Characteristics of the halogenation of 2-substituted 6-benzhydryl-4(3H)- pyrimidinones

Article abstract of DOI:10.1007/s10593-006-0231-y

The halogenation of 2-substituted 6-benzhydryl-4(3H)-pyrimidinones has been investigated. Bromination with Py?Br₂ and iodination with I₂ solution in alkali occurs exclusively at the CH hydrogen of the benzhydryl group. Springer Scien

Full text of DOI:10.1007/s10593-006-0231-y

Chemistry of Heterocyclic Compounds, Vol. 42, No. 9, 2006
CHARACTERISTICS OF THE
HALOGENATION OF 2-SUBSTITUTED
6-BENZHYDRYL-4(3H)-PYRIMIDINONES
I. A. Novakov, B. S. Orlinson, and M. B. Nawrozkij
The halogenation of 2-substituted 6-benzhydryl-4(3H)-pyrimidinones has been investigated.
Bromination with Py·Br2 and iodination with I2 solution in alkali occurs exclusively at the CH hydrogen
of the benzhydryl group.
Keywords: 6-benzhydryl-4(3H)-pyrimidinones, bromination, halogenation, iodination.
Derivatives of 6-benzhydryl-4(3H)-pyrimidinones with alkoxy [1], alkylamino [2], or alkylsulphanyl [3]
groups in position 2 of the pyrimidine heterocycle are of considerable interest as antiviral materials. At the same
time their analogs containing benzhydryl units in position 6 of the pyrimidine ring, are devoid of anti-HIV1
activity, but possess cytotoxic properties [4].
In a continuation of the study of new derivatives of 6-benzhydryl-4(3H)-pyrimidinones as possible
cytotoxic agents, we have investigated the halogenation of 2-amino-6-benzhydryl-4(3H)-pyrimidinone (1a) and
6-benzhydryl-2-(methylsulfanyl)-4(3H)-pyrimidinone (1b). As a result it has been shown that both bromination
and iodination of compound 1a occurs at the CH group of the benzhydryl fragment, even in the absence of a free
radicals initiator, to give 2-amino-6-[bromo(diphenyl)methyl]-4(3H)-pyrimidinone (2a) and 2-amino-6-
[iodo(diphenyl)methyl]-4(3H)-pyrimidinone (3) respectively.
Scheme 1
O
O
N
Br2 / Py
HN
HN
HN
R
N
CHPh2
R
CPh2
Br
1a,b
2a,b
O
–
I2 / OH
1a
H2N
N
CPh2
I
3
1, 2 a R = NH2; b R = SMe
__________________________________________________________________________________________
Volgograd State Technical University, Volgograd 400131, Russia; e-mail: thiouracil@rambler.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1418-1420, September, 2006. Original article
submitted May 19, 2005.
0009-3122/06/4209-1233©2006 Springer Science+Business Media, Inc.
1233

