Iron-catalyzed Rearrangements and Cycloaddition Reactions of 2H-Chromenes

Abstract

Iron(III) salts catalyse the tandem rearrangement/hetero-Diels—Alder reaction of 2H-chromenes to yield tetrahydrochromeno heterocycles. The process can occur as a homodimerization and cycloaddition process using electron rich dienophiles. Deuterium labeling and mechanistic studies revealed a hydride shift and ortho-quinone methide cycloaddition reaction pathway.

The tetrahydrochromeno polycyclic core is a characteristically unique structure among the large number of biologically active phenolic compounds isolated from Nature.¹ Natural product examples include mulberrofuran G², australisine A³ and sorocenol E ⁴, bearing a quaternary ketal carbon (Figure 1). Mulberrofuran, australisine and sorocenol natural products possess hypotensive effects and cytotoxicities against human cancer cell lines.^{2, 3} The dimeric flavonoid dependensin isolated from the antimalarial uvarza dependens also contains a benzopyranobenzopyran polycyclic ring structure.⁵ We envisaged synthetic access to these natural product core structures via tetrahydro-chromeno and benzopyrano starting materials. Herein, we describe an FeCl₃·6H₂O-catalyzed rearrangement and hetero-Diels-Alder reaction of 2H-chromenes with dienophiles to access these unique heterocyclic structures.⁶

Figure 1.

Representative natural products.

We have been interested in the synthesis and utility of 2H-chromenes (4'-methoxyflav-3-enes). ⁷ Homodimerization of small molecules is a highly efficient way to construct complex dimeric structures⁸ and recently, Kumar and co-workers demonstrated the homodimerization of 2H-chromenes under Brønsted acidic conditions.⁹

The homodimerization of 2H-chromenes provides rapid access to ketal polycyclic or benzopyranobenzopyran core structures, but as reported, did not readily provide discrete access to heterodimeric stuctures, similar to those found in Nature. During the course of our study on dimerization of 4'-methoxyflav-3-ene, we discovered that iron salts, especially FeCl₃·6H₂O served as an efficient catalyst for the homodimerization of 2H-chromene 1a (Table 1, entries 1-4). Anhydrous FeCl₃ performed poorly, suggesting the hydrate as FeCl₃·6H₂O is essential for catalytic activity (entry 5). To eliminate the possibility that a trace amount of HCl was acting as the catalytic species, catalytic quantities of aqueous HCl was evaluated in the reaction to afford a low yield of 2a in 1:1 dr (entriy 6). The yield was slightly improved using anhydrous methanol as the solvent but in no diastereo-selectivity (entry 7).⁹ Dry HCl failed to provide product from the reaction (entry 8). Similar yields and diastereo-selectivities were achieved using alternative iron(III) salts (entries 9–10), while other metal chloride salts gave little or no yield (entries 11–12). We chose FeCl₃·6H₂O as the catalyst to further investigate in the reaction.

Table 1.

Acid-catalyzed Homodimeriza-tion of 1a.^a

entry	catalyst	solvent	drb	yieldc
1	FeCl3·6H2O	PhCH3	2:1	40%
2	FeCl3·6H2O	CH3OH		0%
3	FeCl3·6H2O	CH2Cl2	2:1	81%
4d	FeCl3·6H2O	CH2Cl2	3:1	85%
5e	FeCl3	CH2Cl2	2:1	22%
6	HCl(aq)	CH2Cl2	1:1	5%
7f	HCl(aq)	CH3OH	1:1	34%
8	HCl in ether	CH2Cl2		0%
9	Fe(OTs)3·6H2O	CH2Cl2	2:1	80%
10	Fe(OTf)3	CH2Cl2	2:1	85%
11	ZnCl2	CH2Cl2	2:1	14%
12	AlCl3	CH2Cl2	2:1	12%

^aReaction conditions: 0.25 mmol of 1a, 10 mol % catalyst, 0.2 M in the solvent for 12 h at room temperature.

^bRatio was determined by ¹H NMR analysis.

^cIsolated yield.

^d15 mol % FeCl₃·6H₂O.

^eAnhydrous conditions.

