Synthesis of C-8 alkyl xanthines by pentaamminecobalt(III) complex

doi:10.4236/abc.2013.36058

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Advances in Biological Chemistry, 2013, 3, 521-524 ABC

http://dx.doi.org/10.4236/abc.2013.36058 Published Online December 2013 (http://www.scirp.org/journal/abc/)

Synthesis of C-8 alkyl xanthines by

pentaamminecobalt(III) complex

Renuka Suravajhala

Department of Science, Systems and Models, Roskilde University, Roskilde, Denmark

Email: [email protected]

Received 8 September 2013; revised 15 October 2013; accepted 29 October 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Alkyl xanthines underwent selective homolytic aro-

matic substitution at C-8 position with alkyl groups of

pentaamminecobalt(III) complex. In this process of

synthesis, we used monoalkyl hydrazines as the ra-

dical source in aqueous ammonia solution. Evidence

supporting coordination of the alkyl hydrazine to

pentaamminecobalt(III) complex by radical trapping

was in good agreement with literature. The products

were characterized using GC-MS and 1H, 14N and

59Co NMR spectroscopy.

Keywords: Alkyl Hydrazine; Radical Alkylation;

Caffeine; Homolytic Aromatic Substitution;

Pentaamminecobalt(III)

1. INTRODUCTION

Alkyl xanthines belong to purine group of molecules and

are of interest due to their therapeutic value. A number of

xanthines are used as adenosine receptor antagonists to

treat neurodegenerative diseases in humans [1]. Several

xanthines are known to inhibit cells at the G2 checkpoint

in the cell cycle, thereby making cells more sensitive to

DNA damage [2]. Xanthines, such as caffeine, theophyl-

line, theobromine (see Figure 1) and its derivatives have

been used for antihyperuraemic therapy, inhibition of

monoamine oxidase B [3], besides serving as anticancer

agents. Xanthines are known to enhance affinity for cer-

tain receptors selectively as well. This has led to an in-

terest in synthesizing substituted alkyl xanthines.

Aqueous organometallic chemistry and its catalysis

have attracted much interest, partly due to the reduced

requirement for organic solvents [4]. Many organoco-

balt(III) complexes are sensitive to oxygen or moisture.

Hydrolysis of a cobalt(III)-carbon bond is dependent on

the nature of the ligand and requires mild conditions.

Alkylcobalt(III) complex acts as a potential radical sour-

ce, e.g. in organic synthesis [5] such as oxidation, re-

duction, thermolysis, photolysis and sonolysis. Homo-

lytic aromatic substitution is a well-known method for

the preparation of 8-substituted xanthines. Previously,

8-methylcaffeine was known to be prepared by irradia-

tion of a mixture of caffeine and tert-butyl peracetate

with ultraviolet light [6]. Similarly, 8-(1-adamantyl) caf-

feine and 8-cyclohexyl caffeine were obtained by em-

ploying photochemically prepared radicals [7] while

other 8-alkyl xanthines were known to be synthesized by

reaction with solvent-derived alkyl radicals using ben-

zoyl peroxide as a radical initiator [8].

Till date, no studies have been focused on Cobalt cat-

alysed synthesis of C-8 alkyl xanthines. In this study, an

attempt was made to synthesize and purify C-8 substi-

tuted alkyl xanthines.

2. MATERIAL AND METHODS

Concentrated aqueous NH3 (5 mL) was added to a solu-

tion of Co (NO3)2·6H2O (30 mg, 0.1 mmol), the mo-

noalkyl hydrazine (2.0 mmol), and methyl xanthine (1.0

mmol) in H2O (10 mL). The mixture was stirred for 8 -

10 h at room temperature in presence of atmospheric

dioxygen. The reaction was monitored by GC-MS after

extraction into CH2Cl2. Following completion, the prod-

uct was extracted into CH2Cl2 (25 mL) and the solvent

was removed by rotary evaporation. The resulting solid

was dissolved in a 2:3 mixture of ethoxyacetate, n-hex-

ane (5 mL) and purified by column chromatography us-

ing silica gel (mesh, 11, 3.5 cm) and a 2:3 mixture of

ethoxyacetate and n-hexane as eluent. The pure com-

pounds were isolated and further characterized by GC-

MS, 1H NMR and elemental analysis (See Figure 2).

