28]
p-BrC6H4 80 [28]
p-O2NC6H4 58 [28]
Me SBn Me 1 M Na2CO3,
EtOH, H2O (5:1, v/v)
reflux, 1 h.
Ratio
CCC / NCN / base =
1 : 1.2 : 1.2
77 [28]
Ph 94 [28]
p-MeC6H4 84 [28]
p-MeOC6H4 62 [28]
p-FC6H4 64 [28]
p-BrC6H4 89 [28]
p-O2NC6H4 94 [28]
H Me Et N/A N/A [120]
H o-tolyl Et NaOAc, p-xylene,
reflux, 36 h
36 [74]
H NH2 Et Et3N, EtCN,
100 °C, 24 h
27 [123]
Scheme 19. Synthesis of 2-methylthiopyrimidine-4-carboxylates.
Scheme 20. The reactivity pattern of β-alkoxyvinyl α-ketoesters
49a-c.
Moreover, heterocyclization reactions of 2-(ethoxy-
methylene)-3-oxosuccinate 50 for the synthesis of
2-substituted pyrimidine-4,5-dicarboxylates have been
widely studied (Table 6); EtONa in EtOH was typically
used.
Table 6. Heterocyclizations of 2-(methylene)-3-oxosuc-
cinate 50.
R Conditions Yield, %
NH2 EtONa, EtOH, 1.5 h, 0 °C to rt. 57 [124]
OH neat, heat 70а [124]
H benzene, reflux, 2.5 h 68 [125]
H
EtONa, EtOH, 0 °C to rt, 5 h
(overnight)
37 [126]
Me N/Ab [127]
Et 40 [126]
CH2OH 29 [126]
n-pentyl 51 [126]
Ph 85 [126]
m-MeC6H4 76 [126]
p-ClC6H4 93 [126]
p-O2NC6H4 84 [126]
p-MeOC6H4 53 [126]
napht-2-yl 53 [126]
pyridin-2-yl 87 [126]
furan-2-yl 89 [126]
thien-2-yl 90 [126]
a The intermediate diethyl ureidomethylene oxaloacetate was isolated with
pyrimidine, the overall yield is given b Yield was not reported.
Enaminone 51 bearing an additional ester group also
proved to be a good reagent for the preparation of
pyrimidines (Scheme 21); representative examples included
acetal 52 [128-130] and 2-(β-D-ribofuranosyl)pyrimidine
53 (via the condensation of 27) [131].
Scheme 21. Synthesis of pyrimidines 52 and 53.
The scope of reported enones included derivative 54
[132, 133] decorated with two glyoxylate moieties (Scheme
22) and other polycarbonyl enones 55. An interesting study
revealed that their condensation with NCN binucleophiles,
e.g. benzamidine, could occur at both competing carbonyl
groups and, therefore, could result in the formation of
pyrimidine-4-carboxylate 56 (the major or the only product
in most cases) or pyrimidine-5-glyoxylate 57 (Table 7)
[134]. The observed regioselectivity could be explained by
the more electrophilic nature of the carbonyl group adjacent
to the ester moiety as compared to the benzoyl-type
fragment, with an exception of CF3-substituted ketone
moiety.
Scheme 22. Heterocyclization of bis-glyoxylate-derived enone 54.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
62
This trend was confirmed in other works describing the
use of 1H-pyrazole-1-carboximidamide for the regio-
selective synthesis of biaryl derivatives 58 (Scheme 23)
[135].
Table 7. Regioselectivity in heterocyclizations of
enaminone 55.
O
R NMe2
NN
Ph
CO2EtPh
NH2H2N
CO2EtO
Cl
R O
NN
Ph
R
+
O CO2Et
MeCN, reflux, 1 h
55 56 57
R Ratio 56 : 57 Yield, %a
Ph 10:1b 84
p-MeC6H4 1:0 86
p-MeOC6H4 1:0 78
p-BrC6H4 5:1 81
p-ClC6H4 10:1 72
p-FC6H4 1:0 82
p-O2NC6H4 2:1 78
thien-2-yl 1:0 70
benzofuran-2-yl 3:1 81
CF3 0:1 50
a Yield is given for both regioisomers b Reverse regioselectivity has been
also reported [132, 133].
