4-Methyl- and 4-(halophenyl)pyrimidinium (4-halobenzoyl)methylides. Correlation of structure, stability, reactivity, and biological activity

Article abstract of DOI:10.1002/hlca.200590214

For the first time in the cycloimminium ylide series, we present a theoretical and experimental study concerning the correlation between structure, stability, reactivity, and biological activity of 4-(R)-pyrimidinium (4-halobenzoyl)methylides (R = Me and

Full text of DOI:10.1002/hlca.200590214

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4-Methyl- and 4-(Halophenyl)pyrimidinium (4-Halobenzoyl)methylides.
Correlation of Structure, Stability, Reactivity, and Biological Activity
by Costel C. Moldoveanu and Ionel I. Mangalagiu*
Organic Chemistry Department, ‘Al. I. Cuza’ University Iasi, 11 Carol I Bd., 700506 Iasi, Romania
(phone: +40232201343; e-mail: ionelm@uaic.ro)
For the first time in the cycloimminium ylide series, we present a theoretical and experimental study con-
cerning the correlation between structure, stability, reactivity, and biological activity of 4-(R)-pyrimidinium (4-
halobenzoyl)methylides (R=Me and 4-chlorophenyl; hal=X=F, Cl, Br, I; see 5 and 6 in Scheme 1). The 4-
methylpyrimidinium (4-halobenzoyl)methylides 5 are relatively stable compounds, while the (4-chlorophenyl)-
pyrimidinium (4-halobenzoyl)methylides 6 are more unstable. Their stability varies with the nature of the sub-
stituents at the ylide carbanion and pyrimidinium cation moieties as confirmed by quantum-chemical calcula-
tions. The latter also disclose the possibility to use pyrimidinium ylides as nucleophilic reagents as well as
1,3-dipoles in reactions with appropriate reagents. The experimental data obtained confirm the calculations con-
cerning the nucleophilicity and reactivity of the ylides 5 and 6. Moreover, the influence of microwave irradiation
on the synthesis of the pyrimidinium salts 3 and 4 from pyrimidine and an organic halide is studied and reveals a
remarkable reaction-rate increase under microwave irradiation as compared to classical conditions; this allows
the general and facile synthesis of the salts 3 and 4 (Scheme 1, Table 1). The in vitro biological activity of the
newly obtained 4-methylpyrimidine compounds is also tested. Some of them exhibit a remarkable activity
against different microorganisms (germs and fungi) which allows to establish structure–activity correlations.
Introduction. – According to the literature [1–21], the chemistry of cycloimminium
ylides is widely discussed due to their theoretical importance [1–17] as well as their
practical applications (biological [18], acido-basic [19], semiconductor properties
[20], etc.). In the case of cycloimminium (4-halobenzoyl)ylides (hal=X=F, Cl, Br,
I), we did not find any systematic [1–21] study concerning the correlation between
structure, stability, and biological activity.
The aim of this work was to study the correlation between structure, stability, reac-
tivity, and biological activity in the series of cycloimminium (4-halobenzoyl)ylides.
Results and Discussion. – For the synthesis of new pyrimidinium ylides derived
from 4-methylpyrimidine (1) and 4-(4-chlorophenyl)pyrimidine (2), we used the salt
method described by Kröhnke [22]. Thus, the pyrimidinium salts 3a–d and 4a–d, pre-
pared by treating 1 or 2 with 4-halophenacyl bromides (=2-bromo-1-(4-halophenyl)-
ethanones), were subjected to alkali carbonates in aqueous solution to afford the cor-
responding pyrimidinium ylides 5a–d and 6a–d (Scheme 1).
A main disadvantage of the quaternization of pyrimidines 1 and 2 is the fact that
under classical conditions (refluxing in a solvent), the reaction time is very long, 60
min for 1 and 5 days for 2. Moreover, since only a few reports on the influence of micro-
wave on the quaternization process of heterocycles are known [23–25], we decided to
synthesize the desired cycloimminium salts by microwave heating. In Table 1 a compar-
© 2005 Verlag Helvetica Chimica Acta AG, Zürich

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Scheme 11)
ison of the reaction results under microwave heating and under classical conditions is
presented. Thus, both methods give comparable yields, but under microwave irradia-
tion, reaction times decrease dramatically, from 60 min to 5 min, and from 5 days to
20 min, respectively.
Table 1. Synthesis of Cycloimminium Salts under Microwave Heating and under Classical Conditions
Microwave heating
Classical conditions
Reaction time
Reaction temp. [8]
Yield [%]
Reaction time
Reaction temp. [8]
Yield [%]
3a
3b
3c
3d
4a
4b
4c
4d
5 min
5 min
5 min
70
70
70
70
90
90
90
90
92
94
96
89
80
70
73
65
60 min
60 min
60 min
60 min
5 days
5 days
5 days
5 days
50
50
50
91
94
96
90
76
68
70
67
5 min
50
20 min
20 min
20 min
20 min
110
110
110
110
To establish a correlation between structure, stability, and reactivity in the 4-(R)-
pyrimidinium (4-halobenzoyl)methylide series, we performed a theoretical study by
means of the general theory of perturbation limited to the frontier molecular orbitals
[26–30]. Thus, the heat of formation (Table 2), the atomic charges, the coefficients of
the atomic orbitals, and the values of the energy of the frontier molecular orbitals
for ylides 5b and 6b (Table 3) were calculated with the PM3 [30] method (for the
other ylides, the results are similar).
