A One-Pot Synthesis of 2-Aminopyrimidines from Ketones, Arylacetylenes, and Guanidine

Article abstract of DOI:10.1021/acs.joc.6b02233

The three-component reaction of ketones, arylacetylenes, and guanidine catalyzed by the KOBu^t/DMSO system leads to 2-aminopyrimidines in up to 80% yield. Depending on structure of the starting ketones, the aromatization of intermediate dihydropyrimidines occurs either with loss of hydrogen molecules or methylbenzenes. The latter process takes place in the ketones, in which one of the substituents is not a methyl group. The reaction conditions are tolerable for dialkyl-, aryl(hetaryl) alkyl-, and cycloalkyl ketones.

Full text of DOI:10.1021/acs.joc.6b02233

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Article
A One-Pot Synthesis of 2#Aminopyrimidines
from Ketones, Arylacetylenes and Guanidine
Elena Yu Schmidt, Inna V. Tatarinova, Nadezhda I. Protsuk, Igor A. Ushakov, and Boris A. Trofimov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02233 • Publication Date (Web): 01 Dec 2016
Downloaded from http://pubs.acs.org on December 2, 2016
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A One-Pot Synthesis of 2‑Aminopyrimidines from Ketones, Arylacetylenes
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and Guanidine
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Elena Yu. Schmidt, Inna V. Tatarinova, Nadezhda I. Protsuk, Igor’ A. Ushakov and Boris A.
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Trofimov*
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A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1
Favorsky Str., 664033 Irkutsk, Russia
Eꢀmail: boris_trofimov@irioch.irk.ru
Graphical abstract
ABSTRACT
The threeꢀcomponent reaction of ketones, arylacetylenes and guanidine catalyzed by the
KOBut/DMSO system leads to 2ꢀaminopyrimidines in up to 80% yield. Depending on structure
of the starting ketones, the aromatization of intermediate dihydropyrimidines occurs either with
loss of hydrogen molecule or methylbenzenes. The latter process takes place for the ketones, in
which one of the substituents is not a methyl group. The reaction conditions are tolerable for
dialkylꢀ, aryl(hetaryl) alkylꢀ and cycloalkyl ketones.
Introduction
The pyrimidine structural motif is a fundamental part of nucleic acids and associated with
numerous biological activities.1 Substituted aminopyrimidine nuclei are common in the marketed
drugs such as antiꢀatherosclerotic Aronixil®, antiꢀhistaminic Thonzylamine® (I), antianxielytic
Buspirone® (II), antiꢀpsoriatic Enazadrem® (III), and other medicinally relevant compounds
(Fig. 1).2
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Figure 1. Approved drugs containing aminopyrimidine scaffold
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The discovery of a series of aminopyrimidine derivatives inhibiting the protein kinases is
one of the most important advances in the field of synthetic chemistry of aminopyrimidines.1a,3
Some other biological activities of these molecules include antitubercular,4 adenosine receptor
antagonists,5 analgesic6 and antiꢀinflammatory.5
An essential role of these compounds as potential drugs for treating oncologic diseases
makes the development of the methods for their preparation one of the priority goals of fine
organic synthesis. The various routes to aminopyrimidines and their derivatives are known.7 A
popular approach is the condensation of chalcones with guanidine (Scheme 1).8
Scheme 1. Synthesis of 2ꢀamonopyrimidines from chalcones and guanidine8
These methods are actually twoꢀstep since they require preliminary preparation of
chaclones and are limited in the substrate scope (mostly aromatic substituents). Despite a number
of existing protocols for the construction of this exceptionally valuable heterocyclic core, there is
still a lot of space for finding other rational approaches in terms of both interesting chemistry and
novel structures.
Results and Discussion
Nowadays, the recently discovered baseꢀcatalyzed addition of ketones to alkynes to
afford β,γꢀethylenic ketones9 has been successfully employed as the intermediate step for an
efficient oneꢀpot synthesis of 2ꢀisoxazolines,10 2ꢀpyrazolines11 and 1ꢀformylꢀ2ꢀpyrazolines,12
benzoxepines,13 2,5ꢀdiaryl furans9a,14 and acylated therphenyls.15
As further development of this original methodology for the assembly of valuable carboꢀ
and heterocyclic compounds, we disclose here a new general oneꢀpot strategy for the synthesis of
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2‑aminopyrimidines via the sequential threeꢀcomponent reaction between ketones 1,
arylacetylenes 2 and guanidine (Table 1).
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The overall synthesis of aminopyrimidines 3,4 is implemented as follows: to a mixture of
ketone 1 and arylacetylene 2 in the KOBut/DMSO system kept at 100 °C for 30 min, water and
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guanidine salt (e.g., nitrate, hydrochloride) are added at 70 C, and after 0.5ꢀ4.0 h the reaction
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mixture is treated with KOH (in equimolar ratio relative to the reactants) at the same temperature
for 30 min.
Table 1. Synthesis of 2ꢀaminopyrimidines 3 and 4 from ketones 1, arylacetylenes 2 and
guanidinea
entry
1
ketone
arylacetylene
product, yield (%)b
1a
2a
3a, 51
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2b
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4a, 68
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1b
4a, 60
4a, 63
2b
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3c, 32
4b, 31
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4c, 70
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3h, 31
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15c
aReagents and conditions: 1) ketone 1 (5 mmol), arylacetylene 2 (5 mmol), KOBut (6 mmol, 0.67 g),
DMSO (10 mL), 100 oC, 30 min; 2) H2O (5 mmol, 0.09 g), (NH2)2C=NH·HA (6 mmol), 70 oC, 0.5 h for
ketones 1f,i,j, 3 h for ketones 1a-e, 4 h for ketones 1g,h; 3) KOH·0.5 H2O (5 mmol, 0.33 g), 70 oC, 0.5 h.
bIsolated yield after the workup and column chromatography (Al2O3, benzeneꢀdiethyl ether with gradient
from 1 : 0 to 10 : 1). cThese experiments were carried out under the argon.