Scheme 23. 2-(1H-Pyrazol-1-yl)pyrimidine-4-carboxylates 58.
Cyclic β-alkoxy- and β-diaminoalkyl enones
An important chemotype is presented by pyrimidines
fused with saturated rings that can be obtained by reactions
of amidines with cycloalkanones bearing an exocyclic
double bond, e.g. 2-(methoxymethylene)cyclohexan-1-one
(59) [136] or analogous enaminone 60 [137-144] (Scheme
24).
NMe2O
CH3OCH2CH2OH,
MW, 180°C, 1 h
(R = XC6H4NH, X = Me,
Et, CF3, OMe, OEt)
NMe2
N N
R
R
NH2HN
O
Boc
N
NBoc
n n
EtONa, EtOH, 45 °C
or Et3N, EtOH, reflux
n = 1, 2
R = Me; CF3; cyclopropyl;
NHAlk: Alk = Me, Et, i-Bu,
t-Bu, CH2CH2OH, 4-THP,
cyclopentyl, propan-1-ol,
3-cyclopentanol; NHAc, (Het)ArNH
NMe2
O
S
NMe2
O
S
R
NH2HN
MeONa, MeOH, 36 h N N
R
YX
X = S, Y = CH2;
X = CH2, Y = S;
R = SH, NH2,
Ph, thein-2-yl
O
NN
R
OMe
R
NH2H2N
Cl
NaOAc, EtOH, reflux, 1 h
(R = Ph, o-ClC6H4, p-FC6H4,
p-MeOC6H4, 3,4-Cl2C6H3
cyclohexyl, 3-Ph-1-prop-1-yl)
59 60
R
NH2HN
or
m
m
61, m = n = 1
62, m = 1 n = 2
63, m = 2 n = 1
64 65
Scheme 24. Heterocyclizations of (hetera)cycloalkanone deriva-
tives 59-65.
Promising derivatives could be obtained from saturated
heterocyclic ketones, i.e. pyrrolidone 61 [145, 146],
isomeric piperidones 62 and 63 [145, 147], thiolanones 64
and 65 [148], etc. [149]. Enones 66 [26] and 67 [150, 151]
derived from dihydroresorcinol provide an entry to fused
pyrimidines with carbonyl group (Scheme 25). Other
transformations included the use of substituted cyclic di-
ketones [150, 152, 153] in reactions with amidines [150,
154] and guanidines [150, 153-155].
Scheme 25. Heterocyclizations of 2-methylene-cyclohexane-1,3-
diones 66 and 67.
Tetrahydropyridine-derived glyoxylate 68 with an
endocyclic C=C bond was used for the preparation of
functionalized fused pyrimidine by the reaction with
isothiourea (Scheme 26) [156]. Heterocyclizations of
3-acetyl-2-methoxycyclohepta-2,4,6-trienone [157, 158] or
2-oxo-2H-pyran-5-carbaldehyde [159] bearing the β-alko-
xyenone motif have also been reported.
Scheme 26. Heterocyclization of tetrahydropyridine-derived glyo-
xylate 68.
Interesting results can be obtained with enones where a
push-pull-type alkoxide motif is a part of a cyclic system,
which results in recyclization of the enone system upon the
reaction with NCN binucleophile. A prominent example of
cyclic β-alkoxyenones with an exocyclic C=C bond
reactivity included recyclizations of tetrahydrofuranyl
enones 69 with acetamidine or formamidine that resulted in
the formation of γ-hydroxypropyl moieties at the C(4)-
position of pyrimidine (Table 8) [160].
Table 8. Recyclization of tetrahydrofuranyl enones 69.
R1 R2 R3 R4 Yield, %
Ph H H Me 41
Ph H H Ph 60
Ph H H NH2 56
Ph H Me Me 47
Ph H Me Ph 50
Ph H Et Me 42
Ph H Et Ph 57
Ph Me H Me 41
Ph Me H Ph 45
Ph Et H Ph 55
Ph CH2Cl H Ph 85
Ph CH2Br H Ph 79
Me CH2Br H Ph 91
Me CH2OH H Ph 88
In turn, a sugar-derived enone, i.e. 2-formylgalactal 70
[161], reacted with amidines and guanidine to give
interesting C(5)- functionalized pyrimidines (Scheme 27).
