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DOI: 10.1039/C5RA26524J (Communication) RSC Adv., 2016, 6, 11378-11381

An efficient synthesis of 2-thio-5-amino substituted benzoquinones via KI catalyzed cascade oxidation/Michael addition/oxidation starting from hydroquinone†

Yihuan Lu, Yuqiong Zhao, Shucheng Wang, Xin Wang, Zemei Ge* and Runtao Li*
State Key Laboratory of National and Biomimetic Drugs, School of Pharmaceutical Science, Peking University, Beijing 100191, P. R. China. E-mail: zmge@bjmu.edu.cn; lirt@bjmu.edu.cn; Fax: +86 10 82805954; Tel: +86 82805954

Received 12th December 2015 , Accepted 20th January 2016

First published on 22nd January 2016

Abstract

A simple and efficient synthesis of 2-thio-5-amino substituted benzoquinones via KI catalyzed cascade oxidation/S-Michael addition/oxidation/N-Michael addition/oxidation starting from hydroquinone, amines and S-alkylisothiouronium salts was described. Various 2-thio-5-amino substituted benzoquinones were obtained by this method in moderate to good yields. The use of S-alkylisothiouronium salts as thiol equivalents is more convenient and environmental friendly.

The benzoquinone core is an important structural motif that is found in many natural products, pharmaceuticals and biologically active compounds.1–5 Examples include the well-known natural products geldanamycin,5 thymoquinone,6,7 mitomycin C (MMC), embelin,8 and novel anticancer agents mitoxantrone9,10 and carboquone11 (Fig. 1). Thus, the investigation of synthesis and biological activities of benzoquinones has attracted considerable attention in past decades. Many kinds of benzoquinone derivatives have been prepared by different methods.12–18 Surprisingly, only a few reports were found for the synthesis of 2-thio-5-amino substituted benzoquinones.19,20 As shown in Scheme 1, there are two strategies for the preparation of 2-thio-5-amino substituted benzoquinones on the basis of the different order of the introduction of the desired substituents into the benzoquinone core. The first strategy is that the amino group is introduced first usually via displacement of halogen or an alkoxy group from the appropriate quinone. The thiol moiety is then introduced by displacement of another halide or alkoxy moiety on the same quinone21–23 (Scheme 1a). The second strategy, a less widely accepted approach, is that thiol group is introduced first12,24 (Scheme 1b). However both strategies usually require the presence of at least two good leaving groups in the starting quinone, thus limiting their scope and the accessibility. Recently, Katritzky and co-workers reported an efficient addition/oxidation method for the preparation of 2-thio-5-amino substituted benzoquinones from simple quinone, thiol and amine19 (Scheme 1c). Despite this method is successful, the use of the highly volatile and foul smelling thiols will lead to serious environmental and safety problems. Moreover, the substrate scope and yields still require to be improved. Therefore, it is necessary to develop a more environmental friendly and efficient procedure for the synthesis of this class of compounds.
image file: c5ra26524j-f1.tif
Fig. 1 Presentative compounds containing quinone cores.

image file: c5ra26524j-s1.tif
Scheme 1 Known synthetic routes for the 2-thio-5-amino substituted benzoquinones.

Multicomponent reactions (MCRs) are increasingly valued as powerful tools to give rapid access to complex products from three or more simple and flexible building blocks in a one-pot procedure with minimal effort.25–27 In the meantime, S-alkylisothiouronium salts have been successfully used to replace the thiols in the thia-Michael addition in our previous work to avoid the foul smell and toxicity of thiols (Scheme 2, eqn (1)).28,29 Considering the continues of our work and the advantages of MCRs, we envisaged that the 2-thio-5-amino substituted benzoquinones would be prepared using S-alkylisothiouronium salts as equivalents of thiols and starting from hydroquinone via cascade oxidation/Michael addition/oxidation strategy (Scheme 2, eqn (2)).


image file: c5ra26524j-s2.tif
Scheme 2 Design of the new synthetic procedure.