In further study we have shown that bromination of compound 1b also occurs at the CH group of the
benzhydryl fragment to give 6-[bromo(diphenyl)methyl]-2-(methylsulfanyl)-4(3H)-pyrimidinone (2b).
The signal of the CH proton of the benzhydryl group (in the region of 5.3 ppm) is absent from the
1H NMR spectrum of compounds 2a,b and 3 but the signal of the C(5)H proton of the pyrimidine ring (in the
5.9-6.0 ppm region) is retained.
It should be noted that the direction of the halogenation is not trivial. It has been shown previously [5]
that both bromination and iodination of 6-alkyl- and 6-(arylmethyl)-4(3H)-pyrimidinones occurs exclusively at
position 5 of the heterocycle. Since addition, not substitution, is characteristic of pyridine dibromide [6], it is
possible that the change in direction of bromination of compounds 1a,b is connected with the participation of the
tautomeric form A (Scheme 2), stabilized by two phenyl groups.
Scheme 2
OH
OH
Py / Br2
HN
HN
1a,b
2a,b
CPh2
Br
.
– Py
HBr
R
N
CPh2
R
N
Br
A
In the case of the iodination reaction, the halogenating reagent is the I– – IO– system (the product of the
reaction of I2 with aqueous alkali) which also indicates that the reaction may proceed by an addition-elimination
mechanism.
Compounds 1a,b were synthesized according to a method described previously [7], by the reaction of
methyl (4,4-diphenyl-3-oxo)butanoate (4) with guanidine or 5-methylisothiourea respectively.
EXPERIMENTAL
1H NMR spectra of DMSO-d6 solution with HMDS as internal standard (δ = 0.05 ppm) were recorded
on a Varian-Mercury 300B (301 MHz). Melting points were determined with MelTemp 3.0 instrument at rate of
heating of 10°C/min.
Methyl 4,4-Diphenyl-3-oxobutanoate (4) was prepared by a method we have described [8]. Yield 98%;
bp 172-174° (1-2 mm Hg), n20D 1.5654 which agree with the literature results [9].
6-Diphenylmethyl-2-(methylsulfanyl)-4(3H)-pyrimidinone (1b). A mixture of 50% aqueous solution
of K2CO3 (5.2 g, 37.6 mmol), the ester 4 (5 g, 18.6 mmol), EtOH (15 ml), and (H2NC(SMe)NH)2·H2SO4 (5.2 g,
18.7 mmol) was stirred at room temperature for 1 week, neutralized with 1N HCl, the reaction product was
filtered off, dried, and crystallized. Yield 4.0 g (70%); mp 234-236°C (DMF–EtOH) which agrees with literature
data [9].
2-Amino-6-diphenylmethyl-4(3H)-pyrimidinone Sesquihydrate (1a·1.5H2O). A solution of ester 4
(5 g, 18.6 mmol), (H2N)2CNH·AcOH (4.5 g, 37.8 mmol), and NaOMe (3 g, 55.5 mmol) in abs. MeOH (100 ml)
was boiled for 72 h with the exclusion of moisture and CO2. The solvent was removed in vacuum, 1N AcOH
(100 ml) was added to the residue, the desired product was filtered off, dried and crystallized. Yield 3.8 g (67%);
mp 167°C ( - H2O), 237°C anhydrous (EtOH). 1H NMR spectrum, δ, ppm (J, Hz): 5.07 (1H, d, J = 6.11, 5-CH);
5.17 (1H, d, J = 4.89, CH); 6.51 (2H, s, NH2); 7.14-7.27 (10H, m, (C6H5)2); 10.70 (1H, s, NH). Found, %: C
66.50; H 6.01; N 13.73. C17H15N3O·1.5H2O. Calculated, %: C 67.09; H 5.96; N 13.81.
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6-[Bromo(diphenyl)methyl]-2-(methylsulfanyl)-4(3H)-pyrimidinone (2b). Bromine (0.35 ml, 1.09 g,
6.8 mmol) was added to a suspension of pyrimidinone 1b (2 g, 6.8 mmol) in a mixture of anhydrous Py (6 ml,
5.87 g, 74.3 mmol) and anhydrous DMF (10 ml). The reaction mixture was stirred for 5 h at room temperature,
diluted with water (150 ml) and extracted with CHCl3 (4 × 50 ml). The organic phase was consolidated, washed
with water (2 × 50 ml), saturated Na2S2O5 (25 ml), the brine (2 × 25 ml), and dried over Na2SO4. It was filtered,
the filtrate was concentrated in vacuum and the residue was concentrated in vacuum with toluene (25 ml) and
1
crystallized. Yield 1.9 g (76%); mp 228-230°C (PhMe). H NMR spectrum, δ, ppm (J, Hz): 2.23 (3H, s, CH3);
5.76 (1H, s, 5-CH); 7.18-7.26 (10H, s, (C6H5)2); 13.21 (1H, br. s, NH). Found, %: C 55.42; H 3.94; Br 20.60;
N 7.03; S 8.07. C18H15BrN2OS. Calculated, %: C 55.82; H 3.90; Br 20.63; N 7.23; S 8.28.
2-Amino-6-[bromo(diphenyl)methyl]-4(3H)-pyrimidinone (2a) was prepared analogously to
1
compound 2b. Yield 61%; mp 287-288°C (dec.) (EtOH). H NMR spectrum, δ, ppm: 5.76 (1H, s, 5-CH); 6.65
(2H, s, NH2); 7.16-7.23 (10H, m, (C6H5)2); 11.31 (1H, s, NH). Found, %: C 56.99; H 3.90; Br 22.51; N 11.47.
C17H14BrN3O. Calculated, %: C 57.23; H 3.96; Br 22.43; N 11.80.
2-Amino-6-[iodo(diphenyl)methyl]-4(3H)-pyrimidinone (4). Pyrimidinone sesquihydrate 1a·1.5H2O
(1.5 g, 4.9 mmol) was added to solution of KOH (0.4 g, 6.0 mmol) in water (20 ml) and the mixture was heated
to form a clear solution. The solution was cooled to room temperature, CH2Cl2 (40 ml) and iodine (1.4 g,
5.5 mmol) were added and the reaction mixture was stirred vigorously at room temperature for 5 h, saturated
aqueous solution of Na2S2O5 (10 ml) was added and the mixture was stirred for 5 min more. The precipitate was
filtered off and crystallized. Yield 0.7 g (35%); mp 273-274°C (dec.) (EtOH–DMF). 1H NMR spectrum, δ, ppm:
5.76 (1H, s, 5-CH); 6.60 (2H, s, NH2); 7.16-7.23 (10H, m, (C6H5)2); 11.14 (1H, s, NH). Found, %: C 50.50; H
3.50; I 30.99; N 10.33. C17H14IN3O. Calculated, %: C 50.64; H 3.50; I 31.74; N 10.42.
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