Analogous transformations were reported for the case of
B. V. Vashchenko, O. O. Grygorenko et al.
63
PMB-protected analogues [162,163], as well as p-Me- and
p-Cl-substituted bezamidines [164]. It should be noted that
aminoalkyl-substituted pyrimidines could be obtained in the
same manner from the corresponding enaminones [165].
Scheme 27. Recyclizations of 2-formylgalactal 70 [161].
An interesting type of enone recyclizations in the
presence of NCN binucleophiles could be observed for
1,3-dioxolane-containing enone 71 decorated with
exocyclic C=C double bond at the C(2)-position (Scheme
28) [33].
Scheme 28. Recyclizations of 1,3-dioxolane-containing enones.
This transformation resulted in 2-((2-aminopyrimidin-4-
yl)oxo)ethanol with hydroxyethyl ether fragment derived
from the dioxolane cycle. If the alkenyl fragment was
located at the C(4) position of 1,3-dioxolane core, e.g. in
enone 72, pyrimidinyl methanols were formed (Scheme 28)
[150, 151].
The use of cyclic dienones with an endocyclic C=C
double bond is used to synthesize 5,5'-bipyrimidines with
hydroxyalkyl substituents [117]. In particular, five-
membered dienone 73 reacts with benzamidine to form
5,5'-bis(2-hydroxyethyl)pyrimidine in low yield, while the
six-membered homolog 74 was converted to 5.5'-bis(2-
hydroxypropyl)pyrimidine in 67% yield alongside with
formation of a monoheterocyclization product (Scheme 29).
Scheme 29. Synthesis of 5,5'-bipyrimidines from 73 and 74.
3-Formylchromone 75 is known to react via recyclization
with amidines [166-169], guanidines [166, 168, 170, 171],
thiourea [171], 2-methylisothiourea [172], carbonohydrazo-
nic diamides [173] to give pyrimidines decorated with the
salicylic moiety or the corresponding cyclic fused
hemiacetal products [172, 174] (Scheme 30). Moreover, the
reactions of 3-formylchromone with amidoximes were used
for the instant preparation of pyrimidine-N-oxides [175-
178]. The scope of this type of heterocyclization was
extended to derivatives substituted by benzene ring [179],
the corresponding ketochromones [180], di- and
trifluoromethyl ketones [181, 182], glyoxylate [183], which
all underwent recyclization with NCN binucleophiles [182].
Aside from the common reaction conditions for the
heterocyclization with NCN binucleophiles, which typically
relied on using alkali or alcoholates (rarely, K2CO3 or Et3N)
as bases, significant synthetic advances were achieved by
using TMSCl in DMF, which was disclosed in a series of
papers by Volochnyuk, Ryabukhin, and co-workers [184-
188].
Scheme 30. Recyclizations of 3-formylchromones 75.
Recyclization of carbonyl-substituted 4Н-chromenes and
1Н-benzo[f]chromenes by the treatment with amidines and
guanidines has also been reported [189]. In addition to the
two-component condensations, three-component reactions,
i.e. Biginelli pyrimidine synthesis, are also common for
these substrates [190-192].
Heterocyclizations with aminoheterocycles
Electron-rich aminoheterocycles, i.e. N-unsubstituted
aminopyrazoles, amino-1,2,4-triazoles, 1H-benzimidazole-
2-amine, 2-amino-1H-imidazoles, aminouracyls, etc., react
with CCC bis-electrophiles analogously to acyclic NCN
binucleophiles providing fused heteroaromatic pyrimidines.
In particular, 3-formylchromones mentioned just above
were studied in such heterocylizations [193].
The simplest open-chain enones have been widely
studied in these reactions and used for the preparation of
fused pyrimidines by reactions with aminoheterocycles.
Starting from the reaction of ethyl 3-ethoxyacrylate with
ethyl 5-amino-1H-pyrazole-4-carboxylate [194, 195], the
scope of known transformations included reaction of the
simplest derivative 8 [196] or 3-(dimethylamino)-N,2-
diformylacrylamide 14 [52] (Scheme 31).
Scheme 31. Reactions of β-alkoxyenones with 5-aminopyrazoles.
