Microwave-promoted solvent-free synthesis of para-quinone methides (p-QMs) derivatives

Journal of Saudi Chemical Society (2019) xxx, xxx–xxx

King Saud University

Journal of Saudi Chemical Society www.ksu.edu.sa www.sciencedirect.com

ORIGINAL ARTICLE

Microwave-promoted solvent-free synthesis of para-quinone methides (p-QMs) derivatives Zhang-Qin Liu *, Peng-Sheng You, Chuan-Hua Wu, Yang-Hong Han Key Laboratory of Applied Chemistry of Chongqing Municipality, College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China Received 24 September 2019; revised 15 October 2019; accepted 16 October 2019

KEYWORDS Para-Quinone methides (p-QMs); Green chemistry; Microwave irradiation; Environment friendly synthesis

Abstract A rapid and efficient methodology for the synthesis of polysubstituted para-quinone methides (p-QMs) from aldehyde and 2,6-di-tert-butylphenol has been achieved in solvent-free and microwave irradiation condition within 33 min. This strategy displays the advantages including high atom economy, good functional group tolerance, and environmentally friendly operation. Ó 2019 King Saud University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction para-Quinone methides (p-QMs), a type of quinonoid compounds with aromatic zwitterionic resonances [1] owing to its special structure containing a cyclohexadienone moiety conjugating with a methylene group, have been known as an important structure moieties presented in natural products [2–5] and electrophotographic photoreceptor [6–9] (Fig. 1). In addition, as reactive intermediates [10], p-QMs are widely used to synthesize drug substances such as DPP-IV inhibitors [11], thrombin inhibitors [12], antibacterials [13], (+)-BW37U86 [14], melains [15], and so on. Moreover it can be used as an effective DNA crosslinking agent and directed alkylation reagent [16]. Among the p-QMs family, the 6-ditert-butyl-7-substituted quinone methides hold an essential * Corresponding author. E-mail address: [email protected] (Z.-Q. Liu). Peer review under responsibility of King Saud University.

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position, due to their idiosyncratic properties such as stability, antipolymerant and antioxidant characteristics [17–18]. Therefore, the synthesis of aforementioned compounds has attracted a great deal of attention. Several methods have emerged [19–22], such as organolithium [19] or Grignard reagents [20] participated Aldol approach, Mannich synthesis [21] and methylene oxidation [22]. In despite of these advances, most of the reported methods still suffer from long reaction time, low reactivity, multistep operation, consuming toxic and costly reagents or solvents (toluene, CH3CN, DMF and DMSO). With regard to green synthesis concerned, a more efficient and convenient method is still highly desired. High efficient organic synthesis methods have received continuous attention recently [23–31]. Microwave irradiation as a well-controlled and powerful heating source get more popular in organic synthesis, because microwave-assisted organic reactions have many distinctive advantages such as high yields and purities, saving time and energy, high efficiency compared with the conventional method [32–37]. Herein, we describe an efficient methodology for the synthesis of polysubstituted paraquinone methides (p-QMs) via the reaction of aldehyde and 2,6-di-tert-butylphenol under solvent-free and microwave irradiation condition in short time (Scheme 1).

https://doi.org/10.1016/j.jscs.2019.10.001 1319-6103 Ó 2019 King Saud University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Z.-Q. Liu et al., Microwave-promoted solvent-free synthesis of para-quinone methides (p-QMs) derivatives, Journal of Saudi Chemical Society (2019), https://doi.org/10.1016/j.jscs.2019.10.001

2

Z.-Q. Liu et al. 2.2.2. 4-Benzylidene-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (3a) Yellow solid; m. p. 72–73 °C; 81% yield; 1H NMR (400 MHz, CDCl3) d 7.45 (d, J = 2. 2 Hz, 1H), 7.37 (d, J = 4.7 Hz, 4H), 7.34–7.29 (m, 1H), 7.11 (s, 1H), 6.94 (d, J = 2.3 Hz, 1H), 1.26 (s, 9H), 1.22 (s, 9H). 13C NMR (151 MHz, CDCl3) d 185.56, 148.43, 146.86, 141.37, 134.96, 134.07, 131.01, 129.32, 128.03, 127.75, 126.75, 34.43, 33.99, 28.54, 28.52; HRMS calculated for [M+Na]+ C21H26ONa+, m/z 317.1876, found 317.1877. 2.2.3. 2,6-di-tert-Butyl-4-(4-fluorobenzylidene)cyclohexa-2,5dien-1-one (3b)

Fig. 1

Representative quinone methides derivatives.