As seen from Table 1, two series of aminopyrimidines can be separately obtained, 4ꢀ
benzylꢀsubstituted (3a-h) and unsubstituted at the position 4 (4a-f), i.e. those resulted from
elimination of methyl benzenes. The latter are formed in the case, when the substrates are not
methyl ketones (R2 ≠ H).
The strategy for oneꢀpot synthesis of aminopyrimidines is effective for a diversity of
ketones 1 such as dialkyl 1a, cycloalkyl 1b-e, and alkylaryl 1f-h as well as for the substituted
arylacetylenes. Acetyl naphthalene 1i and acetyl thiophene 1j tolerate the reaction conditions and
also afford the desired products, though in modest yields. Apart from 3,3ꢀdimethylꢀbutanꢀ2ꢀone
1a (Table 1, entries 1,2), two other dialkyl ketones (butanꢀ2ꢀone and 4ꢀmethylꢀpentanꢀ2ꢀone),
which could give mixtures of regioisomers, have also been tested in this reaction. In both the
cases complex mixtures of inseparable products were formed. Certainly, it is understood that
each combination of the reactants requires its own optimization.
Upon comparison of this synthesis with the previous ones based on chaclones (Scheme
1), the following advantages seem obvious: (i) oneꢀstep protocol, (ii) a greater diversity of the
substituents nature, (iii) the possibility to introduce the above substituents in different
combinations. All together this allows a better structural diversity to be attained.
The mechanism of the aminopyrimidine formation deserves a special physicalꢀchemical
investigation. In this paper, focused mainly on the synthesis, it could be relevant to consider just
plausible schemes. It might be assumed that the assembly of 2ꢀaminopyrimidines 3 and 4
consists of the following key steps (Scheme 2): dienolates A, the primary adducts of ketones 1 to
arylacetylenes 2,9 react with water to release β,γꢀunsaturated ketones B, which interact with
guanidine giving the openꢀchain intermediates C. The latter undergo the ring closure to
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dihydropyrimidines D. The cyclization does not require the preliminary conversion of the
adducts C to the corresponding α,βꢀunsaturated isomers since the nucleophilic addition to the
styrene moiety is also possible.16 The further aromatization of dihydropyrimidines D leads to
products 3 or 4.
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The aromatization follows the two pathways: when R2 = H, intermediates D normally
lose a hydrogen molecule to give aminopyrimidines 3 (Scheme 2), while when R2 ≠ H, the
elimination of methyl benzenes from the dihydropyrimidine ring (identified by GLC) takes place
to deliver benzylꢀfree aminopyrimidines 4 (Scheme 2).
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Scheme 2. Plausible scheme of the assembly of 2ꢀaminopyrimidines 3,4 from ketones 1,
arylcetylenes 2 and guanidine
The experiments with cyclohexanone 1b and 4ꢀfluoromethylacetylene 2b or 4ꢀ
methylphenylacetylene 2c have shown that during both reactions, the elimination of the expected
1ꢀmethylꢀ4ꢀfluorobenzene and 1,4ꢀdimethylbenzene occur to result in approximately the same
yields of the final products (Table 1). This demonstrates that aromatization of
dihydropyrimidines with elimination of the expected methyl aromatics does not significantly
influence by electronꢀdonating and electronꢀwithdrawing substituents (R3). Recently,15 the same
aromatization with elimination of methyl aromatics from the dihydrobenzene moiety under
similar conditions (KOBut/DMSO) has been observed during the synthesis of terphenyls from
ketones and arylacetylenes.
The only exception, when both dehydrogenation and debenzylation takes place is the
reaction with 4ꢀmethylcyclohexanone 1c. This interesting fact does not find so far a clearꢀcut
rationalization and will be specially addressed during further investigations.
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Since the aromatization of the intermediate dihydropyrimidines D does not proceed
without addition of KOH, it may be suggested that the ambient oxygen probably does not
participate in this process. To check whether the air oxygen is involved in the aromatization, the
selected experiments (Table 1, entries 8,11,13ꢀ15) under the argon with degassed solvent
(DMSO) have been carried out. The results obtained shows that the aromatization does take
place also in this case. By the way, those amounts of oxygen, which is contained in volume of
closed reaction vessel (5 mmol of the reactants, 10 ml of DMSO in 30ꢀml vessel) would be
enough only to aromatize just a few percent of dihydropyrimidines D.
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Dehydrogenation with the hydride ion abstraction/transfer in strongly basic media is wellꢀ
known classic chemistry, e.g. the DumasꢀStass name reaction.17
Also, according to18 one might suppose that DMSO plays a role of an oxidant in this case.
However, the GCꢀMS analysis does not detect even traces of Me2S in the reaction mixture after
completion of aminopyrimidines synthesis, thus clearly indicating that DMSO is not an oxidant
in this process.
It is worthwhile to underline again that without additional feeding of KOH after
neutralization of KOBut on the first stage of the reaction, the aromatization does not occur: the
reaction products represent a mixture of isomeric dihydropyrimidines D. It means that the
basicity function (i.e. ability of the medium to deprotonate intermediates) is a key factor in the
aromatization of intermediate dihydropyrimidines D. Besides, as it has been shown in the
previous publications,9 the addition of ketones to acetylenes (the first step of the reaction,
Scheme 2) did not proceed in solvents other than DMSO (benzene, THF, DMF, Nꢀ
methylpyrrolidone).
