A novel approach toward the synthesis and characterization of pyrimidyl chalcogen compounds

Article abstract of DOI:10.1080/10426500801900972

A variety of hitherto unknown symmetrical and unsymmetrical pyrimidyl chalcogen compounds have been synthesized and characterized by elemental analysis using various spectroscopic techniques viz. NMR 1H, 13C, 77Se and infrared. Two different methodologies were employed. The first method involves the use of hydrazine hydrate as reducing agent to generate dichalcogenide anions followed by reaction with 2, 4-dichloropyrimidine to give the dichalcogenide compounds in good yield. The second method employs chlorine-magnesium exchange of 2,4-dichloropyrimidine using iso propyl magnesium chloride. The synthesis of the mixed phenyl pyrimidyl selenides have been achieved using sodium borohydride in ethanol as a reductive reagent to cleave Se-Se bond followed by alkylation with 2-chloro-4, 6-dimethylpyrimidine and 2, 4-dichloropyrimidine.

Full text of DOI:10.1080/10426500801900972

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Phosphorus, Sulfur, and Silicon
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A Novel Approach Toward the
Synthesis and Characterization
of Pyrimidyl Chalcogen
Compounds
K. K. Bhasin a , Ekta Arora a , Rishu a , Shivani
Doomra b , Nishima a , Yogesh Nagpal a , Rajeev
Kumar a , W. Weigand c & S. K. Mehta a
a Department of Chemistry and Centre of Advanced
Studies in Chemistry , Panjab University ,
Chandigarh, India
b Department of Chemistry , D.A.V. College ,
Chandigarh, India
c Universitaet Jena, Institute fuer Anorganische und
Analytische Chemie , Jena, Germany
Published online: 29 Oct 2008.
To cite this article: K. K. Bhasin , Ekta Arora , Rishu , Shivani Doomra , Nishima ,
Yogesh Nagpal , Rajeev Kumar , W. Weigand & S. K. Mehta (2008) A Novel Approach
Toward the Synthesis and Characterization of Pyrimidyl Chalcogen Compounds,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:4, 986-991, DOI:
10.1080/10426500801900972
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Phosphorus, Sulfur, and Silicon, 183:986–991, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500801900972
A Novel Approach Toward the Synthesis and
Characterization of Pyrimidyl Chalcogen Compounds
K. K. Bhasin,1 Ekta Arora,1 Rishu,1 Shivani Doomra,2
Nishima,1 Yogesh Nagpal,1 Rajeev Kumar,1 W. Weigand,3
and S. K. Mehta1
1Department of Chemistry and Centre of Advanced Studies in
Chemistry, Panjab University, Chandigarh, India
2Department of Chemistry, D.A.V. College, Chandigarh, India
3Universitaet Jena, Institute fuer Anorganische und Analytische
Chemie, Jena, Germany
A variety of hitherto unknown symmetrical and unsymmetrical pyrimidyl chalco-
gen compounds have been synthesized and characterized by elemental analysis us-
1
13
77
ing various spectroscopic techniques viz. NMR H, C, Se and infrared. Two
different methodologies were employed. The first method involves the use of hy-
drazine hydrate as reducing agent to generate dichalcogenide anions followed
by reaction with 2, 4-dichloropyrimidine to give the dichalcogenide compounds
in good yield. The second method employs chlorine-magnesium exchange of 2,4-
dichloropyrimidine using iso propyl magnesium chloride. The synthesis of the mixed
phenyl pyrimidyl selenides have been achieved using sodium borohydride in ethanol
as a reductive reagent to cleave Se-Se bond followed by alkylation with 2-chloro-4,
6-dimethylpyrimidine and 2, 4-dichloropyrimidine.
Keywords 2,4-dichloropyrimidine; diselenide; pyrimidine; selenium
INTRODUCTION
Hetrocycles are major building blocks in many biologically active
molecules and their functionalization is an active field of research.1
The pyrimidine moiety is widely found in natural products and its
compounds are widely used as inhibitors of human immunodeficiency
virus,2 act as effective anti-cancer drugs,3 and as anti-rejection drugs4
in transplantations. It is curious to note, however, that the pyrimi-
dine compounds of sulfur and selenium do not occupy the appropriate
The authors gratefully acknowledge the Department of Science and Technology,
New Delhi, for financial support.
Address correspondence to K. K. Bhasin, Department of Chemistry, Panjab University,
Chandigarh 160 014, India. E-mail: kkbhasin@pu.ac.in
986