2. Experimental 2.1. Materials and apparatus All reagents were purchased from the market without any purification. All 1H NMR, and 13C NMR spectra were recorded using a Bruker Avance 400 MHz and 600 MHz spectrometer in CDCl3 unless otherwise noted. Tetramethylsilane (TMS) served as internal standard (d = 0). Chemical shifts are reported in parts per million as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). High resolution mass spectra (HRMS) (ESI) were recorded on Bruker impact II 10,200 mass spectrometer. The synthesis of polysubstituted para-quinone methides (p-QMs) was performed in a microwave reactor (Sineo, MAS-II Plus, China). Column chromatography purifications were performed by flash chromatography using Merck silica gel 400.

Yellow solid; m. p. 109–110 °C; 66% yield; 1H NMR (600 MHz, CDCl3) d 7.36 (dd, J = 8.6, 5.7 Hz, 3H), 7.11– 7.04 (m, 3H), 6.92 (d, J = 2.2 Hz, 1H), 1.25(s, 9H), 1.22 (s, 9H). 13C NMR (151 MHz, CDCl3) d 186.53, 163.89, 162.23, 149.66, 147.97, 140.86, 134.92, 132.17, 132.12, 131.94, 127.32, 116.06, 115.91, 35.46, 35.01, 29.54, 29.51; HRMS calculated for [M+Na]+ C21H25FONa+, m/z 335.1782, found 335.1784. 2.2.4. 2,6-di-tert-Butyl-4-(4-chlorobenzylidene)cyclohexa-2,5dien-1-one (3c) [38] Yellow solid; m. p. 144–145 °C; 61% yield; 1H NMR (600 MHz, CDCl3) d 7.35 (d, J = 8.7 Hz, 3H), 7.31 (d, J = 8.4 Hz, 2H), 7.03 (s, 1H), 6.92 (d, J = 2.0 Hz, 1H), 1.25 (s, 9H), 1.22 (s, 9H); HRMS calculated for [M+Na]+ C21H25ClONa+, m/z 351.1486, found 351.1489. 2.2.5. 4-(4-Bromobenzylidene)-2,6-di-tert-butylcyclohexa-2,5dien-1-one (3d) [39] Yellow solid; m. p. 146–147 °C; 68% yield; 1H NMR (600 MHz, CDCl3) d 7.58 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 1.9 Hz, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.08 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 1.33 (s, 9H), 1.29 (s, 9H); HRMS calculated for [M +Na]+ C21H25BrONa+, m/z 395.0981, found 395.0985.

2.2. Preparation methods and physical data of products 2.2.1. General reaction procedure for synthesis of p-QMs In a 25 mL flask with a Teflon stirring bar, 2,6-di-tertbutylphenol (9.69 mmol, 1 equiv) and corresponding benzaldehyde (11.63 mmol, 1.2 equiv) were added. The mixture was stirred and heated under 300 W microwave irradiation. When the temperature reached 120 °C, anhydrous piperidine (9.69 mmol, 1 equiv) was added dropwise within 3 min. After reacting for 30 min at 120 °C, acetic anhydride (9.69 mmol, 1 equiv) was added immediately. After 3 min, the mixture was cooled and treated with 10 mL of distilled water, and extracted with 3  10 mL of ethyl acetate, dried over anhydrous MgSO4, and purified by flash chromatography to give the corresponding product.