3. RESULTS AND DISCUSSION

The 8-alkyl xanthines have been synthesized and cha-

racterized using GC-MS and 1H NMR. Further elemental

analysis of the isolated compounds was done which were

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R. Suravajhala / Advances in Biological Chemistry 3 (2013) 521-524

522

Figure 1. Structures of xanthine and its derivatives.

Figure 2. Preparation of C-8 substituted alkyl xanthines.

in agreement with respect to molecular structures. While

the following seven compounds synthesized, viz. 8-tert-

butyl caffeine, 8-tertbutyl theophylline, 8-tertbutyl-3-

isobutyl-1-methyl-theophylline,8-isopropyl -3- isobutyl-

1-methyl theophylline, 8-isopropyl caffeine,8-isopropyl

theophylline and 8-isopropyl theobromine; had a con-

version of 60% - 90% (See Table 1). These were further

used to study their effect in cancer cell lines. However,

two compounds, viz. 8-ethyl caffeine and 8-ethy tertbutyl

theobromine were not considered due to their insolubility

in aqeous solution. Although we tried to synthesize many

compounds, we wereable to get good yields for se-

condary and tertiary alkly hydrazines which have pre-

dominantly yielded 8-substituted alkly xanthines

The reaction of monoalkyl hydrazines with cobalt (III)

in aqueous ammonia in the presence of atmospheric oxy-

gen was analysed by 14N and 59Co NMR. A solution of

0.1 M Co(NO3)2 in 4 M NH3 provided a 59Co NMR sig-

nal at 8759 ppm (line width at half height, Δυ½ = 11.2

kHz), which was assigned to the diamagnetic

[(NH3)5CoOOCo(NH3)5]4+ and is in agreement with the

literature [11]. Addition of a stoichiometric amount of a

methyl hydrazine (or another alkyl hydrazine) to the so-

lution resulted in immediate disappearance of the 59Co

NMR signal. Rapid gas evolution (presumably O2) toge-

ther with the disappearance of [(NH3)5CoOOCo(N H3)5]4+

was consistent with methyl hydrazine displacing the co-

ordinated dioxygen to give a cobalt(III) compound. This

was oxidized slowly to the [Co(NH3)5 (CH3)]2+ cation

which was evident by the appearance of a 59Co signal at

7370 ppm (Δυ½ = 13.2 kHz) (Figure 3) [9].

Magnetic susceptibility measurements in solution fol-

lowing Evans method [10] using tert-butanol with 1H

NMR detection showed that a solution of 0.1 M

Co(NO3)2 in 4 M NH3 was essentially diamagnetic and

consistent with formation of the [(NH3)5CoOOCo(NH3)5]4+

cation. Addition of a stoichiometric amount of methyl

hydrazine resulted in a paramagnetic species. This was

consistent with the disappearance of the 59Co NMR sig-

nal. Coordination of dioxygen to yield diamagnetic co-

balt(III) complexes, as indicated by the 59Co NMR sig-

nals, was conceivable indicating that dioxygen oxidizes

the alkyl hydrazine via simultaneous coordination to the

cobalt ion. Although many cobalt-dioxygen complexes

are known to form in aqueous solution [11], to our

knowledge, there are no reports on cobalt coordination

compounds with both alkyl hydrazines and dioxygen

ligands. Nevertheless, in view of many studies on co-

balt-dioxygen complex formation with nitrogen donor

ligands [12], it appears plausible that such species may

form as intermediates. The 1H NMR spectra of the reac-

tion mixtures showed that oxidation, e.g. of ethyl hydra-

zine gives a [Co(NH3)5(CH2CH3)]2+ cation prior to xan-

thine alkylation. The ethyl 1H NMR resonance signals of

the ethyl hydrazine gradually decreased and instead, two

new resonances at 3.90 and 3.97 ppm appeared. These

were assigned to the [Co(NH3)5(CH2CH3)] 2+ cation by

comparison with data for the isolated coordination com-

pound [12].

