Biomimetic synthesis of symmetric acyclic diketones

Article abstract of DOI:10.1081/SCC-200028613

A convenient synthetic method for the preparation of symmetric acyclic diketones from dicarboxylic acids is provided. Three bis-benzimidazolium salts were used as tetrahydrofolate coenzyme model, thus the biomimetic synthesis of three symmetric acyclic diketones was successfully accomplished by using the addition-hydrolysis reaction of corresponding bis-benzimidazolium salts with methyl magnesium iodide.

Full text of DOI:10.1081/SCC-200028613

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Biomimetic Synthesis of
Symmetric Acyclic Diketones
Yuan Guo a & Zhen Shi a
a Department of Chemistry , Northwest
University , Xi'an, 710069, P.R. China
Published online: 10 Jan 2011.
To cite this article: Yuan Guo & Zhen Shi (2004) Biomimetic Synthesis of Symmetric
Acyclic Diketones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:17, 3183-3189, DOI: 10.1081/
SCC-200028613
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 17, pp. 3183–3189, 2004
Biomimetic Synthesis of Symmetric
Acyclic Diketones
*
Yuan Guo and Zhen Shi
Department of Chemistry, Northwest University, Xi’an, P.R. China
ABSTRACT
A convenient synthetic method for the preparation of symmetric acyclic
diketones from dicarboxylic acids is provided. Three bis-benzimida-
zolium salts were used as tetrahydrofolate coenzyme model, thus the bio-
mimetic synthesis of three symmetric acyclic diketones was successfully
accomplished by using the addition-hydrolysis reaction of corresponding
bis-benzimidazolium salts with methyl magnesium iodide.
Key Words: Biomimetic synthesis; Symmetric acyclic diketone; bis-
Benzimidazolium salt; Grignard reagent.
Acyclic diketones are an important class of compounds in view of their
distinct structural feature and wide utility in the medical industry, dyeing
*
Correspondence: Zhen Shi, Department of Chemistry, Northwest University, Xi’an
710069, P.R. China; Fax: þ86-29-88303798; E-mail: yuanorganic@163.com.
3183
DOI: 10.1081/SCC-200028613
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Guo and Shi
industry, and organic synthesis.[1] A number of methods have been reported so
far for the synthesis of diketones.[2] However, some of these methods suffer
from disadvantages with respect to convenience, selectivity, or efficiency
and have limited applicability in preparing diketones containing fewer than
six methylenes.
Recently, the function of tetrahydrofolate coenzymes for organisms and
the use in biomimetic synthesis have been an important subject of biochemis-
try.[3] The tetrahydrofolate coenzymes are involved in the biochemical trans-
fer of a one-carbon fragment at different oxidation levels. The structure is as
shown in Sch. 1, which is at the formic acid oxidation level.
The five-membered ring structure is the active site.[4] bis-Benzimida-
zolium salt contains two of this kind of five-membered ring and can be used
as the tetrahydrofolate coenzyme model at formic acid oxidation level.
We reported the reaction of benzimidazolium salts with Grignard reagents
in which a novel synthetic method for ketone was provided.[5] In extention of
our method, the reaction of bis-benzimidazolium salts with methyl mag-
nesium iodide was studied, and a convenient synthetic method for the prep-
aration of several symmetric acyclic diketones containing more than six
methylenes was provided (Sch. 2).
It has been reported that compounds with a quaternary C55N doubly group
react with Grignard reagents.[6] But the method for preparing symmetric acyclic
diketones containing more than six methylenes from dicarboxylic acids and
methyl magnesium iodide as Grignard reagent via bis-benzimidazolium salts
has not been reported in literature. Since bis-benzimidazole can be prepared
from dicarboxylic acid, the method provides an important route for preparing
symmetric acyclic diketones from dicarboxylic acid and Grignard reagent.
In our experiments, the addition of Grignard reagent to bis-benzimida-
zolium salt was carried out. bis-Benzimidazolidine obtained from the addition
reaction could be hydrolyzed directly to give diketone in acidic solution after
the addition reaction was finished, so a convenient and simple synthetic
method for symmetric diketone was realized.
Scheme 1.

Biomimetic Synthesis of Symmetric Acyclic Diketones
3185
PPA ¼ Polyphosphoric acid; a: m ¼ 6; b: m ¼ 7; c: m ¼ 8
Scheme 2.
Compared with the synthetic methods described in the literature, our
method employed o-phenylenediamine, dicarboxylic acids, and iodomethane
as starting materials, which are readily available. Three symmetric acyclic
diketones (3a, 3b, and 3c) were synthesized in two steps from bis-benzimida-
zolium salts and Grignard reagent. bis-Benzimidazolium salts (2a, 2b, and 2c)
can be synthesized from dicarboxylic acids, phenylenediamine, and iodo-
methane.[7,8] Grignard reagent was prepared according to the literature.[9]
The method is simple and the yield is high. This is a new entry to the synthesis
of symmetric acyclic diketones containing more than six methylenes.
The mechanism for the reaction of benzimidazolium salt with nucleophile
has been proposed in our earlier paper.[5] The preparative reaction described in
this paper can be reasonably explained by the addition reaction of nucleophilic
Grignard reagent with polarized C55N bond of bis-benzimidazolium salt and
the formation of bis-benzimidazolidine, which can be hydrolyzed in acidic
solution to give the corresponding diketone (Sch. 3).
EXPERIMENTAL
Melting points were taken on a XT-4 micro-melting apparatus (Beijing)
and uncorrected. TLC analysis was carried out on glass plates coated with
silica gel-G, and spots were visualized using an ultraviolet (UV) lamp.
Elemental analyses were performed with a Vario EL-III instrument
(Germany) infrared (IR) spectra in cm21 were recorded on a Brucker