Scheme 1

2.2.6. 4-(2-Bromobenzylidene)-2,6-di-tert-butylcyclohexa-2,5dien-1-one (3e) [39] Yellow solid; m. p. 116–117 °C; 60% yield; 1H NMR (600 MHz, CDCl3) d 7.68 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 4.3 Hz, 2H), 7.29–7.22 (m, 3H), 7.07 (d, J = 2.1 Hz, 1H), 1.34 (s, 9H), 1.27 (s, 9H); HRMS calculated for [M +Na]+ C21H25BrONa+, m/z 395.0981, found 395.0983. 2.2.7. 2,6-di-tert-Butyl-4-(2-methoxybenzylidene)cyclohexa2,5-dien-1-one (3f) [38] Yellow solid; m. p. 141–142 °C; 75% yield; 1H NMR (600 MHz, CDCl3) d 7.46 (d, J = 2.1 Hz, 1H), 7.43–7.32 (m, 3H), 7.07 (d, J = 2.2 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 3.89 (s, 3H), 1.34 (s, 9H), 1.29 (s, 9H);

Synthesis route of para-quinone methides (p-QMs) derivatives under microwave.

Please cite this article in press as: Z.-Q. Liu et al., Microwave-promoted solvent-free synthesis of para-quinone methides (p-QMs) derivatives, Journal of Saudi Chemical Society (2019), https://doi.org/10.1016/j.jscs.2019.10.001

Microwave-promoted solvent-free synthesis of para-quinone methides (p-QMs) derivatives HRMS calculated for [M+Na]+ 347.1982, found 347.1985.

C22H28O2Na+,

m/z

2.2.8. 2,6-di-tert-Butyl-4-(3-methoxybenzylidene)cyclohexa2,5-dien-1-one (3 g) [38] Yellow solid; m. p. 85–86 °C; 65% yield; 1H NMR (600 MHz, CDCl3) d 7.56 (d, J = 1.7 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.16 (s, 1H), 7.04 (t, J = 8.2 Hz, 1H), 7.02–6.98 (m, 2H), 6.95 (dd, J = 8.2, 2.0 Hz, 1H), 3.85 (s, 3H), 1.33 (s, 9H), 1.30 (s, 9H); HRMS calculated for [M+Na]+ C22H28O2Na+, m/z 347.1982, found 347.1986.

3

2.2.9. 2,6-di-tert-Butyl-4-(4-methoxybenzylidene)cyclohexa2,5-dien-1-one (3 h) Yellow solid; m. p. 119–120 °C; 63% yield; 1H NMR (600 MHz, CDCl3) d 7.56 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.13 (s, 1H), 6.99 (dd, J = 11.5, 5.5 Hz, 3H), 3.87 (s, 3H), 1.33 (s, 9H), 1.32 (s, 9H). 13C NMR (151 MHz, CDCl3) d 186.50, 160.62, 149.06, 147.28, 142.55, 135.33, 132.20, 130.58, 128.72, 127.78, 114.45, 55.40, 35.43, 34.96, 30.37, 30.34, 29.59, 29.53; HRMS calculated for [M +Na]+ C22H28O2Na+, m/z 347.1982, found 347.19844. 2.2.10. 2,6-di-tert-butyl-4-(2-methylbenzylidene)cyclohexa-2,5dien-1-one (3i) [38] Yellow solid; m. p. 94–95 °C; 62% yield; 1H NMR (600 MHz, CDCl3) d 7.27 (d, J = 1.8 Hz, 1H), 7.25–7.21 (m, 2H), 7.20 (dd, J = 8.7, 4.8 Hz, 3H), 6.99 (d, J = 1.9 Hz, 1H), 2.31 (s, 3H), 1.27 (s, 9H), 1.19 (s, 9H); HRMS calculated for [M +Na]+ C22H28ONa+, m/z 331.2032, found 331.2033. 2.2.11. 2,6-di-tert-butyl-4-(3-methylbenzylidene)cyclohexa-2,5dien-1-one (3j) [38] Yellow solid; m. p. 71–72 °C; 61% yield; 1H NMR (600 MHz, CDCl3) d 7.47 (d, J = 2.1 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.22–7.16 (m, 2H), 7.12 (d, J = 7.5 Hz, 1H), 7.08 (s, 1H), 6.93 (d, J = 2.2 Hz, 1H), 2.32 (s, 3H), 1.26 (s, 9H), 1.22 (s, 9H); HRMS calculated for [M+Na]+ C22H28ONa+, m/z 331.2032, found 331.2033. 2.2.12. 2,6-di-tert-butyl-4-(4-methylbenzylidene)cyclohexa-2,5dien-1-one (3 k) [38]

Scheme 2 Proposed mechanism for microwave promoted synthesis of para-quinone methides (p-QMs) derivatives.