^f0.32 mmol of 1a in 20 mL of methanol, with 10 drops of HCl, then refluxed at 65 °C for 12 h.⁹

The optimized reaction conditions proved general for a range of 2H-chromenes investigated (Table 2). The reaction proceeded smoothly with 6-methyl chromene 1b, affording chromeno[2,3-b]chromene dimer 2b in good yields (entry 2). Electron-deficient chromenes 1c-1e underwent dimerization in a similar fashion, providing compounds 2c-2e in moderate to good yields, but ultimately requiring longer reaction times (entries 3-5). The relative stereochemistry of both the major and minor diastereomers was determined by single crystal X-ray analysis of the dimer 2d.¹⁰ A change in chemoselectivity was observed in the dimerization of 7-methoxy chromene 1f. Pyran 1f afforded isomer 3f as the major product in good yield at room temperature; only a trace amount (<5%) of isomer 2f was identified (entry 6). The chemoselectivity reverted to the hetero-Diels—Alder chromeno[2,3-b]chromene dimer product with the methoxy group in the 6-position (4',6-dimethoxy-3-flavene 1g, Table 2, entry 7). Electron rich chromene 1h did lead to the formation of isomer 3h in good yield (entry 8). Alternatively, the use of the dimethyl carbamate protecting group attenuated the reactivity of 7-oxygenated arene 1i to yield the chromeno[2,3-b]chromene dimer 2i (entry 9). The more electron rich chromene reaction partners appeared to have the appropriate reactivity profile to react with the heterodiene as it was being formed in the reaction mixture.

Table 2.

FeCl₃·6H₂O Catalyzed Dimerization^a

entry	2H-chromene (1)	drb	2:3	yieldc
1	R1 = H, R2 = H (1a)	3:1	>99:1	85% (2a)
2	R1 = CH3, R2 = H (1b)	3:1	>99:1	89% (2b)
3	R1 = H, R2 = Cl (1c)	3:1	>99:1	82% (2c)
4d	R1 = Br, R2 = H (1d)	3:1	>99:1	86% (2d)
5e	R1 = NO2, R2 = H (1e)	1.5:1	>99:1	72% (2e)
6	R1 = H, R2 = OCH3 (1f)	>99:1	5:95	86% (3f)
7	R1 = OCH3, R2 = H (1g)	2:1	>99:1	87% (2g)
8	R1, R2 = 6,7-(OCH2O) (1h)	>99:1	3:97	66% (3h)
9	R1 = H, R2 = OCON(CH3)2 (1i)	3:1	>99:1	70% (2i)

^a0.25 mmol of 1, 15 mol % FeCl₃·6H₂O, 0.2 M in CH₂Cl₂ for 12 h at rt.

^b1H NMR analysis of 2 or 3.

^cIsolated yield.

^d24 h.

^e72 h.

The Fe-catalyzed reaction was utilized in the synthesis of dependensin (5) via the homodimerization of 5,7,8-trimethoxyflav-3-ene 4; easily prepared in three steps from commercially available starting materials. Dependensin has been previously synthesized¹¹ in a similar fashion with our route demonstrating a reduction in reaction sequence steps in high stereocontrol (Scheme 1). Subjecting 5,7,8-trimethoxy-3-flavene 4 to the optimized FeCl₃-dimerization conditions afforded (±)-dependensin (5) as a single diastereomer in 29% overall yield from 1,2,3,5-tetramethoxybenzene.

Scheme 1.

Synthesis of (±)-Dependensin

We designed experiments to gain insight into the reaction sequence leading to the dimerization product. We postulated use of 2-deutero-4'-methoxyflav-3-ene 1-D in the dimerization reaction would illustrate the isomerization of the chromene to the dienophile. The chromene 1-D was synthesized via boronate addition onto the deuterated 2-ethoxy-2H-chromene. Subjecting 1-D to the dimerization conditions led to the formation of dimer 2-D; epimeric at the benzylic positions (Scheme 2). Under uv irradiation, oxa-6π rearrangement of chromenes¹² results in the formation of the corresponding ortho-quinone methide (oQM).¹³ We propose the similar oxa-6π rearrangemof 2H-chromene could occur under Fecatalyzed conditions. Illustrated in Scheme 3, the Fecatalyst is responsible for promoting the hydride shift to yield the dienophile and the ring opening reaction.

Scheme 2.

Deuterium-labeled 1a in the Homodimerization

Scheme 3.

Proposed Mechanism for Cycloaddition

The ring opening process can lead to the formation of Z-ortho-quinone methide that rapidly equilibrates to the E-conformer under the reaction conditions (E)-7-D.¹⁴ The second 2H-chromene undergoes a hydride shift to yield the 4'-methoxy-2-flavene 6-D as the reactive dienophile.¹⁵ Cycloaddition of the E-configured vinyl oQM (E)-7-D and 6-D in an inverse electron demand [4+2] fashion furnishes the dimer 2-D. The chemoselectivity observed in the 4',7-dimethoxy-3-flavene 1f dimerization (Table 2, entry 7) is rationalized by a [4+2] cycloaddition of a highly electron rich olefin with the oQM at a faster rate than the hydride shift.

