Study of Diels–Alder Reactions of Purpurogallin Tetraacetate with Various Dienophiles ^†

Abstract

Purpurogallin or (6E,8Z)-2,3,4,6-tetrahydroxy-5H-benzo[7]annulen-5-one is a benzotropolone possessing a dienic system and known to inhibit the TLR1/TLR2 activation pathway. We have recently described the easy green synthesis of purpurogallin from pyrogallol catalyzed by a copper complex or by vegetable oxidases. The purpurogallin was acetylated and the tetra-acetate derivative thus obtained was engaged in a Diels–Alder reaction with various dienophiles (benzoquinone, maleic anhydride, ethylmaleimide, phenylmaleimide, etc.). The results obtained are presented and discussed.

1. Introduction

The benzotropolones represent a class of natural products, which consist of a tropolone unit (hydroxycycloheptatrienone) fused to a benzene ring. The most popular is purpurogallin (1) (Figure 1) present in Quercus trees and displaying biological properties [1,2,3,4,5,6,7,8,9].

Many benzotropolones are known as secondary metabolites, such as fomentariol from the fungus Fomes fomentarius [10], goupiolone A, isolated from the aerial parts of Goupia glabra, a plant from the Amazon region of Peru [11], and crocipodin, a pigment extracted from the fungus Leccinum crocipodium (Boletales) [12], see Figure 2.

We have shown that purpurogallin (1) can be obtained by catalytic oxidation of pyrogallol according to our previous work [13]. Purpurogallin (1) presents an intramolecular hydrogen bond which makes it difficult to modify the hydroxyl involved in this bond (see Figure 3).

Purpurogallin (1) can yet be converted into purpurogallin tetraacetate by peracetylation with acetic anhydride in the presence of DMAP [14] as catalyst in a yield of 87% according to the Scheme 1).

Purpurogallin, which possesses an antiaromatic tropolone nucleus, is able to behave like a diene [15]. So, we describe herein the Diels–Alder reaction of purpurogallin tetraacetate with different dienophiles in refluxing bromobenzene (154 °C) according to Scheme 2.

The products formed were isolated by chromatography on a silica column and were identified by NMR and mass spectroscopy. The results are summarized in Table 1, with the yields corresponding to the pure isolated products.

2. Materials and Methods

Melting points were measured on a Kofler apparatus and are reported uncorrected. IR spectra were obtained with solids with a Fourier transform Perkin-Elmer Spectrum One with ATR accessory. The frequencies of absorption are given in cm⁻¹. Only significant absorptions are listed. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded while using CDCl₃ or DMSO-d6 with TMS as an internal standard on a Bruker DPX 400 NMR spectrometer. Chemical shifts are reported in ppm. Mass spectra were recorded on a Xevo G2-XS QTof (Waters), mass range (50–1000 m/z), source temperature 120 °C, desolvatation temperature 500 °C, with electrospray ionization (ESI, positive mode), lock spray PEG.

We already reported the synthesis of purporogallin from pyrogallol under green conditions [13].

The geometries of the neutral molecules were optimized using B3LYP. The single point calculations were performed using the B3LYP/6-31G* method of the Spartan program [16]. Calculations in bromobenzene (ε = 5.4) were performed using SM8 [17,18].

2.1. Synthesis of Purpurogallin Tetraacetate (2)

In a 100 mL flask fitted with a condenser and a magnetic bar and a CaCl₂ guard, 0.1 mole of purpurogallin is dissolved in a mixture of 40 mL of acetic anhydride and N,N-dimethyl-4-aminopyridine (DMAP) (4 mmol). The reaction mixture is heated to 130 °C for 20 h. After cooling, the solvent is evaporated off, a solid is recovered which is purified by column chromatography with, as eluent, hexane/ethyl acetate (1:1). A yellow solid is obtained with 87% yield.

m.p = 190–192 °C.

FT-IR (cm⁻¹): 2940; 1769; 1631.

¹H NMR δ (400 MHz, DMSO-d6, ppm): δ 7.26 (1H, s,); 6.91 (1H, d); 6.58 (1H, d); 6.34 (1H, dd,); 2.13 (3H, s,); 2.11 (3H, s); 2.09 (3H, s); 2.06 (3H, s).

¹³C NMR (100 MHz, DMSO d6, ppm): δ 180.9, 168.2, 167.8, 167.2, 166.6, 149.9, 145.2, 143.8, 136.9, 134.7, 134.0, 128.0, 123.5, 123.1, 122.3, 20. 5.

HRMS: for C₁₉H₁₆O_9, (M+1Na): found 411.

2.2. General Experimental Procedure for [4+2] Cycloaddition

• Products 4a-d.

The purpurogallin tetraacetate (2) (10 mmol) and the (3a-d) compound (20 mmol) are dissolved in 10 mL of bromobenzene. The mixture is heated under reflux at 150 °C for 5 h. The reactional mixture is chromatographied on a silica column with cyclohexane/ethyl acetate (1/1) as solvent.

