Simple and convenient two step synthesis of 5-bromo-2,3-dimethoxy-6-methyl-1,4-benzoquinone

Abstract 5-bromo-2,3-dimethoxy-6-methyl-1,4-benzoquinone 3, a key intermediate for preparing coenzyme Q compounds, was readily synthesized in two steps by a reaction sequence starting from the commercially available 3,4,5-trimethoxytoluene 1 via bromination and oxidation reactions. Persulfate salts were first employed as oxidants to synthesize 1,4-benzoquinone, the overall yield of title compound 3 was 65%.


Introduction
Let F denote a eld and let V denote a vector space over F with nite positive dimen pair A, A * of diagonalizable F-linear maps on V, each of which acts on an eigenbasis for irreducible tridiagonal fashion. Such a pair is called a Leonard pair (see [13, De nition 1.1 A, A * is said to be self-dual whenever there exists an automorphism of the endomorphis swaps A and A * . In this case such an automorphism is unique, and called the duality A The literature contains many examples of self-dual Leonard pairs. For instance (i) the ated with an irreducible module for the Terwilliger algebra of the hypercube (see [4,Corol Leonard pair of Krawtchouk type (see [10, De nition 6.1]); (iii) the Leonard pair associated module for the Terwilliger algebra of a distance-regular graph that has a spin model in th bra (see [1,Theorem], [3,Theorems 4.1,5.5]); (iv) an appropriately normalized totally bi (see [11,Lemma 14.8]); (v) the Leonard pair consisting of any two of a modular Leonard t De nition 1.4]); (vi) the Leonard pair consisting of a pair of opposite generators for the bra, acting on an evaluation module (see [5,Proposition 9.2]). The example (i) is a specia examples (iii), (iv) are special cases of (v).
Let A, A * denote a Leonard pair on V. We can determine whether A, A * is self-dual i By [13, Lemma 1.3] each eigenspace of A, A * has dimension one.
i= in an irreducible tridiagonal fashion. If the orderin then the ordering {θ d−i } d i= is also standard, and no further ordering is standard. Similar A * . Let {θ i } d i= denote a standard ordering of the eigenvalues of A. Then A, A * is self-dual is a standard ordering of the eigenvalues of A * (see [7,Proposition 8.7]).
is also a key intermediate [5] in the preparation of other biologically active coenzyme Q analogues [6]. In 2000, Jung and co-workers [7] reported that coupling of compound 3 with isoprenylstannanes could efficiently produce coenzyme Q 10 and its analogues, as shown in Scheme 1. CoQ 10 is a lipid-soluble benzoquinone with a side-chain of 10 isoprenoid units (Scheme 1), acts as a free radical scavenging antioxidant [3]. CoQ 10 has been widely used in the treatment of mitochondria disorders [8].
To date, methods for the synthesis of compound 3 are limited [9]. Most of the methods used CoQ 0 as starting material, compound 3 was obtained by reaction with toxic bromine [10], and few syntheses leading to compound 3 have been disclosed [11]. Hence, based on our previous work on the synthesis of CoQ analogues [12][13][14][15][16], we now report an efficient synthetic path for compound 3 as shown in Scheme 2. The reaction is operationally simple and could be used in the preparation of other coenzyme Q analogues.

Synthesis of compound 3
Method (1)  The data is consistent with the literature [4].

Results and discussion
As shown in Scheme 2, treatment of 3,4,5-trimethoxytoluene (1) with NaBr and 30% in acetic acid at 40°C gave compound 2 in 100% yield. Finally, compound 2 was oxidized with a persulfate compound in HOAc-H 2 SO 4 mixed solvent (v/v = 10:1) to afford compound 3 ( Table 1). The reaction is conducted without using any metal catalyst. This environmentally friendly procedure is based on the persulfate oxidant as an oxygen atom donor, and the HOAc-H 2 SO 4 solvent as proton atom in this transformation [2]. The use of (NH 4 ) 2 S 2 O 8 as oxidant in HOAc-H 2 SO 4 (10:1) mixed solvent gave 3 in a yield of 40% (entry 3, Table 1). When utilized K 2 S 2 O 8 as oxidant in the same mixed solvent HOAc-H 2 SO 4 (10:1) can improve the reaction yield to 60% (entry 2, Table 1). The best yield was obtained using Na 2 S 2 O 8 as oxidant in HOAc-H 2 SO 4 (10:1) solvent system, which gave the desired compound 3 in 65% yield (entry 1, Table 1).

Conclusion
In summary, we developed a two-step synthetic protocol for the preparation of 5-bromo-2,3-dimethoxy-6-methyl-1,4-benzoquinone (3) from the cheap and readily available 3,4,5-trimethoxytoluene (1). The bromination reaction utilize NaBr-H 2 O 2 system as a green brominating agent instead of bromine and NBS, the reaction is clean and easy work up without purification. Persulfate salts were first employed as oxidants to synthesize 1,4-benzoquinone under mild condisitons, the chemistry was clean and easy work up. This method is potentially applicable for the the synthesis of a wide variety of coenzyme Q compounds [14,15].