1
)
Arbitrary atom numberings; for systematic names, see Exper. Part.

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From the calculated data listed in Table 2, two main conclusions concerning the sta-
bility can be drawn: 1) The substituent R at C(4) of the pyrimidinium ring influences
the stability, the 4-methylpyrimidinium ylides 5 being more stable than the 4-(4-chloro-
phenyl)pyrimidinium ylides 6. 2) The halogen atom at C(4) of the benzoyl group also
influences the stability, in both series 5 and 6, since the stability decreases with decreas-
ing electronegativity of the halogen atom (F>Cl>Br>I).
Table 2. Heat of Formation [kcal/mol] for 4-(R)-Pyrimidinium [4-(X)-Benzoyl]methylides 5 and 6
X=F
X=Cl
X=Br
X=I
5 (R=Me)
6 (R=4-Cl-C6H4)
À7.59
29.33
56.53
43.80
71.01
57.47
84.66
19.62
From the data of Table 3, the following is deduced: 1) The ylide C-atoms, C(7) have
a negative atomic charge, low but significant. 2) The ylide N-atoms N(1) have a positive
atomic charge, also low but significant, and smaller (in absolute value) than those of the
ylide C-atoms. 3) The ring C-atoms in a-position, i.e., C(2) and C(6), have small nega-
tive atomic charges, both being low.
Table 3. Coefficients of Atomic Orbitals (pz), Total Atomic Charge Q, and Energies [eV] of Ylides 5b and 6b.
Arbitrary numbering of atoms (see Scheme 1)1).
Energy
[eV]
Coefficients of atomic orbitals (pz)
N(1)(ylide) C(7)(ylide) C(2)
C(6)
N(3)
C(8)
O(8’)
5b HOMO À8.3671 +0.0617
LUMO À1.0739 À0.5202
À0.6659
+0.2825
À0.6947
À0.6014
+0.2885
À0.6835
+0.3602 +0.3413 À0.0904 À0.0991 +0.2706
+0.3280 +0.1735 +0.0826 +0.2600 À0.2435
À0.3717 À0.4103 +0.0318 +0.4183 À0.3953
+0.3343 +0.3055 À0.1137 À0.0923 +0.2411
+0.2151 +0.1729 +0.1783 +0.2179 À0.2145
À0.3731 À0.4092 +0.0379 +0.4177 À0.3903
Q
+0.8276
6b HOMO À8.3072 +0.0819
LUMO À1.4167 À0.4739
Q
+0.8266
The low total atomic charges indicate the delocalization of the anionic charge from
the ylide C-atom center to the ylide substituent and of the positive charge from the
ylide N-atom to the pyrimidine heterocycle as shown by A–D in Scheme 2. Conse-
quently a relatively good stability is predicted for these ylides.
The significant negative atomic charge at the ylide C-atoms suggests that pyrimidi-
nium ylides could be used as nucleophilic reagents in appropriate reactions. Also, the
data from Table 3 and Scheme 2 show that the ylides 5 and 6 have a 1,2-dipolar structure
(octet form, canonical structure A), a dipole which could accept a 1,3-dipolar structure
(sextet form without double bond, canonical structures B and C). The 1,3-dipolar activ-
ity could involve either the 2- or 6-position of the pyrimidine ring – a regiochemical
problem. However, position 6 is less electron-deficient (atomic charge Q ca. À0.4)
than position 2 (atomic charge Q ca. À0.2), therefore more suitable for reaction with
an electron-deficient dipolarophile. As in related cases [15][16], we expect that reac-
tions of pyrimidinium (4-halobenzoyl)methylides with an electron-deficient dipolaro-
phile should occur as an ordinary [3+2] dipolar cycloaddition leading to azabicyclic
compounds at the 2- or 6-position.

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Scheme 2
The experimental data obtained confirm the theoretical data concerning the stabil-
ity and reactivity. Thus, the new ylides 5a–d and 6a–d have indeed different stabilities
according to the nature of their substituents. Thus, 4-methylpyrimidinium ylides 5 are
moderately stable (for several days), while 4-(4-chlorophenyl)pyrimidinium ylides 6
underwent a rapid dimerization after their preparation (via a [3+3] dipolar cycloaddi-
tion) yielding an ylide 6/dimer 7 mixture (within 24 h) (Scheme 1). The nucleophilicity
of the pyrimidinium ylides 5 and 6 was established by their protonation with hydrochlo-
ric acid giving the appropriate pyrimidinium chloride salts 8 and 9, respectively
(Scheme 3).
Moreover, the ability of pyrimidinium (4-halobenzoyl)methylides 5 and 6 to react
with an electron-deficient dipolarophile via a [3+2] dipolar cycloaddition was estab-
lished by their reaction with methyl prop-2-ynoate which gave a mixture of pyr-
rolo[1,2-c]pyrimidine 11a,b (cycloaddition at C(6) of 5b or 6b) and pyrrolo[1,2-a]pyri-
midine 12a,b (cycloaddition at C(2) of 5b or 6b), besides dimer 7 (Scheme 3). Concern-
ing the regiochemical outcome, the isomers from the cycloaddition at the 2- and 6-posi-
tions of the pyrimidine ring were obtained with different rates, the cycloaddition at
position 6 being favored (Table 4).