Yellow solid; m. p. 143–144 °C; 64% yield; 1H NMR (600 MHz, CDCl3) d 7.55 (d, J = 1.6 Hz, 1H), 7.37 (d,

Table 1 Effect of microwave power, temperature, reaction time 1 and deamination time 2 on the synthesis of para-quinone methides (p-QMs) under microwave irradiation.a

Entry

Time 1 (min)

Temp (°C)

Power (W)

Time 2 (min)

Yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13

30 30 30 30 40 40 40 30 40 30 30 30 30

120 120 120 120 120 120 120 110 110 130 120 120 120

300 200 300 400 200 300 300 300 300 300 300 300 300

3 5 5 5 5 5 3 5 5 5 4 10 15

81 54 70 56 67 60 63 49 57 45 59 50 46

The bold values is used to emphasis the best reaction condition. a 2,6-di-tert-Butylphenol (9.69 mmol), benzaldehyde 1a (11.63 mmol), piperidine (9.69 mmol), acetic anhydride (9.69 mmol). b Isolated yield after flash chromatography.

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4

Z.-Q. Liu et al. Table 2

Entry

Microwave promoted synthesis of para-quinone methides (p-QMs) derivatives.a

Substrate

1

Product

3

Yield (%)b

1

1a

3a

81

2

1b

3b

66

3

1c

3c

61

4

1d

3d

68

5

1e

3e

60

6

1f

3f

75

7

1g

3g

65

8

1h

3h

63

9

1i

3i

62

10

1j

3j

61

11

1k

3k

64

12

1l

3l

75

13

1m

3m

53

14c

1n

3n

61

15c

1o

3o

75

a General reaction conditions unless otherwise specified: 2,6-di-tert-butylphenol (9.69 mmol), aldehyde 1 (11.63 mmol), piperidine (9.69 mmol), acetic anhydride (9.69 mmol), solvent-free, 120 °C, 300 W, reaction time 1 = 30 min, deamination time 2 = 3 min. b Isolated yield after flash chromatography. c microwave power = 400 W, reaction time 1 = 33 min, deamination time 2 = 3.5 min.

J = 7.9 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 7.16 (s, 1H), 7.01 (d, J = 2.0 Hz, 1H), 2.41 (s, 3H), 1.33 (s, 9H), 1.31 (s, 9H); HRMS calculated for [M+Na]+ C22H28ONa+, m/z 331.2032, found 331.2035.

2.2.13. 2,6-di-tert-Butyl-4-(2,4-dimethylbenzylidene)cyclohexa2,5-dien-1-one (3 l) Yellow solid; m. p. 124–125 °C; 75% yield; 1H NMR (600 MHz, CDCl3) d 7.30 (d, J = 2.1 Hz, 1H), 7.18 (d,

Please cite this article in press as: Z.-Q. Liu et al., Microwave-promoted solvent-free synthesis of para-quinone methides (p-QMs) derivatives, Journal of Saudi Chemical Society (2019), https://doi.org/10.1016/j.jscs.2019.10.001

Microwave-promoted solvent-free synthesis of para-quinone methides (p-QMs) derivatives Table 3

5

Comparative results under microwave and oil bath heating conditionsa

Product

Method

Time (min)

Temp (°C)

Yield (%)c

3a 3ab 3ab 3f 3fb 3fb

MW D D MW D D

33 33 180 33 33 180

120 120 120 120 120 120

81 30 45 75 33 48

a General reaction conditions unless otherwise specified: 2,6-di-tert-butylphenol (9.69 mmol), aldehyde 1 (11.63 mmol), piperidine (9.69 mmol), acetic anhydride (9.69 mmol), solvent-free. b Traditional oil bath heating method. c Isolated yield after flash chromatography.