As an additional test of the proposed scheme of 2ꢀaminopyrimidines 3 formation, we
have implemented the reaction of the preliminarily isolated intermediates B (β,γꢀunsaturated
ketones 5a,i) with guanidine nitrate under the above conditions. The expected pyrimidines 3a,f
were obtained in reasonable yields (Scheme 3).
Scheme 3. Transformation of intermediate β,γꢀunsaturated ketones 5a,i into 2ꢀ
aminopyrimidines 3a,f
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The loss of a benzyl group was also observed, when the reaction of intermediate B (β,γꢀ
unsaturated ketone 5b), preliminarily obtained from cyclohexanone 1b and phenylacetylene 2a,
was treated with guanidine nitrate under the above conditions (Scheme 4). The expected
aminopyrimidine 4a was isolated in 72 % yield.
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Scheme 4. Transformation of intermediate β,γꢀunsaturated ketone 5b into 2ꢀ
aminopyrimidine 4a
The reaction of cyclohexanone 1b with guanidine nitrate without phenylacetylene does
not result in the formation of aminopyrimidine 4a (except for a complex mixture of the ketone
autocondensation products has been formed) thus indicating that the additional carbon atom in
the aminopyrimidine ring is delivered from phenylacetylene.
As an alternative one might suppose that the aminopyrimidine assembly is preceded by
isomerization of enolates A or β,γꢀethylenic ketones B to the corresponding α,βꢀethylenic
isomers. Afterwards, the reaction could follow the way described by W. Guo.7f However, the
previous publications9 show that such isomerization does not take place to significant degree for
these substrates: it has been found that α,βꢀethylenic ketones were minor admixtures (5ꢀ10%) in
major β,γꢀisomers. Consequently, if the former participate in this cyclization, it could be just a
minor channel compared to a major reaction via β,γꢀethylenic ketones.
The variable yields of aminopyrimidines appear to be indicative of the fact that, as shown
above, the overall process involves several mechanistic steps (Scheme 1): addition of ketones to
arylacetylenes, the reaction of the resulted β,γꢀunsaturated ketones B with guanidine, cyclization
of the adducts C and aromatization. Consequently, in this case, the yield is a complex function of
a number of parameters: substituents effect, reaction temperature and time, catalyst
concentration, basicity/acidity, properties of the reaction medium, all those being altered during
the process. Therefore it is not surprising that a range of the yield was obtained.
In conclusion, a oneꢀpot synthesis of 2ꢀaminopyrimidines, medicinally important building
blocks, has been developed via sequential threeꢀcomponent reaction between ketones,
arylacetylenes and guanidine. This methodology has several synthetically attractive features:
operationally simple procedure, the use of readily available starting materials (ketones and
arylacetylenes), simple transition metalꢀfree catalytic system (KOBut, KOH) and diverse
structural variation in the products.
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Experimental section
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General remarks. Н (400.1 MHz), 13С (100.6 MHz), 15N (40.5 MHz) NMR spectra
were recorded in СDСl3 with hexamethyldisiloxane (HMDS) as an internal standard. Chemical
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shifts (δ) are given in ppm, coupling constants (J) in Hz. The assignment of signals in the Н
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NMR spectra was made using COSY and NOESY experiments. Resonance signals of carbon
atoms were assigned based on 1Hꢀ13C HSQC and 1Hꢀ13C HMBC experiments. The values of the
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15N were measured through the 2D Hꢀ15N HMBC experiment. The 15N chemical shifts were
referenced to MeNO2. IR spectra were taken with FTꢀIR. All chemicals and solvents are
commercially available and were used without further purification. The elaborated procedure
does not require degassing of DMSO or use of inert atmosphere. The benefit of DMSO as a
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solvent is that it is stable up to 150 C for a long time (24 h, weight lost 0.1ꢀ1.0%).19 The
formation of methylbenzenes was detected by GLC analysis of reaction mixture using standards.
General procedure for the synthesis of aminopyrimidines 3,4. A mixture of ketone 1
(5 mmol), arylacetylene 2 (5 mmol), and KOBut (6 mmol, 673 mg) in DMSO (10 mL) was
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heated (100 C) and stirred at 100 C for 30 min. After cooling (70 С), H2O (5 mmol, 90 mg)
and (NH2)2C=NH⋅HNO3 (6.0 mmol, 733 mg) or (NH2)2C=NH⋅HCl (6.0 mmol, 573 mg) were
added to the reaction mixture and stirred at 70 oC for 0.5 h (for ketones 1f,i,j), 3.0 h (for ketones
1a-e) and 4.0 h (for ketones 1g,h). Then KOH⋅0.5H2O (5 mmol, 325 mg) was added and the
mixture was stirred at 70 oC for 30 min. The reaction mixture, after cooling (rt), was diluted with
H2O (15 mL), neutralized with NH4Cl and was extracted with CHCl3 (10 mL × 4). The organic
extract was washed with H2O (5 mL × 3) and dried (MgSO4). CHCl3 was evaporated in vacuum
and the residue was purified by column chromatography (Al2O3, eluent C6H6/Et2O with gradient
from 1:0 to 10:1).