The product (4a) was obtained from N-phenylmaleimide:

White solid, yield: 39%, m.p > 276 °C.

FT-IR (cm⁻¹): 2989; 1781; 1713; 1598.

¹H NMR δ (400 MHz, CDCl₃, ppm): δ 7.46 (1H, t, J = 7.3 Hz); 7.41 (2H, dd, J = 7.3 Hz, J = 4.0 Hz); 7.22 (2H, d, J = 4 Hz); 6.79 (1H, s); 6.68 (1H, d, J = 8.0 Hz); 6.06 (1H, dd, J = 8.0 Hz; J = 9.9 Hz); 4.72 (1H, dd, J = 9.9, J = 1.8 Hz); 4.39 (1H, d, J = 5.8 Hz); 3.64 (1H, dd, J = 5.8 Hz, J = 1.8 Hz); 2.32 (3H, s); 2.30 (6H, s); 2.24 (3H, s).

¹³C NMR (400 MHz, CDCl₃ ppm): δ 175.1; 169.5; 168.1; 167.6; 167.1; 166.9; 146.6; 146.5; 140.6; 136.1; 135.0; 131.5; 129.3; 129.0; 126.4; 126.2; 120.2; 83.8; 47.3; 43.3; 41.1; 23.1; 21.5; 20.8: 20.7; 20.5.

HRMS: for (C₂₉H₂₃NO₁₁Na): calculated: 584.1169; found 584.1.

The product (4b) was obtained from N-ethylmaleimide:

White solid, yield: 36%, m.p > 276 °C.

FT-IR (cm⁻¹): 2983; 1780; 1711; 1601.

¹H NMR δ (400 MHz, CDCl₃, ppm): δ 6.71 (1H, s); 6.62 (1H, d, J = 7.8 Hz); 6.02 (1H, dd, J = 8.7 Hz, J = 7.8 Hz), 4.32 (1H, d, J = 6.2 Hz); 3.60 (2H, q, J = 7.2 Hz); 3.55 (1H, dd, J = 6.2, J = 1.8 Hz); 3.48 (1H, dd J = 8.7, J = 1.8 Hz); 2.33 (3H, s); 2.32 (3H, s); 2.29 (3H, s); 2.27 (3H, s); 1.16 (3H, t, J = 7.2 Hz).

¹³C NMR (400 MHz, CDCl₃, ppm): δ 175.1; 169.5; 168.1; 168.0; 167.1; 166.4; 147.6; 146.6; 146.4; 136.0; 134.1; 131.3; 129.2; 120.1; 112.2; 84.2; 47.2; 43.7; 40.1; 34.5; 21.2; 20.8, 20.5; 20.1; 13.0.

HRMS: for (C₂₅H₂₃NO₁₁Na): calculated: 536.1169; found 536.1.

The product (4c) was obtained from maleic anhydride:

White solid, yield: 58%, m.p > 276.

FT-IR (cm⁻¹): 2979; 1777; 1715; 1599.

¹H NMR δ (400 MHz, CDCl₃, ppm): δ 6.63 (1H, dd, J = 9.2 Hz, J = 7.1 Hz); 6.48 (1H, s); 6.15 (1H, d, J = 7.1 Hz); 4.17 (1H, dd, J = 7.4 Hz, J = 2.1 Hz); 3.77 (1H, d, J = 7.4 Hz); 3.65 (1H, dd, J = 9.2 Hz, J = 2.1 Hz); 2.31 (3H, s); 2.29 (3H, s); 2.26 (3H, s); 2.23 (3H, s).

¹³C NMR (400 MHz, CDCl₃, ppm): δ 176.1; 172.6; 168.0; 167.4; 167.1; 166.4; 152.0; 137.1; 136.1; 134.7; 133.9; 131.3; 127.4; 121.7; 106.2; 88.3; 48.7; 47.5; 43.5; 21.2; 20.7; 20.4; 20.2.

HRMS: for (C₂₃H₁₈O₁₂Na): calculated: 509.0938; found 509.1.

The product (4d) was obtained from 1,4-benzoquinone:

Green solid, yield: 41%, m.p > 276 °C.

FT-IR (cm⁻¹): 2979; 1777; 1715; 1599.

¹H NMR δ (400 MHz, CDCl₃, ppm): 6.76 (1H, s); 6.66 (1H, dd, J = 17.2 Hz, J = 8.4 Hz); 6.12 (1H, d, J = 17.2 Hz); 4.54 (1H, dd, J = 7.3 Hz, J = 3.1 Hz); 4.09 (1H, d, J = 7.3 Hz); 3.37 (1H, dd, J = 8.4 Hz, J = 3.1 Hz); 2.31 (9H, s); 2.13 (3H, s).