J = 6.6 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.00 (d, J = 11.2 Hz, 2H), 6.97 (d, J = 2.2 Hz, 1H), 2.29 (s, 3H), 2.27 (s, 3H), 1.27 (s, 9H), 1.20 (s, 9H); 13C NMR (151 MHz, CDCl3) d 186.65, 149.00, 147.54, 141.81, 139.44, 137.76, 134.96, 132.02, 131.66, 131.38, 130.93, 128.41, 126.63, 35.39, 35.00, 29.55, 29.54, 21.29, 20.10; HRMS calculated for [M +Na]+ C23H30ONa+, m/z 345.2189, found 345.2190. 2.2.14. 2,6-di-tert-Butyl-4-(2,4,6trimethylbenzylidene)cyclohexa-2,5-dien-1-one (3 m) Light yellow solid; m. p. 96–97 °C; 53% yield; 1H NMR (600 MHz, CDCl3) d 7.12 (s, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.92 (s, 2H), 6.77 (d, J = 2.0 Hz, 1H), 2.32 (s, 3H), 2.17 (s, 6H), 1.34 (s, 9H), 1.20 (s, 9H). 13C NMR (151 MHz, CDCl3) d 185.73, 147.79, 146.55, 141.27, 136.97, 135.26, 133.08, 132.28, 130.62, 127.70, 127.50, 34.15, 33.96, 28.54, 28.52, 20.08, 19.71; HRMS calculated for [M+Na]+ C24H32ONa+, m/z 359.2345, found 359.2346. 2.2.15. 2,6-di-tert-Butyl-4-(2-(trifluoromethyl) benzylidene)cyclohexa-2,5-dien-1-one (3n) [40] Yellow solid; m. p. 128–129 °C; 61% yield; 1H NMR (600 MHz, CDCl3) d 7.69 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.30 (s, 1H), 7.10 (d, J = 1.7 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 1.27 (s, 9H), 1.17 (s, 9H); HRMS calculated for [M+Na]+ C22H25F3ONa+, m/z 385.1750, found 385.1752. 2.2.16. 2,6-di-tert-Butyl-4-(3-(trifluoromethyl) benzylidene)cyclohexa-2,5-dien-1-one (3o) [41] Yellow oil liquid; 75% yield; 1H NMR (600 MHz, CDCl3) d 7.63 (s, 1H), 7.55 (dd, J = 15.1, 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 2.1 Hz, 1H), 7.09 (s, 1H), 6.94 (d, J = 2.2 Hz, 1H), 1.26 (s, 9H), 1.21 (s, 9H); HRMS calculated for [M+Na]+ C22H25F3ONa+, m/z 385.1750, found 385.1753. 3. Result and discussion As show in Scheme 2, the synthesis route contains two steps: firstly, amine promoted Mannich base 2 formation; secondly, anhydride promoted Mannich base decomposition to form target product 3.

In initial study, 2,6-di-tert-butylphenol and benzaldehyde were chosen as model substrate for the optimization of the reaction conditions. Under solvent free condition, when piperidine was used as condensation reagent, the yield was still unsatisfied, even after reacting at 120 °C for 24 h by using oil bath heating. Since long-time oil bath heating have little efficient, we try to use the microwave irradiation to promote this process. To our delight, the yield was improved sharply to 70% under solvent-free condition by microwave irradiation for 30 min at 300 W (Table 1, entry 3). Base on the result, we investigated the effect of other reaction parameters including microwave output power, temperature, reaction time 1 and deamination time 2. When the reaction was carried out at 120 °C for 30 min (condensation reaction time 1) and 3 min (deamination time 2) with the microwave output power of 300 W, the desired product 3a was obtained in 81% yield (Table 1, entry 1). Given either a lower or higher temperature or microwave output power, the yields decreased (Table 1, entry 2–13). With the optimized reaction conditions in hand, we continued to probe the generality of this transformation for various aldehydes. The results are summarized in Table 2. A number of aldehyde were examined with 2,6-di-tert-butylphenol. Various 4-benzylidene-2,6-di-tert-butyl-2,5-cyclohexadien-1-one derivatives were conveniently prepared (Table 2, entries 1–11). Both electron-donating (entries 6–13) and electronwithdrawing substituents (entries 2–5, 14–15) on the phenyl ring of benzaldehyde at either the para-, ortho- or metaposition did not have obvious influence on the yields. Fluoro, chloro, bromo, methyl, methoxyl, and trifluoromethyl groups were well tolerated to afford the corresponding para-quinone methides (p-QMs) derivatives in good to mediate yields (entries 2–15). Actually, trisubstituted benzaldehyde leads to a decrease of yield due to steric hindrance. When otrifluoromethyl benzaldehyde and m- trifluoromethyl benzaldehyde were employed, the yields were unsatisfied under the optimized condition. After increasing microwave output power to 400 W and prolonging the reaction time (condensation time 1 = 33 min, deamination time 2 = 3.5 min), acceptable yields were obtained (entries 14–15). To compare the differences between conventional heating method and microwave irradiation, thermostated oil-bath and microwave irradiation heating method were used respectively to synthesis of para-quinone methides derivatives 3a and 3f under otherwise identical conditions (Table 3). Not