We proposed further experiments based on our mechanistic hypothesis aimed at the heterodimerization process. We first postulated that 4'-methoxy-2-flavene 6 would react with the oQM generated in situ from 2H-chromene 1h under the Fe-promoted conditions (Scheme 4, reaction 1). The reaction proceeded well yielding the corresponding heterodimer 9h in high yield and 4:1 diastereoselectivity, with only trace amounts (<5%) of homodimer 3h formed. We demonstrated the intermediacy of the oQM by making (E)-8 and reacting it with dienophile 6 under the same reaction conditions (Scheme 4, reaction 2).¹⁶ The product was isolated in comparable yield and the same diastereoselectivity to provide further evidence for the intermediacy of both reaction partners in the [4+2] cycloaddition pathway.

Scheme 3.

Cycloaddition Reactions of 4'-Methoxy-2-flavene 6

We envisaged a cyloaddition processes to occur with electron rich dienophiles utilizing 2H-chromenes as oQM precursors based on our preliminary studies of the reaction. ¹⁷ Inspired by natural products such as the mulberrofurans and australisine we first evaluated hetero-Diels-Alder reactions between 2H-chromenes 1 and 4'-methoxy-2-flavenes 6 under the Fe-promoted conditions.

The reactions proceeded well with 6-methyl and 1,3-benzodioxol substituted chromenes 1b and 1j (Table 3, entries 1 and 9). Electron-deficient 2H-chromenes 1c-1e were also able to participate, but at a slower rate (entries 2-4). Electron-rich 2H-chromenes 1f-1h underwent hetero-Diels—Alder reaction in good yields, providing selectively functionalized 9f-9h with similar diastereoselectivities (entries 5-7). Attenuating the electron-donating group with a dimethyl carbamate did not affect the yield or selectivity of the reaction (entry 8).

Table 3.

Cycloaddition Reactions using 4’-Methoxyflav-2-ene as the Dienophile

entry	2H-chromene (1)	dr	yielda
1	R1 = CH3, R2 = H, R3 = 4-OCH3 (1b)	3:1	87% (9b)
2	R1 = H, R2 = Cl, R3 = 4-OCH3 (1c)	3:1	87% (9c)
3	R1 = Br, R2 = H, R3 = 4-OCH3 (1d)	2:1	72% (9d)
4b	R1 = NO2, R2 = H, R3 = 4-OCH3 (1e)	3:1	65% (9e)
5	R1 = H, R2 = OCH3, R3 = 4-OCH3 (1f)	3:1	87% (9f)
6	R1 = OCH3, R2 = H, R3 = 4-OCH3 (1g)	2:1	83% (9g)
7	R1, R2 = 6,7-(OCH2O), R3 = 4-OCH3 (1h)	4:1	81% (9h)
8	R1 = H, R2 = OCON(CH3)2, R3 = 4-OCH3 (1i)	4:1	89% (9i)
9	R1 = R2 = H, R3 = 3,4-(OCH2O) (1j)	2:1	90% (9j)

^aIsolated yield.

^b24 h, another 0.186 mmol of 6 and 40 mol % FeCl₃·6H₂O were added after first 12 h.

We further explored the scope of the cycloaddition reaction pathway using the in situ generated oQM of chromene 1f with dienophiles 10 (Table 4). Under the optimized reaction conditions, p-methoxystyrene and its derivatives 10a–10c successfully afforded chromans 11a–11c in good yields (Table 4, entries 1-3). Furthermore, dihydronaphthalene 10d yielded the [4+2] adduct 11d as a single diastereomer (entry 4). Electron rich indene 10e was also a suitable dienophile (entry 5) and the reaction proceeded smoothly with dihydropyran 10f to produce the corresponding acetal (entry 6).

Table 4.

Cycloaddition Reactions using the Ortho-quinone methide Precursor 4',7-Dimethoxy-3-flavene 1f

^aIsolated yield. Ar = PMP (para-methoxyphenyl)

In conclusion, we have developed an iron-catalyzed tandem rearrangement/hetero-Diels—Alder approach to access tetrahydrochromeno heterocycles. Our studies have revealed an oQM involved cycloaddition reaction mechanism. Further mechanistic evidence, including trapping of the in situ generated oQM and use of the oQM (E)-8, supports the proposed multi-step process. Ongoing studies include expansion of the scope and synthetic utility of the reaction sequence.