Pyrimidyl Chalcogen Compounds
987
SCHEME 1
place in the literature as compared to alkyl/aryl/pyridyl chalcogenides.
In this paper, we wish to report a mild, convenient and economical
method for the synthesis of some newly designed pyrimidyl chalcogen
compounds (Scheme 1).
RESULTS AND DISCUSSION
Jerchel et al.5 were the first to explore the chemistry of pyridyl se-
lenium compounds and synthesize bis (4-pyridyl) diselenide and bis
(4-pyridyl) selenide by reacting N-pyridyl (4-pyridinium) chloride with
hydrogen selenide. We, therefore, felt it necessary to develop a safe and
convenient method for its preparation. Subsequently, the method was
improved by reducing elemental selenium with sodium borohydride in
different solvents by various coworkers.6 Different methodologies in the
subsequent years explored variations of the published procedures to im-
prove the yield of 2,2’-dipyridyl diselenide. Bhasin et al.7have developed
and optimized the conditions for the preparation of stable bis (2-pyridyl)
diselenide/ditelluride by lithiation of pyridine using BF3-Et2O complex
followed by insertion of elemental selenium/tellurium and subsequent
oxidation.
In pursuance of our work on the synthesis of dipyridyl diselenide, we
report herein a convenient, operationally simple and facile synthetic
route for the synthesis of hitherto unknown dipyrimidyl dichalco-
genide and phenyl pyrimidylselenides (Scheme 2). The starting ma-
terials 2-chloro-4, 6-dimethylpyrimidine and 2,4-dichloropyrimidine
were prepared by chlorination of 4,6-dimethyl-2-hydroxypyrimidine hy-
drochloride and 2,4-dihydroxypyrimidine respectively using phospho-
rus oxychloride.
The synthetic strategy that has been followed to prepare
bis [4-dimethylamino-2-pyrimidyl] dichalcogenide employs hydrazine

988
K. K. Bhasin et al.
SCHEME 2
hydrate as the reducing reagent for chalcogens (S, Se) in dimethyl-
formamide. It has been found that dimethyl formamide acts both as
solvent and a nucleophile, leading to nucleophilic substitution of chlo-
rine at fourth position by dimethyl amino group, -NMe2.
Attempts to prepare the titled dichalcogenides by chlorine- magne-
sium exchange reaction employing isoopropylmagnesium chloride at
fourth position was not successful.
To synthesize unsymmetrical pyrimidyl selenides, ethanolic sodium
borohydride was used for the reductive cleavage of Se Se bond in
diphenyl diselenide (Scheme 3). Dimethyl formamide (DMF) has been
employed as co-solvent in this reaction. It has been found that DMF
improves the yield of the desired product by solubilizing the phenylse-
lenolate ion, which is otherwise known to exist as a boron complex
possessing diminished nucleophilicity.8,9
SCHEME 3

Pyrimidyl Chalcogen Compounds
989
The disulfide/diselenide and monoselenides thus prepared are sta-
ble enough to be purified by column chromatography (silica gel using
hexane-ethyl acetate) on a laboratory bench. The compounds are sol-
uble in conventional organic solvents and have a shelf life of several
months without any sign of decomposition even at room temperature.
The compounds prepared have been fully characterized with the help
of various spectroscopic techniques.
EXPERIMENTAL
All experiments were carried out in dry oxygen–free nitrogen atmo-
sphere. IR spectra were recorded between KBr plates on a Perkin-Elmer
Model 1430 ratio recording spectrometer.1H NMR and 13C NMR spec-
tra were recorded in CCl4/CDCl3 using tetramethylsilane as an internal
77
standard and Se with dimethylselenide as an external reference on
a Jeol 300MHz spectrometer. Carbon, Hydrogen and Nitrogen were es-
timated micro analytically on a Perkin-Elmer 2400 CHN Elemental
analyzer.
Synthesis of 4, 6-Dimethyl-2-hydroxypyrimidine
Hydrochloride
Urea (12 g) in 100 ml of boiling ethanol (b.pt. 78◦C) was treated with
acetyl acetone (20 g) and the hot solution was treated with 27 ml of
conc. HCl with stirring. The mixture was refluxed for 24 h after which
time 24.0 g (75%) of 4, 6-Dimethyl-2-hydroxypyrimidine hydrochloride
was isolated by filtration and subsequent washing with cold ethanol
and diethyl ether.
Synthesis of 4, 6-Dimethyl-2-chloropyrimidine
The mixture of 4, 6-Dimethyl-2-hydroxypyrimidine hydrochloride
(20.0 g, 0.125 mol) and phosphorous oxychloride (110 ml) was refluxed
for 10 h, after which time the residual phosphorous oxychloride was re-
moved in vacuo. The residual oil was poured into 50 g of ice and neutral-
ized below 10◦C with a concentrated solution of potassium hydroxide.
The resulting mixture and 300 ml diethyl ether was vigorously stirred
for 10 h. The organic extract was evaporated to dryness. The residual
crude product was recrystallized from a minimal amount of petroleum
ether (b.pt. 40–70◦C) giving 13.8 g (77%) of colorless 4, 6-Dimethyl-2-
chloropyrimidine plates. M.pt.37–38◦C. 1H NMR (CDCl3/CCl4); δ 6.89(s,
1H), 2.37(s, 6 H).