Please cite this article in press as: Z.-Q. Liu et al., Microwave-promoted solvent-free synthesis of para-quinone methides (p-QMs) derivatives, Journal of Saudi Chemical Society (2019), https://doi.org/10.1016/j.jscs.2019.10.001

6 surprisingly, traditional thermal conditions gave lower yields with a longer reaction time, indicating that the microwave irradiation really provide much better convenience and efficiency. 4. Conclusion In summary, we have developed a highly efficient and rapid methodology for the synthesis of polysubstituted para-quinone methides (p-QMs) from aldehyde and 2,6-di-tertbutylphenol under solvent-free and microwave irradiation condition within 33 min. This strategy displays the advantages including high atom economy, good functional group tolerance, and environmentally friendly operation. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant No. 21402159), the Fundamental Research Funds for the Central Universities (XDJK2019AA003), the Chongqing Postdoctoral Science Foundation (Xm2016110). Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] A. Baeyer, V. Villiger, Dibenzalaceton und triphenylmethan, Ber. Dtsch. Chem. Ges. 36 (1903) 2774–2796. [2] B.E. Barraga´n-Huerta, J. Peralta-Cruz, R.F. Gonza´lez-Laredo, J. Karchesy, Neocandenatone, an isoflavan-cinnamylphenol quinone methide pigment from dalbergia congestiflora, Phytochemistry 65 (2004) 925–928. [3] K.-i. Takao, T. Sasaki, T. Kozaki, Y. Yanagisawa, K.-I. Tadano, A. Kawashima, H. Shinonaga, Syntheses and absolute stereochemistries of UPA0043 and UPA0044, cytotoxic antibiotics having a p-quinone-methide structure, Org. Lett. 3 (2001) 4291–4294. [4] Y.B. Ryu, S.-J. Park, Y.M. Kim, J.-Y. Lee, W.D. Seo, J.S. Chang, K.H. Park, M.-C. Rho, W.S. Lee, SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from tripterygium regelii, Biorg. Med. Chem. Lett. 20 (2010) 1873–1876. [5] Y. Miyajima, Y. Saito, M. Takeya, M. Goto, K. NakagawaGoto, Synthesis of 4-epi-parviflorons A, C, and E: structureactivity relationship study of antiproliferative abietane derivatives, J. Org. Chem. 84 (2019) 3239–3248. [6] H. Tsurumi, E. Miyamoto, Electrophotog. photosensitive member image forming app process cartridge, JP Pat. JP2019078870A (2019). [7] H. Okada, Electrophotographic photosensitive member, US Pat. US20180157183A1 (2018). [8] H. Okada, Electrophotographic photoconductor containing photosensitive layer for image forming apparatus, JP Pat. JP2018116138A (2018). [9] K.S. Hettie, J.L. Klockow, T.E. Glass, F.T. Chin, Near-infrared fluorescent rosol dye tailored toward lymphatic mapping applications, Anal. Chem. 91 (2019) 3110. [10] J.M. Roper, C.R. Everly, Direct synthesis of spiro[5.5]undeca1,4,7-trienones from phenols via a quinone methide intermediate, J. Org. Chem. 53 (1988) 2639–2642.

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Please cite this article in press as: Z.-Q. Liu et al., Microwave-promoted solvent-free synthesis of para-quinone methides (p-QMs) derivatives, Journal of Saudi Chemical Society (2019), https://doi.org/10.1016/j.jscs.2019.10.001