¹³C NMR (400 MHz, CDCl₃, ppm): δ 171.5; 168.5; 167.7; 167.4; 164.5; 161.0; 146.9; 143.5; 142.4; 140.7; 137.2; 134.8; 130.0; 121.3; 89.3; 48.6; 46.6; 46.0; 31.3; 30.9; 21.4; 21.0; 20.7; 19.7.

HRMS: for (C₂₅H₂₀O₁₁Na): calculated: 519.0903; found 519.1.

3. Result and Discussion

The study of the reactivity of purpurogallin led us to consider the diene system present in this molecule to carry out [4+2] cycloaddition reactions with different dienophiles. However, the purpurogallin was previously acetylated to avoid any interaction of phenolic OHs in the cycloaddition reaction (Scheme 3).

The dienophiles for which the cycloaddition reaction has given acceptable results are cyclic dienophiles which have withdrawing groups (maleimides, maleic anhydride, and benzoquinone). The reaction was carried out without catalysts in refluxing bromobenzene. The results obtained are shown in

Table 1. Products of Diels–Alder reaction isolated.

Entry	Dienophile	Product (3a-d)	Yield
a	N-Phenylmaleimide		39%
b	N-Ethylmaleimide		36%
c	Maleic Anhydrid		58%
d	Benzoquinone		41%

below:

4. Theoretical Studies

The frontier orbitals of purpurogallin tetraacetate (2) and dienophiles (3a-d) were calculated using the DFT-B3LYP with the 6–31G(d) basis set in vacuum and then in bromobenzene (dielectric constant ε = 5.4) using Continuum Solvation Models, SM8, and are reported in

Table 2. Frontier orbitals calculated.

	Product	HOMO (eV)	LUMO (eV)	m Debye	HOMO (eV)	LUMO (eV)	m Debye
		In Vacuum			With Solvent: Bromobenzene
Dienes (Donor)	Purpurogallin (1)	−5.54	−1.89	2.71	−5.59	−1.86	3.36
	Tetraacetylpurpurogallin	−6.43	−1.97	11.07	−6.10	−1.69	12.84
	Tetramethylpurpurogallin	−5.66	−1.44	2.52	−5.65	−1.48	2.88
Dienophiles (Acceptor)	Maleic anhydride 3c	−8.18	−3.75	3.64	−7.99	−2.88	4.15
	N-Phenyl maleimide 3a	−6.50	−2.74	0.91	−6.46	−2.50	1.31
	N-Ethyl maleimide 3b	−7.37	−2.58	0.63	−7.27	−2.33	0.85
	Benzoquinone 3d	−7.36	−3.54	0	−7.11	−3.22	0

.

From the position of the frontier orbitals, i.e., the difference between HOMO^d and LUMO^a and difference between HOMO^a and LUMO^d, the most probable Diels–Alder reaction appears as normal demand with a transfer of electrons from the purpurogallin tetraacetate or tetramethyl purpurogallin as donor to acceptor dienophile in the four cases studied. In the case of non-benzenoid aromatic compounds such as purpurogallin or tetraacetate purpurogallin, the antiaromaticity leads to normal electron demand Diels–Alder reactions.

The bromobenzene solvent somewhat facilitates the reaction by lowering the HOMO (−6.43 eV in vacuum to −6.10 eV) of the purpurogallin tetraacetate which appears to be quite polar (12.84 D) compared to the non-acetylated purpurogallin (3.36 D).

The reaction appears, however, more difficult than with tetramethylpurpurogallin (HOMO −5.65 eV) which has been used in the literature. In bromobenzene, according to the energy values of the LUMOs of dienophiles, benzoquinone (−3.22 eV) is more reactive than maleic anhydride (−2.88 eV), than N-phenylmaleimide (−2.50 eV), and than N-ethylmaleimide (−2.33 eV).

The positions of frontier orbitals in vacuum and in bromobenzene show that increasing polarity has a beneficial effect on DA reactions (use of DMF). Unfortunately, we did not have the means to verify this experimentally due to the circumstances.

5. Stereochemistry

The Diels–Alder reaction is a supra-supra cycloaddition; depending on the arrival of the dienophile relative to the diene (purpurogallin), an exo or endo compound is obtained.

The tetraacetylpurpurogallin (2) molecule is almost flat (see Figure 4) and there is very little difference between the upper faces (exo attack) and the lower face (endo attack); on the other hand, in the cycloaddition products the diedral angles of CH-CH (CO) and CH(CO)-CH (CO) are very similar in the two diastereoisomers according to the molecular modelization after optimization of the exo and endo products, and it is not possible to know if a single isomer or two is formed.

6. Conclusions

Tetraacetylpurpurogallin leads to Diels–Alder reactions with cyclic dienophiles in moderate yield under thermal activation. The use of a solvent more polar than bromobenzene and catalyst should be able to increase the yields. The reactions of purpurogallin tetraacetate 2 with the different dienophiles 3a-d correspond to normal electron demand (NED) Diels–Alder reactions and the stereochemistry shows that it is an endo cycloaddition.