Table 4. Yields of the Cycloadditions of the Pyrimidinium (4-Chlorobenzoyl)methylides 5b or 6b and Methyl
Prop-2-yonate (see Scheme 3)
Cycloaddition at C(6)
Cycloaddition at C(2)
Dimer 7 [%]
Cycloadduct
yield [%]
Cycloadduct
yield [%]
5b (R=Me, X=Cl)
6b (R=4-Cl-C6H4, X=Cl)
11a
11b
31.5
37
12a
12b
7
6
24.5
21
The structure of the new pyrimidine compounds was established by elemental and
1
spectral analysis (IR, H- and 13C-NMR, COSY, HMQC, HMBC; see Exper. Part) as
well as by their chemical transformations (see above).
The in vitro antimicrobial and antifungical activity of the new 4-methylpyrimidine
derivatives 3a–d and 5a–d were tested having in view that in a previous study, related
compounds have shown biological activity [18][31–33]. The biological tests were per-
formed in rustless-steel cylinders by means of the diffusimetric method [33] which is

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Scheme 3
based on the diffusion of the tested substances on the gelose surface (for bacteria) and
Sabouard environment (for fungus Candida albicans). The cylinders were maintained
for 24 h at 348 for bacteria and at 378 for Candida. The substances were tested in
5% (v/v) aqueous DMF solutions against a reference solvent sample. The inhibition
diameter zone (in mm) of development of the microbial strain was measured. A com-
pound is considered active [33] if the difference between its inhibition diameter zone
and that of the reference sample is higher than 2 mm (3–4 mm, moderate activity;
and up to 5 mm, high activity). Comparison of the obtained data (Table 5) leads to
the following conclusions concerning the relation between structure and biological
activity: 1) The salts 3a–c have a remarkably nonselective activity against Gram-pos-
itive and Gram-negative germs as well as against fungus Candida albicans. Salt 3d is
active only against Staphylococcus aureus Oxford. 2) Ylide 5d is active against
Gram-positive and Gram-negative germs, while the other ylides are considered to be
mostly inactive.

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Table 5. In vitro Antimicrobial and Antifungical Activitya) of 4-Methylpyrimidine Derivatives 3 and 5
Staphylococcus aureus Oxford Bacillus Escherichia coli Bacillus proteus Candida
subtilis
vulgaris
albicans
Reference sample 17
10
16
15
15
14
16
16
15
15
15
22
18
21
17
17
16
17
20
15
23
20
22
18
17
16
17
19
15
23
21
23
18
15
16
16
17
3a
3b
3c
3d
5a
5b
5c
5d
25
23
23
23
17
17
15
23
a) Activity expressed in mm of the inhibition diameter zone (see text).
Conclusions. – For the first time in the cycloimminium ylide series, a theoretical and
experimental study concerning the correlation between structure, stability, reactivity,
and biological activity of 4-(R)-pyrimidinium (4-halobenzoyl)methylides (R=methyl
and 4-chlorophenyl, hal=F, Cl, Br, I) is presented. Quantum-chemical calculations
and the experimental data show that the stability of these pyrimidinium methylides
is dependent on the nature of the substituents at the ylide carbanion and pyrimidinium
cation moieties. The quantum-chemical calculations predict the possibility of using pyr-
imidinium ylides as nucleophilic reagents as well as 1,3-dipoles in reactions with appro-
priate reagents. The nucleophilicity of pyrimidinium ylides is established by the forma-
tion of pyrimidinium chloride salts in the presence of hydrochloric adid, and their 1,3-
dipole reactivity by the formation of [3+2] cycloadducts with the electron-deficient
dipolarophile methyl prop-2-ynoate.
The microwave-promoted reaction of 4-(R)-pyrimidine with an organic halide
shows a remarkable rate enhancement as compared to standard heating conditions,
thus allowing a rapid, facile, and general synthesis of cycloimminium salts from N-het-
erocycles and organic halides.
The in vitro biological assays with the new pyrimidine compounds show that some
of them have a remarkable activity against different microorganisms (germs and fungi).
Correlation between structure and biological activity allows to draw the following con-
clusions: 1) Salts are more active that ylides. 2) The influence of the halogen atom at
C(4) of the benzoyl moiety is different in the series of the salts and of the ylides: in
the series of the pyrimidine salts, the F-derivative has an excellent antimicrobial and
antifungal activity (nonselective), while in the series of the pyrimidinium ylides, the
I-derivative has a good antimicrobial (but no antifungal) activity.
CNCSIS Bucuresti, grant no.1322/2003, is acknowledged for financial support. Also, we wish to thank Prof.
Mircea Constantinescu for the calculation with the HyperChem program
Experimental Part
General. The 4-(X)-phenacyl bromides, 4-methylpyrimidine, and methyl prop-2-ynoate were purchased from
Aldrich (Germany). Flash chromatography (FC): silica gel 60 (Aldrich, Germany). Solvent systems for FC and
TLC: CH2Cl2/MeOH 99.5 :0.5 (A), CH2Cl2/acetone 98 :2 (B). Microwave irradiation: monomode reactor Star-2

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(50 W), CHEM Corporation. UV/VIS Spectra: Hitachi-U-2010 spectrometer, MeCN solns.; lmax in nm. IR Spec-
tra: Jasco 660-C spectrometer; in KBr; n in cmÀ1. NMR Spectra: Bruker-Avance-400-DRX instrument (400 MHz);
~
d values rel. to Me4Si in ppm, J in Hz. M.p.: Meltemp-II apparatus; uncorrected. The quantum-chemical calcula-
tions were performed with the HyperChem (vs. 5.02) software for Windows 95 (Hypercub, Inc., Gainsville, USA).