To achieve this goal, a model reaction of hydroquinone (1, 1 mmol), cyclohexylamine (2a, 2 mmol) and S-allylisothiouronium bromide (3a, 1 mmol) was carried out using triethylamine (Et3N, 1 mmol) as base, tetrabutylammonium bromide (TBAB) as catalyst in CH2Cl2/H2O in an open atmosphere at room temperature referring to our previous work.28,29 To our delight, the expected product 2-allylthio-5-cyclohexylamino-1,4-benzoquinone (4aa) was obtained in 19% yield (entry 1, Table 1). To find the optimized reaction conditions, different solvent systems and bases were first screened (entries 2–9, Table 1). It was found that the yield of 4aa raised from 19% to 35% using NH4OAc as base in CH3CN/NaCl(aq)30 (entry 8, Table 1). Next, considering that the reaction process involves the oxidation, different kinds of oxidants, including oxygen, DDQ and NaIO3, were added in the reaction system (entries 10–12, Table 1). However, the yield of 4aa was not improved, indicating that extra oxidant was not necessary for this reaction. Subsequently, we examined the effect of different catalysts on the reaction under the reaction conditions of entry 8 in Table 1 (entries 13–16, Table 1). To our surprise, replacing the catalyst TBAB with TBAI or KI, the yield of 4aa was greatly improved from 35% to 60% (entries 13 and 16, Table 1). Meanwhile, increasing the mole ratio of 1[thin space (1/6-em)]:[thin space (1/6-em)]2a[thin space (1/6-em)]:[thin space (1/6-em)]3a from 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 into 1[thin space (1/6-em)]:[thin space (1/6-em)]3[thin space (1/6-em)]:[thin space (1/6-em)]1, 4aa was obtained in 70% yield (entry 17, Table 1), and the yield did not decrease even in the absence of NH4OAc (entry 18, Table 1). However, increasing the amount of 2a or raising the reaction temperature is unfavorable for the reaction (entries 18–20, Table 1).

Table 1 Optimization of reaction conditionsa

image file: c5ra26524j-u1.tif
Entry Solventb Base (1 equiv.) Oxidantc (1 equiv.) Cat. Ratio (1[thin space (1/6-em)]:[thin space (1/6-em)]2a[thin space (1/6-em)]:[thin space (1/6-em)]3a) Temp. (°C) Yieldd (%)
a Reaction conditions: 1 (1 mmol, 1 equiv.), 2a (x mmol), 3a (1 mmol, 1 equiv.), solvent (20 mL/5 mL), 12 h.b NaCl(aq) was saturated sodium chloride solution.c Air was needed except notation.d Isolated yields.e C21H38BrN: hexadecylpyridinium bromide.f TBP-PP: tetrabutylphosphonium bromide.
1 CH2Cl2/H2O Et3N — TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 19
2 PhCH3/H2O Et3N — TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. <10
3 CCl4/H2O Et3N — TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. <10
4 EtOAc/H2O Et3N   TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t 20
5 CH3CN/NaCl(aq) Et3N — TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 26
6 CH3CN/NaCl(aq) KOH — TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 11
7 CH3CN/NaCl(aq) NaOAc — TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 27
8 CH3CN/NaCl(aq) NH4OAc — TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 35
9 CH3CN/NaCl(aq) DBU — TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 20
10 CH3CN/NaCl(aq) NH4OAc O2 TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 34
11 CH3CN/NaCl(aq) NH4OAc DDQ TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 14
12 CH3CN/NaCl(aq) NH4OAc NaIO3 TBAB 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 31
13 CH3CN/NaCl(aq) NH4OAc — TBAI 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 60
14 CH3CN/NaCl(aq) NH4OAc — C21H38BrNe 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 43
15 CH3CN/NaCl(aq) NH4OAc — TBP-PPf 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 38
16 CH3CN/NaCl(aq) NH4OAc — KI 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 60
17 CH3CN/NaCl(aq) NH4OAc — KI 1[thin space (1/6-em)]:[thin space (1/6-em)]3[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 70
18 CH3CN/NaCl(aq) — — KI 1[thin space (1/6-em)]:[thin space (1/6-em)]3[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 70
19 CH3CN/NaCl(aq) — — KI 1[thin space (1/6-em)]:[thin space (1/6-em)]4[thin space (1/6-em)]:[thin space (1/6-em)]1 r.t. 63
20 CH3CN/NaCl(aq) — — KI 1[thin space (1/6-em)]:[thin space (1/6-em)]3[thin space (1/6-em)]:[thin space (1/6-em)]1 40 60

