Alternative synthesis of 2-(4-benzoyl-piperazin-1-ylmethyl)-5, 6-dimethoxy-3-methyl-[1, 4]benzoquinone

Article abstract of DOI:10.3184/174751911X13099411630089

The title compound was prepared by a reaction sequence starting from 2, 3, 4, 5-tetramethoxytoluene via Blanc chloromethylation reaction, oxidation and alkylation. The described method provides a good yield of the heterocyclic- Coenzyme Q analogue and is

Full text of DOI:10.3184/174751911X13099411630089

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 431
JULY, 431–432
Alternative synthesis of 2-(4-benzoyl-piperazin-1-ylmethyl)-5,
6-dimethoxy-3-methyl-[1, 4]benzoquinone
Jin Wanga, Jian Yangc*, Rong-Guang Zhoub*, Bo Yanga and Yuan-Shuang Wua
aFaculty of Life Science andTechnology, Kunming University of Science andTechnology, NO.296 BailongTemple, Panlong Zone,
Kunming 650224, Yunnan Province, P. R. China
bInstitute for Drug Research and Development of Kunming Pharmaceutical Corporation, NO.141 Chunyu Road, Wuhua Zone,
Kunming 650100, Yunnan Province, P. R. China
cFaculty of Life Science andTechnology, Kunming University of Science andTechnology (ChengGong Campus), Kunming 650500,
Yunnan Province, P. R. China
The title compound was prepared by a reaction sequence starting from 2, 3, 4, 5-tetramethoxytoluene via Blanc
chloromethylation reaction, oxidation and alkylation. The described method provides a good yield of the heterocyclic-
Coenzyme Q analogue and is suitable for the synthesis of other analogues.
Keywords: Blanc chloromethylation reaction, alkylation, Coenzyme Q analogues
Coenzyme Q (CoQ or ubiquinone) is a lipid component of
the electron transport chain required for ATP generation in
mitochondria.1 CoQ also acts as an anti-oxidant by reducing
free radicals that can cause damage to structural lipids or
proteins in membranes.2 The metabolites of CoQ homologues,
and a number of synthetic CoQ analogues have been shown to
be capable of inhibiting, activating, or occupying sites in the
mitochondrial permeability transition pore.3,4
Among the CoQ analogues which have been synthesised
previously, substituted benzoquinone derivatives bearing a
heterocyclic substituent can be useful as blood platelet aggre-
gation inhibitors, vascular relaxants, and cardiovascular
agents.5 However, the methods described in the patent5 for
the preparation of these substituted CoQ analogues have
significant drawbacks such as long reaction times, low yields
of the products and difficult work-up. The development of
simple and efficient methods for the synthesis of substituted
CoQ analogues bearing a heterocyclic unit is therefore desirable.
We now present a convenient route for the synthesis of
the title compound 6 which is useful as a vascular relaxant
according to the patent.5 The synthetic route is described in
Scheme 1.
Results and discussion
The direct alkylation of piperazine produces a mixture of
substitution products from which the isolation of mono-
substituted compounds is difficult or impossible when the
substituting group is relatively small.6 Hence, we synthesised
N-benzoylpiperazine 3 by the literature method.7 This was
reacted with compound 2 which had been synthesised via a
Blanc chloromethylation reaction to furnish unsymmetrically
disubstituted piperazine 4 in good yield (89% based on 2).
However, we could not obtain the desired compound 6 from 4
by oxidation with ceric ammonium nitrate (CAN). We specu-
lated that the piperazine group of compound 4 was also oxi-
dised by CAN in this reaction. Fortunately, we found another
route: treatment of 2 with CAN provided 58 and then alkylation
with N-benzoylpiperazine 3 in the presence of K2CO3 gave 6 in
80% yield (based on 3) under mild conditions.
In conclusion, a short route for the synthesis of the com-
pound 6 has been achieved in overall yield (67%). From the
synthetic point of view, an approach based on the reactions
with 5 looked promising for the synthesis of substituted CoQ
analogues bearing a heterocyclic ring. Moreover, this method
Scheme 1 Reagents and conditions: (a) (HCHO)n, 37%HCl, 40 °C, 96%; (b) K2CO3, DMF, 80 °C, 89%;
(c) CAN, THF/H2O, 0 °C, 87%; (d) K2CO3, CH2Cl2, 40 °C, 80%.
* Correspondent. E-mail: pharmacistkg101@gmail.com