In turn, most of the known transformations relied on
using enones derived from ketoesters 39 (Scheme 32) [197-
203] that were subjected to heterocylizations with
(3)5-aminopyrazoles (mostly substituted by alkyl, aryl,
halogen, nitrile and nitro groups), or diazo
diaminopyrazoles [204, 205]. Other reported reactions
included enones derived from malonates 41 [206-208] or
cyanoacetates 36 [208-214], haloalkyl enones 22-24, and
their analogs [206, 215-220], and functionalized derivatives
bearing sulfonyl [221] or alkynyl [222] groups.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
64
Scheme 32. Reactions of enones derived from ketoesters 39.
Notably, in most cases, the condensation reaction
proceeded in a regioselective manner. However, the
reaction of diaryl-substituted 5-aminopyrazoles 76 was not
regioselective for most examples of β-alkoxyenones or the
corresponding enaminones (Table 9) and resulted in the
formation of two regioisomers 77 (major) and 78 (minor)
[223].
Table 9. Formation of regioisomers 77 and 78.
Reagent Conditions Yield, % Ratio
piperidine, EtOH, reflux,
18 h
46 1:0
piperidine, EtOH, reflux,
1-18 h
45
9:1
36
9:1
35
1:0
HOAc, EtOH, reflux, 1 h
80
1:0
36
4:1
HBr, EtOH, reflux, 1 h
31
7:3
HCl, EtOH, reflux, 1-18 h
51
1:0
Nevertheless, the reactions of simplest β-alkoxyvinyl
ketoesters 49a–c with 5-aminopyrazoles proceeded regio-
selectively to give the corresponding pyrazolo[1,5-
a]pyrimidine-7-carboxylates 79 in high yields (Scheme 33)
[12]. The formation of the second possible regioisomer was
not observed, in contrast to the similar non-regioselective
condensation with acetylpyruvate known from the
literature.
Scheme 33. Regioselective synthesis of pyrazolo[1,5-a]pyrimi-
dine-7-carboxylates 79 from the simplest β-alkoxyvinyl ketoesters
49.
Condensation of enones 49a–c with 5-amino-1H-1,2,4-
triazoles as NCN binucleophiles led to the formation of
complex mixtures of products in most cases, except enone
49b (Scheme 34).
Scheme 34. A representative reaction of 49b with 5-aminotriazole.
Synthesis of dicarboxylates, ketocarboxylates, and
related derivatives 80 from 3-acetyl- or 3-ethoxycarbo-
nylenones also proceeded regioselectively in a short
reaction time (Table 10) [223].
Table 10. Synthesis of pyrazolo[1,5-a]pyrimidine-7-car-
boxylates 80.
R1 R2 Conditions Yield, %
C(O)Me CN EtOH, reflux, 5 min 100
C(O)Me C(O)NH2 EtOH, reflux, 5 min 98
C(O)Me C(O)NHMe EtOH, reflux, 8 min 64
CO2Et CN EtOH, reflux, 5 min 92
CO2Et C(O)NH2 EtOH, reflux, 5 min 95
CO2Et C(O)NHMe EtOH, reflux, 9 min 92
As for the case of symmetric amidines, (thio)ureas, and
guanidines, recyclization reactions of 2-formylgalactal 70
[161] as well as the parent 3,4-dihydro-2H-pyran-5-
carbaldehyde have been reported (Scheme 35) [224].
O
O
N
N
HH2N 52%
NN
N
AcO
MeONa, MeOH, reflux
O
O
OBn
BnO
OBn
N
N
H
NH2
N
N
OBn
OBn
OH
OBn N
52%
N
N
HN
NH2
N
N
OBn
OBn
OH
OBn N
N
55%70
+
HOAc, 90 °C
Scheme 35. Recyclization reactions of cyclic enones with amino-
heterocycles in the preparation of fused pyrimidines.
Heterocyclizations of N-unsubstituted 5-aminopyrazoles
were also performed with cyclic enones 73 and 74. The
process proceeded regioselectively to give the tricyclic
products, i.e. pyrazolo[1,5-a]pyrimidines 81 with an
additional lactone cycle (Scheme 36) [11]. This result could
be explained by the formation of enaminones 82 followed
by intramolecular heterocyclization into hydroxyethyl
pyrimidine 83 and the lactonization reaction by the attack of
the hydroxyl group at the ester moiety. The derivative 84
also was considered as a possible intermediate that could be
transformed into 81.