4-Benzyl-6-(tert-butyl)pyrimidin-2-amine (3a). Following General procedure, 3a was
prepared from 3,3ꢀdimethylꢀ2ꢀbutanone 1a (0.501 g, 5.0 mmol), phenylacetylene 2a (0.510 g,
5.0 mmol), KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HNO3 (0.733 g,
6.0 mmol) and KOH⋅0.5H2O (0.325 g, 5 mmol). 3a was isolated as a cream oil (0.615 g, 51%
yield); elemental analysis calcd (%) for С15H19N3 (241.33): C 74.65%; H 7.94%; N 17.41%;
found: C 74.60%; H 7.98%; N 17.36%. IR (film): νmax 3487, 3398, 3325, 3317, 3062, 3028,
2962, 2928, 2870, 1953, 1885, 1811, 1613, 1577, 1552, 1487, 1448, 1396, 1359, 1237, 1201
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1174, 1155, 1076, 1029, 965, 926, 853, 804, 758, 703, 574, 552, 524 cmꢀ1; H NMR (400.1
MHz, CDCl3): δ 1.20 (s, 9H, 3Me), 3.87 (s, 2H, CH2Ph), 5.02 (br.s, 2H, NH2), 6.44 (s, 1H, H5),
7.20ꢀ7.22 (m, 3Н, Ho,p), 7.27ꢀ7.30 (m, 2Н, Нm) ppm; 13C NMR (100.6 MHz, CDCl3): δ 29.5
(Me), 37.3 (CꢀMe3), 44.4 (CH2Ph), 106.4 (C5), 126.7 (Cp), 128.7 (2Cm), 129.3 (2Co), 138.5 (Ci),
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163.0 (C4), 170.1 (C2), 179.6 (C6) ppm; 15N NMR (40.5 MHz, CDCl3): δ –138.8 (N3), –143.0
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(N1), –306.3 (NH2) ppm.
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4-(4-Fluorobenzyl)-6-(tert-butyl)pyrimidin-2-amine
(3b).
Following
General
procedure, 3b was prepared from 3,3ꢀdimethylꢀ2ꢀbutanone 1a (0.501 g, 5.0 mmol), 4ꢀ
flourophenylacetylene 2b (0.601 g, 5.0 mmol), KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5
mmol), (NH2)2C=NH⋅HNO3 (0.733 g, 6.0 mmol) and KOH⋅0.5H2O (0.325 g, 5 mmol). 3b was
isolated as a cream oil (0.726 g, 56% yield); elemental analysis calcd (%) for С15H18FN3
(259.32): C 69.47%; H 7.00%; F 7.33%; N 16.20%; found: C 69.60%; H 7.04%; F 7.21%; N
16.11%. IR (film): νmax 3477, 3399, 3318, 3200, 2867, 2187, 1891, 1608, 1576, 1551, 1509,
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1446, 1394, 1356, 1271, 1227, 1159, 1092, 1019, 926, 832, 773, 715, 677, 514 cmꢀ1; H NMR
(400.1 MHz, CDCl3): δ 1.20 (s, 9H, 3Me), 3.83 (s, 2H, CH2Ph), 4.89 (br.s, 2H, NH2), 6.42 (s,
1H, H5), 6.95ꢀ6.99 (m, 2Н, Нm), 7.17ꢀ7.21 (m, 2Н, Нo) ppm; 13C NMR (100.6 MHz, CDCl3): δ
29.4 (Me), 37.2 (CꢀMe3), 43.4 (CH2Ph), 106.2 (C5), 115.4 (d, J = 21.2 Hz, Cm), 130.6 (d, J = 8.1
Hz, Co), 134.0 (d, J = 3.1 Hz, Ci), 161.8 (d, J = 244.4 Hz, Cp), 162.8 (C4), 169.8 (C2), 179.7 (C6)
ppm.
4-Benzyl-6-methyl-5,6,7,8-tetrahydroquinazolin-2-amine (3c). Following General
procedure, 3c was prepared from 4ꢀmethylcyclohexanone 1c (0.561 g, 5.0 mmol),
phenylacetylene 2a (0.510 g, 5.0 mmol), KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol),
(NH2)2C=NH⋅HNO3 (0.733 g, 6.0 mmol) and KOH⋅0.5H2O (0.325 g, 5 mmol). 3c was isolated
o
as a cream solid (0.405 g, 32% yield); m.p. 132ꢀ136 C; elemental analysis calcd (%) for
С16H19N3 (253.34): C 75.85%; H 7.56%; N 16.59%; found: C 75.77%; H 7.62%; N 16.69%. IR
(film): νmax 3479, 3387, 3309, 3185, 3085, 3062, 3029, 2949, 2926, 2886, 2867, 1948, 1805,
1633, 1603, 1574, 1557, 1494, 1470, 1454, 1374, 1362, 1345,1337, 1321, 1302, 1288, 1259,
1244, 1223, 1191, 1180, 1165, 1151, 1136, 1096, 1085, 1075, 1030, 1011, 994, 966, 949, 909,
867, 827, 792, 782, 750, 732, 723, 695, 645, 615, 593, 569, 529, 485, 457 cmꢀ1; 1H NMR (400.1
MHz, CDCl3): δ 1.02 (d, J = 6.6 Hz, 3H, Me), 1.30ꢀ1.40 (m, 1H, 7ꢀCH2), 1.72ꢀ1.81 (m, 1H, H6),
1.82ꢀ1.90 (m, 1H, 7ꢀCH2), 2.04 (dd, J = 15.9, 10.3 Hz, 1H, 5ꢀCH2), 2.66 (dd, J = 15.9, 4.9 Hz,
1H, 5ꢀCH2), 2.65ꢀ2.70 (m, 2H, 8ꢀCH2), 3.92 (s, 2H, CH2), 4.88 (br.s, 2H, NH2), 7.17ꢀ7.23 (m,
3H, Ho,p), 7.25ꢀ7.27 (m, 2H, Hm) ppm; 13C NMR (100.6 MHz, CDCl3): δ 21.7 (Me), 29.0 (C6),
30.3 (C7), 32.0 (C8), 32.5 (C5), 40.7 (CH2Ph), 117.5 (C10), 126.3 (Cp), 128.5 (Cm), 128.7 (Co),
137.6 (Ci), 160.8 (C2), 166.4 (C9), 167.4 (C4) ppm; 15N NMR (40.5 MHz, CDCl3): δ –134.6 (N3),
–140.6 (N1), –307.2 (NH2) ppm.