432 JOURNAL OF CHEMICAL RESEARCH 2011
2-(4-Benzoyl-piperazin-1-ylmethyl)-5, 6-dimethoxy-3-methyl-[1, 4]
benzoquinone (6):5 Benzoquinone 5 (0.30 g, 1.3 mmol), N-benzoylpi-
perazine 3 (0.27 g, 1.4 mmol) , and K2CO3 (0.28 g, 2.0 mmol) in
CH2Cl2 were heated at 40 °C for 2 h , After completion of the reaction,
the crude was extracted with three portions of CH2Cl2 (10 mL). The
orange extracts were washed with brine until neutrality, then dried over
anhydrous Na2SO4 and concentrated in vacuo. The crude products
were purified by a silica-gel column chromatography with petroleum
ether and EtOAc (5:1) as eluent to give the desired compound
6 (0.4g); yield 80%, orange solid, m.p. 122.7–124.3 °C [lit.9 122–
124 °C], IR (KBr/cm−1): 2962, 1658, 1619, 1451, 1276, 1211, 1152,
1088, 1042; 1H NMR (500 MHz, C5D5N-d5): 7.35–7.33 (m, 5H, PhH),
3.95 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.69 (brs, 2H, CH2N), 3.37 (s,
2H, CH2), 3.32 (brs, 2H, CH2N), 2.49 (brs, 2H, CH2N), 2.33 (brs, 2H,
CH2N), 2.07 (s, 3H, CH3); 13C NMR (125 MHz, MeOD):184.4, 183.8,
170.2, 144.3, 144.2, 142.9, 137.3, 135.6, 129.6 (CH), 128.4 (2 × CH),
126.9 (2 × CH), 61.2 (2 × OCH3), 53.4 (CH2N), 52.9 (CH2N), 51.5
(CH2), 47.6 (CH2N), 42.0 (CH2N), 12.4. ESI-MS: m/z = 383 (M−-H).
All the compounds were known compounds and were characterised
by comparison of their m.p., IR, 1H NMR, and MS data with those of
authentic samples.
not only has the advantages of mild conditions, easily acces-
sible starting materials and facile separation, and it is also
less expensive, more practical, and environmentally friendly.
Hence, we believe that this experimentally simple approach
could be a useful addition to reported methods of CoQ
analogues.
Experimental
All reactions were monitored by TLC, Melting points were measured
on a YRT-3 temp apparatus and are uncorrected. IR spectra were
recorded on Impact 400 FT-IR instrument. NMR spectral data were
recorded on a Bruker DRX 500 NMR spectrometer and a ZAB-2F
mass spectrometer, respectively.
2, 3, 4, 5-Tetramethoxytoluene 1 and 1-chloromethyl-2, 3, 4, 5-
tetramethoxy-6-methylbenzene 2 were prepared by the literature
method.3
Phenyl-[4-(2, 3, 4, 5-tetramethoxy-6-methyl-benzyl)-piperazin-1-yl]-
methanone (4):9 Compound 2 (2.6g, 10mmol), N-benzoylpiperazine 3
(1.9 g, 10 mmol), and K2CO3 (2.1g, 15 mmol) in DMF (20 mL) were
heated at 80 °C for 4 h , After completion of the reaction, water
(50 mL) was added and the resulting mixture was extracted with
three portions of CH2Cl2 (20 mL). The combined extracts were
washed with brine until neutrality, then dried over anhydrous Na2SO4
and concentrated in vacuo to afford compound 4 3.7g. Yield 89%,
yellow oil, IR (KBr/cm−1): 2936, 2820, 1680, 1464, 1412, 1353, 1159,
1120, 1016; 1H NMR (500MHz, CDCl3): 7.40 (s, 5H, PhH), 4.22 (s,
2H, CH2), 3.94 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.84 (s, 3H, OCH3),
3.79 (s, 3H, OCH3), 3.51–3.37 (m, 4H, CH2NCH2), 2.36–2.27 (m, 4H,
CH2NCH2), 1.62 (s, 3H, CH3).
This study was supported by Fund of Kunming University of
Science and Technology and Office of Education Research
Fund of Yunnan Province.
Received 14 June 2011; accepted 20 June 2011
Paper 1100749 doi: 10.3184/174751911X13099411630089
Published online: 5 August 2011
References
2-Chloromethyl-5, 6-dimethoxy-3-methyl-[1, 4]benzoquinone (5):2
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