In contrast to five-membered enone 73, the condensation
reactions of six-membered counterpart 74 did not lead to
the formation of homologous seven-membered lactones
under similar conditions. Instead, the formation of
B. V. Vashchenko, O. O. Grygorenko et al.
65
pyrazolo[1,5-a]pyrimidines 85 and 86 in a ratio of 3:1 was
observed (Scheme 37). In particular, bicyclic derivative 85
was formed from enaminone 87 formed in the first stage,
which subsequently underwent acetylation of the hydroxy
group of 88 with HOAc at high temperatures of the reaction
mixture. The formation of 86 could be explained by ring-
opening, acylation, and partial decarboxylation of the
intermediate seven-membered lactone 88.
O
O
EtO2C
73 Y
X
NN
N
Y
X
NN
N
HO
Y
X
NHN
N
H
HO
OEtO2C
Y
X
NHN
N
H
O
O
O
or
O O
CO2Et
82 83
HOAc,
reflux, 36 h
6085%
Y
X
NHN
H2N
81
NN
N
Q
O O
R = H (68%),
Me (60%)
NN
N
O O
R = CN (65%),
CO2Et (71%),
C(O)NH2 (85%)
R N
NN
N
O O
R
R = CF3 (62%),
CO2Me (68%)
84
R
Scheme 36. Synthesis of tricyclic pyrazolo [1,5-a]pyrimidines 81.
Scheme 37. Reaction of enone 74 with 5-aminopyrazole.
To prevent the side reactions observed for the case of 74,
reactions with aminoazoles were carried out by refluxing in
EtOH, which enabled the selective synthesis of the
corresponding pyrazolo[1,5-a]pyrimidines 90 and
[1,2,4]triazolo[1,5-a] pyrimidines 91 in high yields
(Scheme 38). In all cases discussed above, the
heterocyclization proceeded regioselectively: only C-7
carboxylates (or the corresponding δ-lactones) were formed.
Scheme 38. Synthesis of pyrazolo[1,5-a]pyrimidines 90 and
[1,2,4]triazolo[1,5-a] pyrimidines 91.
Conclusions
In this review, heterocyclizations of β-alkoxyvinyl and
β-enamino carbonyl compounds as CCC bis-electrophiles
with common NCN binucleophiles leading to pyrimidine
derivatives are covered. It is shown that in most cases, the
reaction is very efficient and demonstrates remarkable
regioselectivity, even with substrates bearing additional
functional groups or fluorinated substituents. With most
cyclic bis-electrophiles, recyclization typically occurs,
whereas with aminoheterocycles as the NCN binucleo-
philes, fused pyrimidine derivatives can be obtained. It is
clear therefore that β-alkoxyvinyl- and β-enaminocarbonyl
compounds are important synthetic equivalents of
β-dicarbonyl compounds in the pyrimidine synthesis,
opening access to functionalized derivatives useful as
building blocks for medicinal chemistry and natural
compound analogs.
Notes
Acknowledgments and finances. The work was funded
by Enamine Ltd. and Ministry of Education and Sciences of
Ukraine (Grants No. 0121U100387 (21BF037-01M),
0119U100340 (19BF037-03), and 0122U001962
(22BF037-02)). The authors thank Prof. Andrey A.
Tolmachev for his encouragement and support, and all the
brave defenders of Ukraine that stood against the russian
full-scale invasion and made this review possible.
The authors declare no conflict of interest.
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Гетероциклізації β-алкокси-, β-діаміноалкіл- та споріднених β-функціоналізованих
енонів (еналів) з NCN-бінуклеофілами
Б. В. Ващенко1,2, О. О. Григоренко1,2*, О. О. Степанюк1,2
1ТОВ НВП «Єнамін», вул. Червоноткацька, 78, Київ, 02094, Україна
2Київський національний університет імені Тараса Шевченка, вул. Володимирська, 60, Київ 01601, Україна
Резюме: Огляд присвячений обговоренню наявних літературних даних щодо β-алкоксивініл- та β-енамінокарбонільних сполук як CCC-біс-
електрофілів у реакціях із класичними NCN-бінуклеофілами. Основна увага приділяється реакціям, що призводять до утворення
низькомолекулярних та функціоналізованих піримідинів як продуктів, що є особливо цікавими як будівельні блоки для створення лікарських
засобів.