Having identified the optimized reaction conditions in hand (entry 18, Table 1), the generality of this unique three-component one-pot reaction was investigated. We first examined the scope of amines 2 (Table 2). A variety of amines were allowed to react with hydroquinone (1) and S-allylisothiouronium bromide (3a) under the optimized reaction conditions. All the reactions proceeded smoothly and led to the desired products in moderate to good yields. Generally, the aliphatic primary amines, benzylamines and allylamines achieved good yields. Even sterically bulky primary amine 2c still gave the product 4ac in 50% yield. Comparatively, low active arylamine and low boiling dimethylamine afforded products in moderate yields (4ah, 40%; 4as, 49%). However, cyclic secondary amines containing hetero atom, such as morpholine (2o), thiomorpholine (2p), 1-methylpiperazine (2q), and cyclic secondary amine bearing hydroxyl group (2r), gave the desired products (4ao–4ar) in high yields (75–82%). Notably, amines with different functional groups including double bond, hydroxyl, alkoxyl, methylsulfanyl, ester and heterocycle, were all well tolerated in this reaction.

Table 2 Reactions of different amines with hydroquinone and S-allylisothiouronium bromidea,b

image file: c5ra26524j-u2.tif
a Reaction conditions: 1 (1 mmol), 2 (3 mmol), 3a (1 mmol) and KI (0.3 mmol) in 20 mL/5 mL CH3CN/NaCl(aq) at ambient temperature for 8–12 h.b Isolated yields.c 0.5 equiv. CsCO3 was added.d Ratio of 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]3a was 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1, and 1 equiv. Et3N was needed.
image file: c5ra26524j-u3.tif

The substrate scope of S-alkylisothiouronium salts (3) was next investigated (Table 3). Various S-alkylisothiouronium salts (3) were all suitable reaction partners and gave the desired products (4) in good yields. In particular, S-methylisothiouronium salt as the equivalent of methanthiol gave the desired product 4mh in 62% yield. In addition, S-alkylisothiouronium salts bearing nitrile and ester groups were well tolerated in this case (4md, 71%; 4me, 70%).

Table 3 Reactions of different S-alkylisothiouronium salts with hydroquinone and amine

image file: c5ra26524j-u4.tif
image file: c5ra26524j-u5.tif

To explore the reaction pathway, we initially tried to capture the key intermediate for this cascade reaction. However, it failed due to the rapid transformation from reaction intermediate to the final product. Hence, we prepared the 2-(benzylthio)-1,4-benzoquinone (7c) according to Katritzky's method.19 Then, using 7c as control and detecting by TLC, we found that the intermediate of the reaction of hydroquinone (1), 3-methoxypropylamin (2m) and benzyl isothiouronium bromide (3c) was consistent with 7c under our reaction conditions. Moreover, under our reaction conditions, the 7c could rapidly react with 2m forming the product 4mc. Therefore, we propose the possible pathway for this novel KI catalyzed cascade reaction as depicted in Scheme 3. The hydroquinone (1) was first oxidized into 1,4-benzoquene (5). Then, the S-Michael addition of 1,4-benzoquene (5) with thiol anion from S-alkylisothiouronium salts (3) led to the formation of 2-alkylthio-1,4-phenol (6). The key intermediate (6) was oxidized again, and the generated 2-alkylthio-1,4-benzoquene (7) was in situ attacked by amine (2) affording the 2-thio-5-amino-1,4-phenol (8). Finally, 2-thio-5-amino-benzoqunone (4) was obtained from the oxidation of 8. The presence of excess amine and catalyst KI may accelerate the oxidation process from hydroquinones (1, 8) to benzoquenes (5, 4).31–35


image file: c5ra26524j-s3.tif
Scheme 3 Proposed reaction pathway and the evidences.

Conclusions

In summary, we have developed a simple and efficient synthesis of 2-thio-5-amino substituted benzoquinones via KI catalyzed cascade oxidation/S-Michael addition/oxidation/N-Michael addition/oxidation starting from hydroquinone, amines and S-alkylisothiouronium salts in moderate to good yields. The mild reaction conditions make this method a broad range of substrate scope. The use of S-alkylisothiouronium salts as thiol equivalents avoids the fetid odor, toxicity and difficulty for operation of thiols. The benzoquinone derivatives are biologically and pharmaceutically active molecules; therefore, the present method will be of wide application in organic chemistry and medicinal chemistry.

Acknowledgements

This work is supported by National Natural Science Foundation of China (No. 21172011).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, copies of the 1H and 13C NMR spectra. See DOI: 10.1039/c5ra26524j
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