The latter compound disappeared slowly and the for-

mation of 8-ethylcaffeine was observed by the presence

of appropriate 13C and 1H resonance signals along with

14N NMR studies. A solution of methyl hydrazine in 6 M

NH3 yielded a broad 14N signal (−299 ppm); addition of a

25 M solution of Co(NO3)2 yielded signals correlating

with -NH-NH2 (−262 ppm, −331 ppm). Thus we observe

that the oxidation of hydrazine with cobalt(III) takes

place prior to alkylation of the alkylated xanthine.

This interpretation implies coordination of the alkyl

hydrazine to cobalt(III) and is supported by the fact that

methyl and ethyl hydrazine have been demonstrated to

act as unidentate or bidentate bridging ligands towards

cobalt(III) [13,14]. The rapid exchange reactions studied

in alkylcobalt(III) complexes allow detection of alkyl

radical released during the decomposition in aqueous

solution. For example, in the case of pentaammine me-

thylcobalt(III) complex [Co(NH3)2 (CH3)(NO3)2] the

methyl radical can be trapped by α-phenyl-N-tert-butyl-

nitrone (PBN) with the appearance of a (14N): 16.89 G

signal, and furthermore, on addition of caffeine, there

were no signals observed due to a methyl adduct of PBN.

R. Suravajhala / Advances in Biological Chemistry 3 (2013) 521-524

523

Table 1. The % conversion of C-8 substituted alkyl xanthines.

Product R1 R

2 R

3 R Conversion

Expected yeild

mmol

Isolated Yeild

g/mmol

8-ethylcaffeine CH3 CH3 CH3Et 20% 0.16 10 mg/0.045 mmol

8-tert-butyl-3-isobutyl-1-methyl xanthine CH3 iBu H tBu85% 0.85 110 mg/0.39 mmol

8-tert-butylcaffeine CH3 CH3 CH3tBu55% 0.35 54 mg/0.2 mmol

8-tert-butyl theophylline CH3 CH3 H tBu95% 0.49 102 mg/0.43 mmol

8-tert-butyl theobromine H CH3 CH3tBu15% 0.1 16 mg/0.17 mmol

8-isopropyl -3-isobutyl-1-methyl xanthine CH3 iBu H iPr 70% 0.7 20 mg/0.75 mmol

8-isopropyl caffeine CH3 CH3 CH3iPr 58% 0.6 40 mg/0.16 mmol

8-isopropyl theophylline CH3 CH3 H iPr 67% 0.67 35 mg/0.15 mmol

8-isopropyl theobromine H CH3 CH3iPr 90% 0.9 30 mg/0.15 mmol

Figure 3. 59Co NMR signal at δ = 8759 ppm [(NH3)5CoOOCo(NH3)5]4+ cation, and δ = 7370 ppm [Co(NH3)5(CH3)]2+ cation in

DMSO-d6.

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4. CONCLUSION

We report that cobalt(III) in aqueous ammonia solution

serves as a catalyst for obtaining new carbon-carbon

bonds by homolytic aromatic substitution. The ammine-

cobalt(III)-promoted aerial oxidation of alkyl hydrazines

afforded alkyl radicals, and some primary alkyl radicals

were trapped by pentaamminecobalt(III) to form alkyl

cobalt(III) cations [15]. However, these compounds are

labile and decomposed to return alkyl radicals. It has been

previously shown that the [Co(NH3)5(CH3)]2+ cation acts

as a methylating agent toward the C-8 atom of purine

nucleotides [16-18]. We have applied a number of alkyl

radicals for the preparation of C-8 substituted alkyl xan-

thines. We were unable to obtain evidence of a cobalt(III)

species with both an alkyl hydrazine ligand and a per-

oxo ligand. However, this does not exclude the possibil-

ity of such a species existing as a reactive intermediate. It

may be speculated that a cobalt(III) species with both an

alkyl hydrazine ligand and a peroxo ligand is very short-

lived due to rapid oxidation of alkylhydrazine.

5. ACKNOWLEDGEMENTS

Grateful appreciations towards financial support for the work carried

out were rendered to the Danish Natural Science Research Council.

The author thanks Drs. Pauli Kofod and AS Kumbhar for reviewing the

manuscript.

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