4-Benzyl-6-phenylpyrimidin-2-amine (3d). Following General procedure, 3d was
prepared from acetophenone 1f (0.605 g, 5.0 mmol), phenylacetylene 2a (0.510 g, 5.0 mmol),
KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HCl (0.573 g, 6.0 mmol) and
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KOH⋅0.5H2O (0.325 g, 5 mmol). 3d was isolated as a cream solid (0.431 g, 33% yield); m.p. 90ꢀ
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94 C; elemental analysis calcd (%) for С17H15N3 (261.32): C 78.13%; H 5.79%; N 16.08%;
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found: C 78.31%; H 5.65%; N 15.95%. IR (film): νmax 3477, 3317, 3183, 3085, 3062, 3029,
2924, 2852, 1954,1891, 1811, 1626, 1600, 1573, 1548, 1495, 1454, 1359, 1238, 1181, 1073,
1030, 1002, 909, 872, 844, 769, 733, 699, 655, 605, 532 cmꢀ1; 1H NMR (400.1 MHz, CDCl3): δ
3.90 (s, 2H, CH2Ph), 5.41 (br.s, 2H, NH2), 6.75 (s, 1H, H5), 7.17ꢀ7.27 (m, 5H, Ho,p,m’), 7.28ꢀ7.35
(m, 3Н, Нm,p’), 7.78ꢀ7.88 (m, 2Н, Нo’) ppm; 13C NMR (100.6 MHz, CDCl3): δ 44.3 (CH2Ph),
107.1 (C5), 126.8 (Cp), 127.1 (Co'), 128.7 (Cm, Cm'), 129.3 (Co), 130.4 (Cp'), 137.6 (Ci’), 138.0
(Ci), 163.4 (C4), 165.8 (C6), 170.9 (C2) ppm; 15N NMR (40.5 MHz, CDCl3): δ –136.8 (N3), –
145.2 (N1), –304.2 (NH2) ppm.
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4-(4-Methylbenzyl)-6-phenylpyrimidin-2-amine (3e). Following General procedure,
3e was prepared from acetophenone 1f (0.605 g, 5.0 mmol), 4ꢀtolylacetylene 2c (0.581 g, 5.0
mmol), KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HNO3 (0.733 g, 6.0
mmol) and KOH⋅0.5H2O (0.325 g, 5 mmol). 3e was isolated as a cream solid (0.564 g, 41%
yield); m.p. 82ꢀ88 oC; elemental analysis calcd (%) for С18H17N3 (275.35): C 78.52%; H 6.22%;
N 15.26%; found: C 78.61%; H 6.15%; N 15.09%. IR (film): νmax 3478, 3315, 3184, 3061, 2925,
2854, 1959,1902, 1801, 1629, 1565, 1455, 1359, 1234, 1180, 1147, 1078, 1028, 913, 811, 765,
733, 696, 643, 555 cmꢀ1; 1H NMR (400.1 MHz, CDCl3): δ 2.30 (s, 3H, Me), 3.90 (s, 2H, CH2Ph),
5.32 (br.s, 2H, NH2), 6.80 (s, 1H, H5), 7.08ꢀ7.20 (m, 4Н, Нo,m.), 7.39ꢀ7.41 (m, 3Н, Нm’,p’), 7.86ꢀ
7.89 (m, 2Н, Нo') ppm; 13C NMR (100.6 MHz, CDCl3): δ 20.9 (Me), 43.8 (CH2Ph), 106.9 (C5),
126.9 (Co'), 128.5 (Cm), 129.2 (Co), 130.1 (Cp'), 130.9 (Cm'), 134.7 (Ci), 136.1 (Cp), 137.4 (Ci’),
163.1 (C4), 165.6 (C6), 171.1 (C2) ppm; 15N NMR( 40.5 MHz, CDCl3): δ –136.6 (N3), –144.7
(N1), –304.1 (NH2) ppm.
4-Benzyl-6-(naphthalene-2-yl) pyrimidin-2-amine (3f). Following General procedure,
3f was prepared from 2ꢀacetylnaphthalene 1i (0.851 g, 5.0 mmol), phenylacetylene 2a (0.510 g,
5.0 mmol), KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HCl (0.573 g, 6.0
mmol) and KOH⋅0.5H2O (0.325 g, 5 mmol) under the argon. 3f was isolated as a white solid
o
(0.763 g, 49% yield); m.p. 163ꢀ168 C; elemental analysis calcd (%) for С21H17N3 (311.38): C
81.00%; H 5.50%; N 13.49%; found: C 80.81%; H 5.55%; N 13.58%. IR (film): νmax 3476,
3313, 3184, 3061, 3027, 2923, 2860, 1918, 1629, 1568, 1551, 1503, 1454, 1366, 1233, 1178,
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1144, 1076, 1027, 904, 852, 808, 752, 704, 568, 471 cmꢀ1; H NMR (400.1 MHz, CDCl3): δ
4.00 (s, 2H, CH2Ph), 5.12 (br.s, 2H, NH2), 6.98 (s, 1H, H5), 7.20ꢀ7.38 (m, 5H, Ho,m,p), 7.47ꢀ7.52
(m, 2H, H10, H11), 7.82ꢀ7.92 (m, 3H, H9, H12, H13), 7.98ꢀ8.01 (m, 1H, H14), 8.43 (s, 1H, H8) ppm;
13C NMR (100.6 MHz, CDCl3): δ 44.4 (CH2Ph), 107.3 (C5), 124.2 (C13), 126.5 (Cp), 126.8 (C9),
127.0 (C11), 127.1 (C12), 127.7 (C14), 128.5 (C10), 128.8 (Cm), 129.0 (C8), 129.3 (Co), 133.3 (C16),
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134.5 (C15), 134.8 (C7), 138.1 (Ci), 163.5 (C4), 165.7 (C6), 171.0 (C2) ppm; 15N NMR (40.5
MHz, CDCl3): δ –136.6 (N3), –144.7 (N1), –304.9 (NH2) ppm.