Pyrimidinium Salts 3a–d, Classical Conditions: General Procedure A (G.P. A). To a soln. of 2-bromo-1-(4-
halophenyl)ethanone (5 mmol) in Et2O (20 ml), 4-methylpyrimidine (5 ml, 5 mmol) was added dropwise within
20 min. The soln. was stirred at r.t. for 5 days. The obtained pyrimidinium salt was filtered and dried in vacuo.
Pyrimidinium Salts 4a–d, Classical Conditions: General Procedure B (G.P. B). A soln. of 4-(4-chlorophe-
nyl)pyrimidine (0.9525 g, 5 mmol) and 2-bromo-1-(4-halophenyl)ethanone (5 mmol) in toluene (20 ml) was
heated to reflux under stirring for 5 days. The obtained pyrimidinium salt was filtered off, dried in vacuo, and
then purified by recrystallization from Et2O.
Pyrimidinium Salts, Microwave Heating: General Procedure C (G.P.C). Caution! It is hazardous to heat a
reaction mixture by microwave rapidly. Typical procedure for the synthesis of cycloimminium salts: The N-het-
erocycle (5 mmol) and the organic halide (5 mmol) were added to toluene (20 ml) in a tube (Pyrex glass or
quartz). The tube was then placed in the microwave cell (one or both cells of the Star reactor can be used)
and heated for the appropriate time while stirring (stirring is desirable but can be replaced by continuously bub-
bling N2 (or air) through the mixture). After completion of the heating cycle, the tube was cooled to r.t. and the
cycloimminium salt filtered off and purified by recrystallization from an appropriate solvent.
Pyrimidinium Ylides: General Procedure D (G.P.D). A soln. of the pyrimidinium salt (1 mmol) H2O/EtOH
1:1 (50 ml) was treated with 40% aq. K2CO3 soln. The ylide was filtered off, washed with a great amount of H2O,
and dried in vacuo. No further purification was required.
Pyrimidinium Chlorides by Reaction of Pyrimidinium Ylides with Hydrochloric Acid: General Procedure E
(G.P. E). The pyrimidinium ylide (0.5 mmol) in H2O was treated with dil. (1 :1) aq. HCl soln., which gave the
pyrimidinium chloride. The salt was filtered, washed with a large amount of H2O and dried in vacuo. No further
purification was required.
Cycloaddition Reactions: General Procedure F (G.P.F). To a soln. of the cycloimminium salt (10 mmol) and
methyl prop-2-ynoate (15 mmol) in MeCN (10 ml) under N2, Et3N (11 mmol) in MeCN (15 ml) was added drop-
wise over 4 days while stirring. The resulting mixture was treated with H2O, the precipitate filtered in vacuo and
washed thoroughly with H2O, and the dried crude product first recrystallized from MeOH and then purified by
FC (silica gel, adequate eluent). The product was then washed with an appropriate solvent.
1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-methylpyrimidinium Bromide (3a). According to the G.P. A and C,
with 2-bromo-1-(4-fluorophenyl)ethanone (1.085 g): Yield 91%. Yellow crystals. M.p. 174–1768. IR: 3100–
3050 (CÀH(arom.)), 1700 (C=O), 1640, 1600, 1500, 1405 (C=C, C=N(arom.)). 1H-NMR ((D6)DMSO)1): 9.80
(s, HÀC(2)); 8.75–8.55 (d, J=6.0, HÀC(5)); 9.40–9.25 (d, J=6.0, HÀC(6)); 6.50 (s, CH2(7)); 8.40–8.10 (d,
J=9.0, 2 H, HÀC(10)); 7.55–7.35 (t, J=9.0, J(H,F)=3.0, 2 H, HÀC(11)); 3.20 (s, MeÀC(4)). Anal. calc. for
C13H12BrFN2O (311.15): C 50.16, H 3.85, N 9.00; found: C 51.02, H 3.90, N 8.92.
1-[2-(4-Chlorophenyl)-2-oxoethyl]-4-methylpyrimidinium Bromide (3b). According to the G.P. A and C,
with 2-bromo-1-(4-chlorophenyl)ethanone (1.168 g): Yield 94%. Orange crystals. M.p. 178–1798. IR: 3100–
3050 (CÀH(arom.)), 1700 (C=O), 1640, 1600, 1550, 1500, 1460, 1405 (C=C, C=N(arom.)). 1H-NMR
((D6)DMSO)1): 9.70 (s, HÀC(2)); 8.35–8.25 (d, J=6.0, HÀC(5)); 9.20–9.10 (d, J=6.0, HÀC(6)); 6.50 (s,
CH2(7)); 8.20–7.50 (d, J=9.0, 2 H, HÀC(10)); 7.70–7.50 (d, J=9.0, 2 H, HÀC(11)); 2.90 (s, MeÀC(4)).
Anal. calc. for C13H12BrClN2O (327.61): C 47.63, H 3.66, N 8.54; found: C 47.80, H 3.72, N 8.39.
1-[2-(4-Bromophenyl)-2-oxoethyl]-4-methylpyrimidinium Bromide (3c). According to the G.P. A and C,
with 2-bromo-1-(4-bromophenyl)ethanone (1.39 g): Yield 96%. Yellow-orange crystals. M.p.: 166–1678. IR:
3100–3050 (CÀH(arom.)), 2980 (CÀH(aliph.)), 1698 (C=O), 1625, 1575, 1460 (C=C, C=N(arom.)). 1H-
NMR ((D6)DMSO)1): 9.60 (s, HÀC(2)); 8.30–8.25 (d, J=5.6, HÀC(5)); 9.16–9.11 (d, J=5.6, HÀC(6)); 6.45
(s, CH2(7)); 7.85–7.70 (m, 4 H, HÀC(10), HÀC(11)); 2.80 (s, MeÀC(4)). Anal. calc. for C13H12Br2N2O
(372.06): C 41.97, H 3.25, N 7.53; found: C 41.80, H 3.30, N 7.30.