Ключові слова: гетероцикли; піримідини; енони; біс-електрофіли; бінуклеофіли.
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| id | oai:ojs2.bioorganica.com.ua:article-13 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:28Z |
| publishDate | 2022 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/c4/69ac3ffb99114bc2553c6d4ba1dd30c4.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-132026-07-19T14:56:52Z Heterocyclizations of β-alkoxy, β-diaminoalkyl, and related β-functionalized enones (enals) with NCN-binucleophiles Гетероциклізації β-алкокси-, β-діаміноалкіл- та споріднених β-функціоналізованих енонів (еналів) з NCN-бінуклеофілами Vashchenko, Bohdan V. Grygorenko, Oleksandr O. Stepaniuk, Oleksandr O. heterocycles pyrimidines enones bis-electrophiles binucleophiles гетероцикли піримідини енони біс-електрофіли бінуклеофіли This review provides a detailed survey of the present literature data on β-alkoxyvinyl- and β-enaminocarbonyl compounds as CCC bis-electrophiles in reactions with the common NCN-binucleophiles. The focus is put mostly on the reactions leading to low-molecular-weight and functionalized pyrimidines as the products that are of special interest as building blocks for drug discovery. Огляд присвячений обговоренню наявних літературних даних щодо β-алкоксивініл- та β-енамінокарбонільних сполук як CCC-біс-електрофілів у реакціях із класичними NCN-бінуклеофілами. Основна увага приділяється реакціям, що призводять до утворення низькомолекулярних та функціоналізованих піримідинів як продуктів, що є особливо цікавими як будівельні блоки для створення лікарських засобів. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2022-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/13 10.15407/bioorganica2022.01.056 Ukrainica Bioorganica Acta; Vol. 17 No. 1 (2022): Ukrainica Bioorganica Acta; 56-71 Ukrainica Bioorganica Acta; Том 17 № 1 (2022): Ukrainica Bioorganica Acta; 56-71 1814-9766 1814-9758 10.15407/bioorganica2022.01 en https://bioorganica.com.ua/index.php/journal/article/view/13/17 Copyright (c) 2022 Bohdan V. Vashchenko, Oleksandr O. Grygorenko, Oleksandr O. Stepaniuk https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | гетероцикли піримідини енони біс-електрофіли бінуклеофіли Vashchenko, Bohdan V. Grygorenko, Oleksandr O. Stepaniuk, Oleksandr O. Гетероциклізації β-алкокси-, β-діаміноалкіл- та споріднених β-функціоналізованих енонів (еналів) з NCN-бінуклеофілами |
| title | Гетероциклізації β-алкокси-, β-діаміноалкіл- та споріднених β-функціоналізованих енонів (еналів) з NCN-бінуклеофілами |
| title_alt | Heterocyclizations of β-alkoxy, β-diaminoalkyl, and related β-functionalized enones (enals) with NCN-binucleophiles |
| title_full | Гетероциклізації β-алкокси-, β-діаміноалкіл- та споріднених β-функціоналізованих енонів (еналів) з NCN-бінуклеофілами |
| title_fullStr | Гетероциклізації β-алкокси-, β-діаміноалкіл- та споріднених β-функціоналізованих енонів (еналів) з NCN-бінуклеофілами |
| title_full_unstemmed | Гетероциклізації β-алкокси-, β-діаміноалкіл- та споріднених β-функціоналізованих енонів (еналів) з NCN-бінуклеофілами |
| title_short | Гетероциклізації β-алкокси-, β-діаміноалкіл- та споріднених β-функціоналізованих енонів (еналів) з NCN-бінуклеофілами |
| title_sort | гетероциклізації β-алкокси-, β-діаміноалкіл- та споріднених β-функціоналізованих енонів (еналів) з ncn-бінуклеофілами |
| topic | гетероцикли піримідини енони біс-електрофіли бінуклеофіли |
| topic_facet | heterocycles pyrimidines enones bis-electrophiles binucleophiles гетероцикли піримідини енони біс-електрофіли бінуклеофіли |
| url | https://bioorganica.com.ua/index.php/journal/article/view/13 |
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