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4-Benzyl-6-(thiophen-2-yl)pyrimidin-2-amine (3g). Following General procedure, 3g
was prepared from 2ꢀacethylthiophene 1j (0.631 g, 5.0 mmol), phenylacetylene 2a (0.510 g, 5.0
mmol), KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HCl (0.573 g, 6.0
mmol) and KOH⋅0.5H2O (0.325 g, 5 mmol) under the argon. 3g was isolated as a cream solid
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(0.401 g, 30% yield); m.p. 180ꢀ185 C; elemental analysis calcd (%) for С15H13N3S (267.35): C
67.39 %; H 4.90%; N 15.72%; S 11.99%; found: C 67.37%; H 4.91%; N 15.62%; S 11.94%. IR
(film): νmax 3485, 3289, 3166, 3100, 3083, 3028, 2920, 1622, 1573, 1556, 1548, 1518, 1494,
1459, 1446, 1416, 1366, 1342, 1227, 1194, 1172, 1074, 1044, 1030, 908, 862, 839, 826, 791,
736, 728, 707, 622, 608, 577, 568, 520 cmꢀ1; H NMR (400.1 MHz, CDCl3): δ 3.93 (s, 2H,
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CH2Ph), 5.05 (br.s, 2H, NH2), 6.72 (s, 1H, H5), 7.06 (dd, J = 3.8, 5.0 Hz, 1H, H9), 7.20ꢀ7.42 (m,
5H, Ho,m,p), 7.41 (d, J = 5.0 Hz, 1H, H10), 7.57 (d, J = 3.8 Hz, 1H, H8) ppm; 13C NMR (100.6
MHz, CDCl3): δ 44.2 (CH2Ph), 105.4 (C5), 126.8 (Cp), 127.0 (C8), 128.1 (C9), 128.7 (Cm), 129.2
(C10), 129.3 (Co), 138.0 (Ci), 143.0 (C7), 160.3 (C6), 163.2 (C4), 170.9 (C2) ppm; 15N NMR (40.5
MHz, CDCl3): δ –136.6 (N3), –148.3 (N1), –305.6 (NH2) ppm.
4-(4-Methylbenzyl)-6-(thiophen-2-yl)pyrimidin-2-amine (3h). Following General
procedure, 3h was prepared from 2ꢀacetylthiophene 1j (0.631 g, 5.0 mmol), 4ꢀtolylacetylene 2c
(0.581 g, 5.0 mmol), KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HNO3
(0.733 g, 6.0 mmol) and KOH⋅0.5H2O (0.325 g, 5 mmol) out under the argon. 3h was isolated as
a cream solid (0.436 g, 31% yield); m.p. 123ꢀ126 oC; elemental analysis calcd (%) for С16H15N3S
(281.38): C 68.30 %; H 5.37%; N 14.93%; S 11.40%; found: C 68.23%; H 5.28%; N 14.78%; S
11.40%. IR (film): νmax 3474, 3318, 3186, 3104, 3025, 2921, 2866, 1626, 1570, 1548, 1446,
1424, 1366, 1232, 1174, 1042, 910, 820, 791, 758, 713, 637, 535 cmꢀ1; H NMR (400.1 MHz,
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CDCl3): δ 2.32 (s, 3H, Me), 3.88 (s, 2H, CH2Ph), 5.07 (br.s, 2H, NH2), 6.72 (s, 1H, H5), 7.07 (dd,
J = 3.7, 5.0 Hz, 1H, H9), 7.10ꢀ7.16 (m, 4H, Ho,m), 7.41 (d, J = 5.0 Hz, 1H, H10), 7.57 (d, J = 3.7
Hz, 1H, H8) ppm; 13C NMR (100.6 MHz, CDCl3): δ 21.1 (Me), 43.9 (CH2Ph), 105.3 (C5), 127.0
(C8), 128.0 (C9), 129.1 (C10), 129.2 (Co), 129.4 (Cm), 134.9 (1C, Ci), 136.4 (Cp), 143.0 (C7),
160.3 (C6), 163.1 (C4), 171.2 (C2) ppm; 15N NMR (40.5 MHz, CDCl3): δ –136.6 (N3), –149.0
(N1), –304.1 (NH2) ppm.
5,6,7,8-Tetrahydroquinazolin-2-amine (4a). Following General procedure, 4a was
prepared from cyclohexanone 1b (0.491 g, 5.0 mmol), phenylacetylene 2a (0.510 g, 5.0 mmol),
KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HNO3 (0.733, g 6.0 mmol)
and KOH⋅0.5H2O (0.325 g, 5 mmol). 4a was isolated as a white solid (0.507 g, 68% yield); m.p.