1-[2-(4-Iodophenyl)-2-oxoethyl]-4-methylpyrimidinium Bromide (3d). According to the G.P. A and C, with
2-bromo-1-(4-iodophenyl)ethanone (1.67 g): Yield 89%. Yellow needles. M.p. 204–2058. IR: 3100–3050
(CÀH(arom.)), 1695 (C=O), 1640, 1580, 1490, 1455, 1415 (C=C, C=N(arom.)). 1H-NMR ((D6)DMSO)): 9.65
(s, HÀC(2)); 8.35–8.20 (d, J=6.0, HÀC(5)); 9.30–9.15 (d, J=6.0, HÀC(6)); 6.45 (s, CH2(7)); 8.15–8.00 (d,
J=9.0, 2 H, HÀC(10)); 7.90–7.75 (d, J=9.0, 2 H, HÀC(11)); 2.90 (s, MeÀC(4)). Anal. calc. for C13H12BrIN2O
(419.06): C 37.26, H 2.88, N 6.68; found: C 37.22, H 2.63, N 6.51.
4-(4-Chlorophenyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]pyrimidinium Bromide (4a). According to the G.P. B
and C, with 2-bromo-1-(4-fluorophenyl)ethanone (1.085 g): Yield 80%. White crystals. M.p. 183–1858. IR: 1626s

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HELVETICA CHIMICA ACTA – Vol. 88 (2005)
(C=O); 1693, 1590, 1462, 1092 (s–m, C=C, C=N(arom.)); 833s–m (CÀH(arom.), def.); 482w(CÀCl); 2910w
(CÀH(aliph.)); 3031 (CÀH(arom.), def). 1H-NMR ((D6)DMSO)1): 9.85 (s, HÀC(2)); 9.48–9.46 (d, J=6.8,
HÀC(6)); 9.06–9.05 (d, J=6.8, HÀC(5)); 8.51–8.49 (d, J=8.0, 2 H, HÀC(2’)); 8.23–8.2 (t, J(H,F)=3.6,
J=8.0, 2 H, HÀC(10)); 7.80–7.78 (d, J=8.0, 2 H, HÀC(3’)); 7.55–7.5 (t, J(HÀF)=8.8, J=8.0, 2 H, HÀ
C(11)). 13C-NMR ((D6)DMSO)1): 188.67 (C(8)=O); 167.35 (C(4)); 164.25 (C(12)); 154.12 (C(2)); 153.00
(C(6)); 139.63 (C(9)); 131.89 (C(1’)); 131.57 (C(4’)); 131.47 (C(10)); 131.29 (C(2’)); 129.92 (C(3’)); 117.94
(C(5)); 116.17 (C(11)); 62.12 (C(7)). Anal. calc. for C18H13BrClFN2O (407.65): C 53.03, H 3.21, N 6.87;
found: C 52.96, H 3.32, N 6.79.
4-(4-Chlorophenyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]pyrimidinium Bromide (4b). According to the G.P. B
and C, with 2-bromo-1-(4-chlorophenyl)ethanone (1.1675 g). Yield 70%. Yellowish crystals. M.p. 228–2308. IR:
1630s (C=O); 1698, 1590, 1454, 1341, 1092 (s–m, C=C, C=N(arom.)); 821, 762 (s–m, CÀH(arom.), def.); 484w
(CÀCl); 2926w (CÀH(aliph.)); 3029 (CÀH(arom.), def.). 1H-NMR ((D6)DMSO)1): 9.8 (s, HÀC(2)); 9.43–9.41
(d, J=6.4, HÀC(6)); 9.04–9.02 (d, J=6.4, HÀC(5)); 8.51–8.49 (d, J=8.4, 2 H, HÀC(2’)); 8.14–8.12 (d, J=8.0, 2
H, HÀC(10)); 7.82–7.76 (m, 4 H, HÀC(11), HÀC(3’)). 13C-NMR ((D6)DMSO)1): 189.11 (C(8)=O); 167.41
(C(4)); 154.15 (C(2)); 153.01 (C(6)); 139.66 (C(9)); 139.39 (C(12)); 131.85 (C(1’)); 131.44 (C(4’)); 130.73
(C(2’)); 129.95 (C(10)); 129.62 (C(3’)); 129.06 (C(11)); 117.95 (C(5)); 62.15 (C(7)). Anal. calc. for C18H13-
BrN2OCl2 (424.10): C 50.97, H 3.08, N 6.60; found: C 51.03, H 3.12, N 6.52.