3186
Guo and Shi
Scheme 3.
1
EQUIOX-55 spectrometer (Germany). Proton magnetic resonance spectra
(H NMR) spectra were recorded at 400 MHz on a Varian INOVA-400 spec-
trometer (USA), and chemical shifts were reported relative to internal Me4Si.
General Procedure for the Preparation of
bis-Benzimidazolium Salts (2a, 2b, and 2c)
bis-Benzimidazolium salt (2a, 2b, or 2c) was prepared by literature pro-
cedures.[8] A solution of sodium (0.02 mol) in ethanol was treated with
0.01 mol of bis-benzimidazole (1a, 1b, or 1c), 0.06 mol of iodomethane, and
25 mL of benzene, then the mixture was refluxed for 18 hr. The solvent was
removed and the residue was recrystallized from water-ethanol (1 : 1) to
give bis-benzimidazolium salt (2a, 2b, or 2c). The bis-benzimidazole (1a,
1b, or 1c) was prepared from o-di-aminobenzene and dicarboxylic acids
in polyphosphoric acid under microwave irradiation according to the
literature.[7] Compound 2a as a yellow solid, yield 90%, m.p. over 3008C.
Anal. C24H32I2N4. Calcd: C 47.4, H 5.47, N 8.51. Found: C 47.1, H 5.25, N
8.17. Compound 2b as a yellow solid, yield 88%, m.p. over 3008C. Anal.
C25H34I2N4. Calcd: C 46.5, H 5.28, N 8.69. Found: C 46.3, H 4.96, N 8.32.
Compound 2c as a yellow solid, yield 91%, m.p. over 3008C. Anal.
C26H36I2N4. Calcd: C 45.7, H5.08, N 8.89. Found: C 45.4, H 4.71, N 8.42.
General Procedure for the Synthesis of Symmetric Acyclic
Diketones (3a, 3b, and 3c)
bis-Benzimidazolium salt (0.01 mol) (2a, 2b, or 2c) was added in small
portions to a solution of Grignard reagent (0.05 mol) in tetrahydrofuran over
30 min. The mixture was stirred for 30 hr at room temperature. A 5% dilute
HCl (30 mL) was added slowly and the mixture was heated in hot water

Biomimetic Synthesis of Symmetric Acyclic Diketones
3187
bath for 1.0–1.5 hr with stirring. Tetrahydrofuran was removed by distillation
and the residue was extracted with chloroform (5 ꢀ 25 mL). The extract was
successively washed with 5% sodium bicarbonate and water to make its pH 7.
The chloroform solution was dried over anhydrous MgSO4 and evaporated to
give the crude product (3a, 3b, or 3c) as a white crystalline mass, which was
purified by chromatography (SiO2, chloroform).
Compound 3a as a white solid, yield: 83%, m.p. 658C–668C (lit.[10]
648C). ymax (KBr): 1710 (C55O), 2930, 2956, 729. 1H NMR (CDC13/
TMS), d (ppm): 1.20–1.90 (m, 8H, 4 ꢀ CH2), 2.10 (s, 6H, 2 ꢀ CH3), 2.35
(t, J ¼ 7 Hz, 4H, 2 ꢀ COCH2). Anal. C10H18O2. Calcd: C 70.59, H 10.59.
Found: C 70.51, H 10.72.
Compound 3b as a white solid, yield: 80%, m.p. 648C–658C (lit.[11]
638C–658C). ymax (KBr): 1708 (C55O), 2940, 2850, 726. 1H NMR
(CDC13/TMS), d (ppm): 1.20–1.90 (m, 10H, 5 ꢀ CH2), 2.13 (s, 6H,
2 ꢀ CH3), 2.42 (t, J ¼ 7 Hz, 4H, 2 ꢀ COCH2). Anal. C11H20O2. Calcd: C
71.74, H 10.87. Found: C 71.28, H 10.65.
Compound 3c as a white solid, yield: 85%, m.p. 678C–688C (lit.[11]
648C–668C), ymax (KBr): 1706 (C55O), 2931, 2853, 718. 1H NMR
(CDC13/TMS), d (ppm): 1.20–1.70 (m, 12H, 6 ꢀ CH2), 2.13 (s, 6H,
2 ꢀ CH3), 2.41 (t, J ¼ 7 Hz, 4H, 2 ꢀ COCH2). Anal. C12H22O2. Calcd: C
72.73, H 11.11. Found: C 72.92, H 11.06.
CONCLUSIONS
A convenient and efficient procedure of synthesis for the preparation of
symmetric acyclic diketone containing more than six methylenes was devel-
oped. The biomimetic synthesis of three symmetric acyclic diketones was
successfully accomplished by using the addition-hydrolysis reaction of corres-
ponding bis-benzimidazolium salts with methyl magnesium iodide.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of
China (20172041).
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Received in Japan March 31, 2004