182ꢀ187 oC; elemental analysis calcd (%) for С8H11N3 (149.19): C 64.40%; H 7.43%; N 28.16%;
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found: C 64.32%; H 7.49%; N 28.10%. IR (film): νmax 3299, 3157, 2991, 2927, 2849, 2838,
2762, 1656, 1650, 1632, 1595, 1572, 1557, 1536, 1510, 1503, 1478, 1454, 1441, 1422, 1416,
1346, 1335, 1314, 1276, 1244, 1213, 1180, 1154, 1143, 1107, 1097, 1077, 1065, 959, 944, 937,
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858, 822, 788, 772, 762, 749, 727, 670, 665, 637, 593, 558, 505 cmꢀ1; H NMR (400.1 MHz,
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CDCl3): δ 1.75ꢀ1.77 (m, 2H, 6ꢀСH2), 1.81ꢀ1.83 (m, 2H, 7ꢀСH2), 2.55ꢀ2.58 (m, 2H, 5ꢀСH2), 2.64ꢀ
2.67 (m, 2H, 8ꢀСH2), 4.94 (br.s, 2H, NH2), 7.95 (s, 1H, H4) ppm; 13C NMR (100.6 MHz,
CDCl3): δ 21.9 (C7), 22.1 (C6), 24.4 (C5), 31.3 (C8), 119.4 (C10), 157.7 (C4), 160.8 (C2), 166.3
(C9) ppm.
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Following General procedure, 4a was also prepared (0.447 g, 60% yield) from
cyclohexanone 1b (0.491 g, 5.0 mmol), 4ꢀfluorophenylacetylene 2b (0.601 g, 5.0 mmol), KOBut
(0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HNO3 (0.733, g 6.0 mmol) and
KOH⋅0.5H2O (0.325 g, 5 mmol).
Following General procedure, 4a was also prepared (0.470 g, 63% yield) from
cyclohexanone 1b (0.491 g, 5.0 mmol), 4ꢀmethylphenylacetylene 2c (0.581 g, 5.0 mmol), KOBut
(0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HNO3 (0.733, g 6.0 mmol) and
KOH⋅0.5H2O (0.325 g, 5 mmol).
6-Methyl-5,6,7,8-tetrahydroquinazolin-2-amine (4b). Following General procedure,
4b was prepared from 4ꢀmethylcyclohexanone 1c (0.561 g, 5.0 mmol), phenylacetylene 2a
(0.510 g, 5.0 mmol), KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HNO3
(0.733, g 6.0 mmol) and KOH⋅0.5H2O (0.325 g, 5 mmol). 4b was isolated as a white solid (0.253
o
g, 31% yield); m.p. 170ꢀ172 C; elemental analysis calcd (%) for С9H13N3 (163.22): C 66.23%;
H 8.03%; N 25.74%; found: C 66.11%; H 8.10%; N 25.69%. IR (film): νmax 3301, 3153, 2989,
2952, 2922, 2849, 1659, 1594, 1555, 1486, 1453, 1435, 1416, 1377, 1350, 1322, 1298, 1265,
1225, 1202, 1180, 1148, 1134, 1095, 1076, 1022, 958, 948, 929, 909, 863, 814, 798, 781, 752,
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730, 695, 646, 603, 513 cmꢀ1; H NMR (400.1 MHz, CDCl3): δ 1.05 (d, J = 6.6 Hz, 3H, Me),
1.43ꢀ1.47 (m, 1H, 7ꢀCH2), 1.80ꢀ1.86 (m, 1H, H6), 1.87ꢀ1.91 (m, 1H, 7ꢀCH2), 2.16 (dd, J = 15.8,
10.5 Hz, 1H, 5ꢀCH2), 2.61 (dd, J = 15.8, 5.2 Hz, 1H, 5ꢀCH2), 2.65ꢀ2.72 (m, 2H, 8ꢀCH2), 4.89
(br.s, 2H, NH2), 7.95 (s, 1H, H4) ppm; 13C NMR (100.6 MHz, CDCl3): δ 21.5 (Me), 28.9 (C6),
30.6 (C7), 31.6 (C8), 33.4 (C5), 119.6 (C10), 158.2 (C4), 161.3 (C2), 166.7 (C9) ppm; 15N NMR
(40.5 MHz, CDCl3): δ –135.3 (N1), –139.1 (N3), –308.8 (NH2) ppm.
6,7,8,9-Tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine (4c). Following General
procedure, 4c was prepared from cycloheptanone 1d (0.561 g, 5.0 mmol), phenylacetylene 2a
(0.510 g, 5.0 mmol), KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HCl
(0.573, g 6.0 mmol) and KOH⋅0.5H2O (0.325 g, 5 mmol). 4c was isolated as a white solid (0.571
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g, 70% yield); m.p. 132ꢀ136 C; elemental analysis calcd (%) for С9H13N3 (163.22): C 66.23%;
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H 8.03%; N 25.74%; found: C 66.29%; H 8.01%; N 25.66%. IR (film): νmax 3319, 3168, 2960,
2918, 2849, 2745, 1661, 1596, 1558, 1488, 1439, 1350,1335, 1326, 1284, 1267, 1236, 1193,
1181, 1151, 1143, 977, 947, 941, 883, 870, 834, 801, 757, 730, 701, 604, 571, 546, 517, 492,
444 cmꢀ1; 1H NMR (400.1 MHz, CDCl3): δ 1.59ꢀ1.60 (m, 2H, 6ꢀCH2), 1.66ꢀ1.67 (m, 2H, 8ꢀCH2),
1.81ꢀ1.84 (m, 2H, 7ꢀCH2), 2.57ꢀ2.59 (m, 2H, 5ꢀCH2), 2.75ꢀ2.77 (m, 2H, 9ꢀCH2), 5.00 (br.s, 2H,
NH2), 7.91 (s, 1H, H4) ppm; 13C NMR (100.6 MHz, CDCl3): δ 26.1 (C8), 28.5 (C6), 31.2 (C5),
32.5 (C7), 39.1 (C9), 125.2 (C11), 156.9 (C4), 161.7 (C2), 172.6 (C10) ppm; 15N NMR (40.5 MHz,
CDCl3): δ –133.0 (N1), –140.6 (N3), –307.2 (NH2) ppm.