1-[2-(4-Bromophenyl)-2-oxoethyl]-4-(4-chlorophenyl)pyrimidinium Bromide (4c). According to the G.P. B
and C, with 2-bromo-1-(4-bromophenyl)ethanone (1.39 g). Yield 73%. Colorless crystals. M.p. 246–2478. IR:
1628s (C=O); 1698, 1587, 1453, 1081 (s–m, C=C, C=N(arom.)); 830s (CÀH(arom.), def.); 482w (CÀCl);
1
2919w (CÀH(aliph.), 3040w (CÀH(arom.)). H-NMR ((D6)DMSO)1): 9.84 (s, HÀC(2)); 9.47–9.45 (d, J=6.8,
HÀC(6)); 9.06–9.04 (d, J=6.8, HÀC(5)); 8.51–8.49 (d, J=8.4, 2 H, HÀC(2’)); 8.05–8.03 (d, J=8.0, 2 H, HÀ
C(10)); 7.91–7.89 (d, J=8.0, 2 H, HÀC(11)); 7.80–7.78 (d, J=8.4, 2 H, HÀC(3’)); 6.54 (s, CH2(7)). 13C-NMR
((D6)DMSO)1): 189.36 (C(8)=O); 167.38 (C(4)); 154.11 (C(2)); 153.00 (C(6)); 139.65 (C(9)); 132.17 (C(1’));
131.99 (C(2’)); 131.47 (C(4’)); 130.72 (C(10)); 129.94 (C(3’)); 129.60 (C(11)); 128.66 (C(12)); 117.95 (C(5));
62.13 (C(7)). Anal. calc. for C18H13Br2ClN2O (468.57): C 46.14, H 2.79, N 5.98; found: C 46.04, H 2.83, N 5.82.
4-(4-Chlorophenyl)-1-[2-(4-iodophenyl)-2-oxoethyl]pyrimidinium Bromide (4d). According to the G.P. B
and C, with 2-bromo-1-(4-iodophenyl)ethanone (1.67 g). Yield 65%. Colorless crystals. M.p. 253–2558. 1H-
NMR ((D6)DMSO)1): 9.73 (s, HÀC(2)); 9.35–9.33 (d, J=6.4, HÀC(6)); 9.00–8.98 (d, J=6.4, HÀC(5));
8.51–8.49 (d, J=8.4, 2 H, HÀC(2’)); 8.11–8.09 (d, J=8.0, 2 H, HÀC(10)); 7.87–7.85 (d, J=8.0, 2 H, HÀ
C(3’)); 7.83–7.80 (d, J=8.0, 2 H, HÀC(11)); 6.38 (s, CH2(7)). 13C-NMR ((D6)DMSO)1): 182.62 (C(8)=O);
167.43 (C(4)); 154.17 (C(2)); 153.03 (C(6)); 139.69 (C(9)); 132.39 (C(1’)); 131.50 (C(4’)); 130.73 (C(2’));
130.03 (C(10)); 129.64 (C(3’)); 129.52 (C(11)); 117.93 (C(5)); 103.68 (C(12)); 62.01 (C(7)). Anal. calc. for
C18H13BrClIN2O (515.58): C 41.93, H 2.54, N 5.43; found: C 41.86, H 2.62, N 5.38.
4-Methylpyrimidinium 2-(4-Fluorophenyl)-2-oxoethylide (5a). According to G.P. D, with 3a (0.311 g,
1.0 mmol). Yield 97%. Brown-red crystals. M.p. 164–1668. IR: 3050 (CÀH(arom.)), 2980 (CÀH(aliph.)),
1705–1650 (br. band with 2 peaks at 1700; C=O, dimer), 1660 (C=O, ylide), 1610, 1580, 1515, 1430 (C=C,
C=N(arom.)). Anal. calc. for C13H11FN2O (230.24): N 12.17; found N 12.09.
4-Methylpyrimidinium 2-(4-Chlorophenyl)-2-oxoethylide (5b). According to G.P. D, with 3b (0.328 g,
1.0 mmol). Yield 98%. Brown crystals. M.p. 148–1518. IR: 3050 (CÀH(arom.)), 2980 (CÀH(aliph.)), 1705–
1650 (br. band with 2 peaks at 1700; C=O, dimer), 1660 (C=O, ylide), 1600, 1570, 1490, 1405 (C=C,
C=N(arom.)). Anal. calc. for C13H11ClN2O (246.70): N 11.35; found N 11.19.
4-Methylpyrimidinium 2-(4-Bromophenyl)-2-oxoethylide (5c). According to G.P. D, with 3c (0.372 g,
1.0 mmol). Yield 99%. Red crystals. M.p. 138–1408. IR: 3050 (CÀH(arom.)), 2980 (CÀH(aliph.)), 1705–1650
(br. band with
2 peaks at 1705; C=O, dimer), 1670 (C=O, ylide), 1590, 1490, 1455, 1400 (C=C,
C=N(arom.)). Anal. calc. for C13H11BrN2O (291.15): N 9.62; found N 9.45.
4-Methylpyrimidinium 2-(4-Iodophenyl)-2-oxoethylide (5d). According to G.P. D, with 3d (0.428 g,
1.0 mmol). Yield 97%. Orange-yellow crystals. M.p. 131–1348. IR: 3050 (CÀH(arom.)), 2980 (CÀH(aliph.)),
1705–1650 (br. band with 2 peaks at 1705; C=O, dimer), 1670 (C=O, ylide), 1600, 1490, 1400 (C=C,
C=N(arom.)). Anal. calc. for C13H11IN2O (338.15): N 8.28; found N 8.20.
4-(4-Chlorophenyl)pyrimidinium 2-(4-Fluorophenyl)-1-oxoethylide (6a). According to G.P. D, with 4a
(0.407 g, 1.0 mmol). Yield 98%. Red-orange crystals. M.p. 165–1688. UV: 504. IR: 1634 (s, br. C=O); 1679,
1586, 1487, 1087 (s–m, C=C, C=N(arom.)); 821s (CÀH(arom.), def.); 498w (CÀCl); 3058w (CÀH(arom.));
2923w (CÀH(aliph.)). Anal. calc. for C18H12ClFN2 (326.75): N 8.57; found N 8.49.