990
K. K. Bhasin et al.
Synthesis of Bis [4-dimethylamino-2-pyrimidyl]
Diselenide/Disulfide
To a vigorously stirred mixture of powdered sodium hydroxide (3.0 g,
75 mmol), elemental chalcogen (S = 1.6 g or Se = 4.0 g, 50 mmol) and
dimethylformamide (30 ml), 100% hydrazine hydrate was added slowly.
After stirring for nearly 6 hr. at room temperature, a solution of 4, 6-
dimethyl-2-chloropyrimidine (100 mmol) dissolved in 15 ml DMF was
added dropwise. The reaction was refluxed for 2–3 h and monitored
by TLC. After completion of reaction, it is diluted with about 250 ml
of distilled water and extracted in dichloromethane (3 × 50 ml). The
organic layer was separated and solvent evaporated to get the crude
product in solid form. The product was subjected to purification on a
silica column using hexane as eluant.
General Procedure for Synthesis of Unsymmetrical
Pyrimidyl Selenides
To a solution of Ar2Se2 (Ar = phenyl) in 50 ml of C2H5OH-DMF (3:2) was
added 0.456 g (12 mmol) of NaBH4 in parts with continuous stirring at
0–5◦C; 10 mmol of alkylating agent (4, 6-dimethyl-2-chloropyrimidine
or 2,4-dichloropyrimidine) diluted with equal volume of DMF was added
drop wise. Reaction was complete within 1–2 h. Extraction is done in
dichloromethane after evaporating ethanol under vacuum. The organic
layer was repeatedly washed with distilled water (3 * 40 ml), dried over
anhydrous sodium sulfate. Solvent was evaporated on rota evaporator
and the product was subjected to purification on a silica column using
hexane as eluant.
Bis [4-dimethylamino-2-pyrimidyl] Diselenide
Yield = 65%, Yellow crystalline solid, m.p. = 79–81◦C, 1H NMR;
δ 7.9 (d, 1H), 6.83 (d, 1 H), 3.14 (s, 6H); 13C NMR; δ161.2,
77
157.1,154.7,107.3,37.0;
Se NMR; 431.57; IR (KBr, cm−1): 2924.4,
2853.3, 1566.0, 1521.4,1458, 1405.3, 1340.4, 786.8, 534.3; Anal. Calcd.
for C12H16N6Se2; C, 33.60, H, 3.96, N, 20.79. Found; C, 34.97, H, 3.13,
N, 16.32.
Bis [4-dimethylamino-2-pyrimidyl] Disulfide
Yield = 67%, Yellow crystalline solid, m.p. = 130◦C, 1H NMR; δ 8.50
(d, 1H), 7.45 (d, 1 H), 3.50 (s, 6H); 13C NMR; δ160.2, 154.1, 150.4, 101.5,
34.0; IR (KBr, cm−1); 2925.4, 1568.3, 1405.4, 1340.6, 1208.3, 790.4,
550.7.

Pyrimidyl Chalcogen Compounds
991
4-6-Dimethyl-2-pyrimidylselenobenzene
1
Yield = 75%, White crystalline solid, m.p. = 58–62◦C, H NMR: δ
7.61(d,2H), 7.31(m,3H), 6.58 (s,1H), 2.28 (s,6 H) ; 13C NMR: δ 170.3,
166.9, 136.9, 136.0, 129.6, 128.2, 117.5, 36.8, 23.8; 77 Se NMR: δ 486.8;
IR (KBr,cm−1 ): 2924.0, 1578.0, 1529.0, 1438.0, 1341.0, 783.0, 542.0;
Anal. Calcd. for C12H12N2Se; C, 54.50; H, 4.54, N, 10.60. Found: C,
37.03, H, 3.36, N, 12.38.
2-Phenylseleno-4-chloropyrimidine
Yield = 75%, White crystalline solid, m.p.= 49–51◦C, 1H NMR: δ
8.08 (d, 1H), 7.00(d, 2H), 7.45 (m, 3H); 13C NMR: δ 162.6, 161.3, 160.8,
159.8, 157.2, 120.0; 77 Se NMR: δ 500.69; IR (KBr, cm−1): 2924.0,1542.0,
1518.0, 1478.0, 1439.0, 790.0, 592.6: Anal. Calcd. for C10 H7Cl N2Se; C,
44.28; H, 2.58, N, 10.33. Found: C, 44.42, H, 1.96, N, 9.71.
In summary, in this present paper, we have proposed a simple and
convenient methodology to prepare novel pyrimidine chalcogen com-
pounds in good to excellent yields.
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