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5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidin-2-amine (4d). Following General
procedure, 4d was prepared from cyclooctanone 1e (0.631 g, 5.0 mmol), phenylacetylene 2a
(0.510 g, 5.0 mmol), KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HNO3
(0.733, g 6.0 mmol) and KOH⋅0.5H2O (0.325 g, 5 mmol) under the argon. 4d was isolated as a
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white solid (0.705 g, 80% yield); m.p. 151ꢀ156 C; elemental analysis calcd (%) for С10H15N3
(177.25): C 67.76%; H 8.53%; N 23.71%; found: C 67.68%; H 8.57%; N 23.67%. IR (film): νmax
3295, 3147, 2918, 2844, 2779, 1663, 1597, 1560, 1489, 1445, 1421, 1347, 1319, 1268, 1225,
1168, 1150, 1131, 1090, 996, 921, 917, 883, 866, 836, 819, 794, 762, 731, 699, 650, 594, 526,
488, 441 cmꢀ1; 1H NMR (400.1 MHz, CDCl3): δ 1.30ꢀ1.48 (m, 4H, 7ꢀCH2, 8ꢀCH2), 1.60ꢀ1.66 (m,
2H, 6ꢀCH2), 1.72ꢀ1.78 (m, 2H, 9ꢀCH2), 2.55ꢀ2.61 (m, 2H, 5ꢀCH2), 2.68ꢀ2.75 (m, 2H, 10ꢀCH2),
4.85 (br.s, 2H, NH2), 7.95 (s, 1H, H4) ppm; 13C NMR (100.6 MHz, CDCl3): δ 25.7 (C9), 25.9
(C6), 28.3 (C7), 29.8 (C8), 32.2 (C5), 33.9 (C10), 123.6 (C12), 157.5 (C4), 162.0 (C2), 170.4 (C11)
ppm; 15N NMR (40.5 MHz, CDCl3): δ –133.7 (N1), –138.8 (N3), –307.1 (NH2) ppm.
5-Methyl-6-phenylpyrimidin-2-amine (4e). Following General procedure, 4e was
prepared from propiophenone 1g (0.671 g, 5.0 mmol), phenylacetylene 2a (0.510 g, 5.0 mmol),
KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HNO3 (0.733 g, 6.0 mmol)
and KOH⋅0.5H2O (0.325 g, 5 mmol) under the argon. 4e was isolated as a cream solid (0.556 g,
60% yield); m.p. 122ꢀ128 oC; elemental analysis calcd (%) for С11H11N3 (185.23): C 71.33%; H
5.99%; N 22.69%; found: C 71.41%; H 5.93%; N 22.61%. IR (film): νmax 3344, 3295, 3163,
2936, 1633, 1593, 1573, 1543, 1477, 1441, 1409, 1385, 1289, 1202, 1180, 1143, 1078, 989, 913,
806, 777, 745, 710, 639, 595, 563 cmꢀ1; 1H NMR (400.1 MHz, CDCl3): δ 2.16 (s, 3H, Me), 5.16
(br.s, 2H, NH2), 7.35ꢀ7.47 (m, 3H, Hm,p), 7.49ꢀ7.55 (m, 2Н, Нo), 8.17 (s, 1H, H4) ppm; 13C NMR
(100.6 MHz, CDCl3): δ 15.9 (Me), 117.4 (C5), 128.3 (Cm), 128.4 (Co), 128.9 (Cp), 138.6 (Ci),
159.9 (C4), 161.7 (C2), 166.2 (C6) ppm; 15N NMR (40.5 MHz, CDCl3): δ –133.8 (N1), –135.9
(N3), –307.1 (NH2) ppm.
5-Ethyl-6-phenylpyrimidin-2-amine (4f). Following General procedure, 4f was
prepared from butyrophenone 1h (0.741 g, 5.0 mmol), phenylacetylene 2a (0.510 g, 5.0 mmol),
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KOBut (0.673 g, 6.0 mmol), H2O (0.090 g, 5 mmol), (NH2)2C=NH⋅HNO3 (0.733 g, 6.0 mmol)
and KOH⋅0.5H2O (0.325 g, 5 mmol). 4f was isolated as a cream solid (0.577 g, 58% yield); m.p.
o
84ꢀ88 C; elemental analysis calcd (%) for С12H13N3 (199.25): C 72.33%; H 6.58%; N 21.09%;
found: C 72.40%; H 6.55%; N 21.00%. IR (film): νmax 3479, 3315, 3183, 3068, 2968, 2924,
2872, 1958, 1889, 1800, 1629, 1585, 1543, 1471, 1411, 1377, 1350, 1326, 1293, 1201, 1071,
1023, 961, 916, 812, 773, 703, 641, 570, 449 cmꢀ1; 1H NMR (400.1 MHz, CDCl3): δ 1.02 (t, J =
7.5 Hz, 3H, Me), 2.47 (q, J = 7.5 Hz, 2H, CH2), 5.61 (br.s, 2H, NH2), 7.38ꢀ7.42 (m, 5H, Ho,m,p),
8.18 (s, 1H, H4) ppm; 13C NMR (100.6 MHz, CDCl3): δ 15.3 (Me), 22.1 (CH2), 123.3 (C5), 128.0
(Cm), 128.1 (Co), 128.6 (Cp), 138.5 (Ci), 158.9 (C4), 161.5 (C2), 166.2 (C6) ppm; 15N NMR (40.5
MHz, CDCl3): δ –133.7 (N1), –136.6 (N3), –304.9 (NH2) ppm.
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Supporting Information Available: Copies of 1H and 13C NMR spectra of all compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
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