4-(4-Chlorophenyl)pyrimidinium 2-(4-Chlorophenyl)-2-oxoethylide (6b). According to G.P. D, with 4b
(0.424 g, 1.0 mmol). Yield 99%. Red crystals. M.p. 148–1508. UV: 506.5. IR: 1632s (br. C=O); 1680, 1586,

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1093 (s–m, C=C, C=N(arom.)); 833s (CÀH(arom.), def.); 497w (CÀCl); 3056w (CÀH(arom.)); 2925w (CÀ
H(aliph.)). Anal. calc. for C18H12Cl2N2O (343.20): N 8.16; found N 8.09.
4-(4-Chlorophenyl)pyrimidinium 2-(4-Bromophenyl)-2-oxoethylide (6c). According to G.P. D, with 4c
(0.468 g, 1.0 mmol). Yield 97%. Red-orange crystals. M.p. 153–1568. UV: 507. IR: 1629s (br., C=O); 1679,
1582, 1455, 1092 (s–m, C=C, C=N(arom.)); 830s (CÀH(arom.), def.); 496w (CÀCl); 3050w (CÀH(arom.));
2920w (CÀH(aliph.)). Anal. calc. for C18H12OBrClN2 (387.66): N 7.23; found: N 7.14.
4-(4-Chlorophenyl)pyrimidinium 2-(4-Iodophenyl)-2-oxoethylide (6d). According to G.P. D, with 4d (0.515
g, 1.0 mmol). Yield 92%. Red-orange crystals. M.p. 163–1668. UV: 508. IR: 1624s (br., C=O); 1679, 1584, 1453,
1092 (s–m, C=C, C=N(arom.)); 834s (CÀH(arom.), def.); 494w (CÀCl); 3048w (CÀH(arom)); 2922w
(CÀH(aliph.)). Anal. calc. for C18H12ClIN2O (434.66): N 6.44; found: N 6.36.
1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-methylpyrimidinium Chloride (8a). According to G.P. E, with 5a
(0.115 g, 0.5 mmol). Yield 91%. Yellow crystals. M.p. 162–1648.
1-[2-(4-Chlorophenyl)-2-oxoethyl]-4-methylpyrimidinium Chloride (8b). According to G.P. E, with 5b
(0.123 g, 0.5 mmol). Yield 93%.Yellowish crystals M.p. 166–1688.
1-[2-(4-Bromophenyl)-2-oxoethyl]-4-methylpyrimidinium Chloride (8c). According to G.P. E, with 5c
(0.145 g, 0.5 mmol). Yield 92%. Colorless crystals. M.p. 154–1568.
1-[2-(4-Iodophenyl)-2-oxoethyl]-4-methylpyrimidinium Chloride (8d). According to G.P. E, with 5d (0.169
g, 0.5 mmol). Yield 90%. Colorless crystals. M.p. 194–1958.
4-(4-Chlorophenyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]pyrimidinium Chloride (9a). According to G.P. E,
with 6a (0.163 g, 0.5 mmol). Yield 91%. Yellowish crystals. M.p. 178–1808.
4-(4-Chlorophenyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]pyrimidinium Chloride (9b). According to G.P. E,
with 6b (0.171 g, 0.5 mmol). Yield 92%. Yellow crystals. M.p. 211–2148.
4-(4-Chlorophenyl)-1-[2-(4-bromophenyl)-2-oxoethyl]pyrimidinium Chloride (9c). According to G.P. E,
with 6c (0.193 g, 0.5 mmol). Yield 91%. Yellow–orange crystals. M.p. 207–2098.
4-(4-Chlorophenyl)-1-[2-(4-iodophenyl)-2-oxoethyl]pyrimidinium Chloride (9d). According to G.P. E, with
6d (0.217 g, 0.5 mmol). Yield 91%. Yellow crystals. M.p. 237–2398.
Methyl 3-Methyl-7-(4-chlorobenzoyl)pyrrolo[1,2-c]pyrimidine-5-carboxylate (11a). According to G.P. F,
with 3b (3.721 g, 10 mmol). Washing with acetone and subsequent FC (silica gel, column 13×2 cm, B) gave yel-
low cubic crystals. M.p. 1958. IR: 1730s (C=O, ester); 1645s (C=O, ketone); 1590, 1515, 1470, 1450, 1405 (s–m,
1
C=C, C=N(arom.)); 1220, 1110s (CÀOÀC); 2950w (CÀH(aliph.)). H-NMR (CDCl3)1): 10.48 (s, HÀC(1));
8.04 (s, HÀC(4)); 7.78 (s, HÀC(6)); 7.78 (d, J=8, 2 H, HÀC(10)); 7.50 (d, J=8, 2 H, HÀC(11)); 3.91 (s,
COOMe); 2.63 (s, Me). 13C-NMR (CDCl3)1): 183.86 (C(8)=O); 163.92 (COOMe); 152.59 (C(1)); 148.88
(C(3)); 140.62 (C(12)); 138.46 (C(4a)); 137.35 (C(9)); 130.37 (C(10)); 129.76 (C(4)); 128.93 (C(11)); 121.78
(C(7)); 117.80 (C(6)); 105.40 (C(5)); 51.51 (MeO), 23.91 (Me). Anal. calc. for C17H13ClN2O3 (328.75): N 8.52;
found: N 8.50.
Methyl 3-(4-Chlorophenyl)-7-(4-chlorobenzoyl)pyrrolo[1,2-c]pyrimidine-5-carboxylate (11b). According to
G.P. F, with 4b (4.68 g, 10 mmol). Washing with MeOH and subsequent FC (silica gel, column 13×2 cm, A) gave
yellowish crystalline plates. M.p. 209–2108. IR: 1711s (C=O, ester); 1622s (C=O, ketone); 1523, 1477, 1443,
1404 (s–m, C=C, C=N(arom.)); 1209, 1090s (CÀOÀC); 2952w (CÀH(aliph.)); 429s (CÀCl). 1H-NMR
(CDCl3)1): 10.53 (s, HÀC(1)); 8.56 (s, HÀC(4)); 8.11–8.09 (d, J=8.8, 2 H, HÀC(10)); 7.81–7.79 (d, J=8.4, 2
H, HÀC(2’)); 7.78 (s, HÀC(6)); 7.57–7,55 (d, J=7.6, HÀC(3)); 7.53–7.51 (d, J=8.4, 2 H, HÀC(3’)); 7.48–
7.46 (d, J=8.8, 2 H, HÀC(11)); 3.94 (s, COOMe). 13C-NMR (CDCl3)1): 183.88 (C(8)=O); 163.79 (COOMe);
148.82 (C(4a)); 140.73 (C(1)); 140.70 (C(1’)); 138.57 (C(3)); 137.13 (C(12)); 136.37 (C(9)); 134.83 (C(4’));
130.36 (C(2’)); 129.73 (C(6)); 129.20 (C(11)); 128.94 (C(3’)); 128.16 (C(10)); 122.13 (C(5)); 108.39 (C(4));
106.93 (C(7)); 51.65 (Me). Anal. calc. for C22H14Cl2N2O3 (425.27): N 6.59; found: N 6.52.
Methyl 2-Methyl-5-(4-chlorobenzoyl)pyrrolo[1,2-a]pyrimidine-7-carboxylate (12a). According to G.P. F,
with 3b (3.7206 g, 10 mmol). Washing with acetone and subsequent FC (silica gel, column 13×2 cm, A) gave yel-
lowish needles. M.p. 1878. IR: 1730s (C=O, ester); 1645s (C=O, ketone); 1590, 1515, 1470, 1450, 1405 (s–m,
1
C=C, C=N(arom.)); 1220, 1110s (CÀOÀC); 2950w (CÀH(aliph.)). H-NMR (CDCl3)1): 7.70 (d, J=7.5, HÀ
C(4)); 5.82 (d, J=7.5, HÀC(3)); 8.24 (s, HÀC(6)); 7.78 (d, J=8, 2 H, HÀC(10)); 7.47 (d, J=8, 2 H, HÀ
C(11)); 3.84 (s, COOMe); 3.73 (s, Me). 13C-NMR (CDCl3)1): 194.12 (C(8)=O); 166.41 (COOMe); 164.21
(C(7a)); 142.31 (C(2)); 138.17 (C(12)); 137.82 (C(5)); 135.01 (C(4)); 134.27 (C(3)); 130.68 (C(10)); 128.83
(C(11)); 128.69 (C(6)); 111.04 (C(7)); 51.86 (MeO); 29.75 (Me). Anal. calc. for C17H13ClN2O3 (328.75): N
8.52; found: N 8.50.
Methyl 2-(4-Chlorophenyl)-5-(4-chlorobenzoyl)pyrrolo[1,2-a]pyrimidine-7-carboxylate (12b). According to
G.P. F, with 4b (4.68 g, 10 mmol). Washing with MeOH and subsequent FC (silica gel, column 13×2 cm, A) gave

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HELVETICA CHIMICA ACTA – Vol. 88 (2005)
yellow needles. M.p. 237–2388. IR: 1711s (C=O, ester); 1622s (C=O, ketone); 1523, 1477, 1443, 1404 (s–m,
C=C, C=N(arom.)); 1252, 1136s (CÀOÀC); 2952w (CÀH(aliph.)); 429s (CÀCl). 1H-NMR (CDCl3)1): 10.12–
10.10 (d, J=7.6, HÀC(4)); 8.24–8.22 (d, J=8.4, 2 H, HÀC(10)); 7.99 (s, HÀC(6)); 7.80–7.78 (d, J=8.4, 2 H,
HÀC(2’)); 7.57–7.55 (d, J=7.6, HÀC(3)); 7.53–7.48 (m, 4 H, HÀC(11), HÀC(3’)); 3.97 (s, COOMe). 13C-
NMR (CDCl3)1): 184.38 (C(8)=O); 163.43 (COOMe); 156.90 (C(2)); 144.86 (C(7a)); 138.42 (C(1’)); 137.85
(C(9)); 137.14 (C(12)); 136.24 (C(4)); 134.67 (C(4’)); 131.01 (C(6)); 130.36 (C(2’)); 129.80 (C(3’)); 129.23
(C(10)); 128.92 (C(11)); 119.04 (C(7)); 107.53 (C(3)); 105.85 (C(5)); 51.72 (Me). Anal. calc. for C22H14Cl2N2-
O3 (425.27): N 6.59; found: N 6.51.
Note. The synthesis of compounds 3c and 5c, as well as of 11a and 12a were published in [17] and [15], resp.
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Received June 27, 2005