Electron Transfer-Initiated Diels-Alder Cycloadditions of 2′-Hydroxychalcones

A number of biologically active prenylflavonoid natural products have been isolated from the mulberry tree and related plants.¹ For example, kuwanon G (1)² and multicaulisin (2)³ are Diels-Alder cycloadducts between prenylflavonoid dienes and 2′-hydroxychalcones (Figure 1). Related Diels-Alder cycloadducts⁴ include (−)-panduratin A (3)⁵ and nicolaioidesin C (4).⁶ In order to access these natural products, we wished to develop methodology to construct the cyclohexenyl chalcone nucleus employing electron rich 2′-hydroxychalcone dienophiles.⁷ In this Communication, we report examples of such [4+2] cycloadditions in a process likely involving electron transfer.⁸

Figure 1.

Select Diels-Alder Natural Products Derived from 2′-Hydroxychalcones

Our studies began with model reactions of trans-2′-hydroxy chalcone 5 and 2,3-dimethylbutadiene 6 (Table 1). Due to our inability to effect cycloaddition using Lewis acid-promoted (“LUMO” lowering) conditions,⁹ we considered alternative modes of catalysis. Based on a recent report involving Diels-Alder dimerization of piperine,¹⁰ we evaluated Co(I) catalysis¹¹ for cycloaddition. Initial studies revealed that cycloadduct 7 was observed as a single trans- diastereomer using CoI₂/1,10-phenanthroline (8)/ZnI₂/Bu₄NBH₄ (10/10/30/10 mol%) (entry 1),¹² which is in contrast to the 1,4-hydrovinylation of dienes and terminal alkenes employing a similar Co(I) catalyst system reported by Hilt and coworkers.^11c Further investigation revealed that the amount of ZnI₂ had a significant effect on the catalytic process (entries 1-3). Near quantitative conversion and isolated yield of 7 were obtained with CoI₂/8/ZnI₂/Bu₄NBH₄ (10/10/60/10 mol%) as catalyst (entry 3). Lower conversion was obtained in the absence of ligand 8 (entry 4). Remarkably, cycloaddition in the absence of cobalt proceeded in slightly lower yield employing ZnI₂ and a catalytic amount of Bu₄NBH₄ (entry 5), either of which did not mediate the reaction alone (entries 6, 7). Moreover, no desired cycloadduct was observed with Zn(BH₄)₂ as catalyst.

Table 1.

Optimization of the Diels-Alder Cycloaddition of 5 and 6^a

entry	CoI2:8:ZnI2:Bu4NBH4	conv. (%)b
1	10:10:30:10 mol%	23
2	10:10:  0:10 mol%	<2d
3	10:10:60:10 mol%	96(95c)
4	10:  0:60:10 mol%	74
5	0:  0:60:10 mol%	85(82c)
6	0:  0:60:  0 mol%	<2d
7	0:  0:  0:10 mol%	<2d

^aSee Supporting Information for experimental details.

^bBased on ¹H NMR integration (average of two experiments).

^cIsolated yield.

^dNot observed.

Further studies were undertaken to probe modifications of the chalcone dienophile (Table 2). Removal or methylation of the 2′- hydroxyl group (entries 1, 2) led to production of cycloadducts in lower overall yield in comparison to 7. Reactions conducted without cobalt generally afforded lower isolated yields. Surprisingly, 4′-hydroxychalcone 13 did not undergo cycloaddition (entry 3), implying that chelation of 5 to ZnI₂¹³ may be necessary for cycloaddition. Additionally, a counterion effect for the Zn(II) source was observed (I > Br > Cl) with ZnF₂, Zn(OAc)₂, and Zn(OTf)₂ proving to be unreactive.¹²

Table 2.

Chalcone modifications

entry	2′-hydroxychalcone	product	conditiona	yield(%)b
1	9: R1, R2 = H	10	A B	38 28
2	11: R1 = OMe, R2 = H	12	A B	55 50
3	13: R1 = H, R2 = OH	14	A B	<2c <2c

^aCondition A: 10/10/60/10 mol% CoI₂/8/ZnI₂/Bu₄NBH₄; condition B: 60/10 mol% ZnI₂/Bu₄NBH₄, see Supporting Information.

^bIsolated yield.

^cNot observed.

Encouraged by the success of the model reaction, we next evaluated a range of dienes and 2′-hydroxychalcones. [4+2] cycloadditions of select dienes and 5 were conducted in satisfactory isolated yield using CoI₂/8/ZnI₂/Bu₄NBH₄ (10/10/60/10 mol%) at 40 °C (Table 3). Reactions without cobalt showed decreased reactivity (entries 1, 2). Notably, single regioisomers were observed for unsymmetrical dienes (entries 1, 4-6). Trisubstituted diene 25, poorly reactive in conventional [4+2] cycloadditions,¹⁴ afforded cycloadduct 26 in moderate yield (entry 6). A number of highly electron-rich 2′-hydroxychalcones were also investigated (Table 4). For these dienophiles, a 20/40/120/20 mol% CoI₂/8/ZnI₂/Bu₄NBH₄ catalyst loading was found to be optimal. Lower yields were obtained with additional alkoxy substitution of the chalcone (entries 1, 3, and 5). The corresponding acetylated 2′-hydroxychalcones maintained high reactivity likely due to their less electron rich character (entries 2, 4, and 6).

Table 3.

Diels-Alder Reactions of 5 and Dienes

entry	diene	product	conditiona	yield(%)b
1			A B	97c 67c
2			A B	97d 65d
3			A	99
4			A	97c,e
5			A	96c
6			A	55c

^aCondition A: 10/10/60/10 mol% CoI₂/8/ZnI₂/Bu₄NBH₄, 40°C; condition B: 60/10 mol% ZnI₂/Bu₄NBH₄, 40°C, see Supporting Information.

^bIsolated yields.

^cSingle regioisomer.

^dSingle endo isomer.

^e1.5:1 exo/endo ratio.

Table 4.

Diels-Alder Reactions of Electron-rich 2′-Hydroxychalcones

entry	2′-hydroxychalcone	product	conditiona	Yield(%)b
1	27: R1=OMe, R2,R3,R4=H	28	A B	68 36
2	29: R1=OAc, R2,R3,R4=H	30	A B	84 55
3	31: R1,R2=OMe, R3,R4=H	32	A	33
4	33: R1,R2=OAc, R3,R4=H	34	A	72
5	35: R1,R3,R4=OMe, R2=H	36	A	18
6	37: R1,R3,R4=OAc, R2=H	38	A	61

^aCondition A: 20/40/120/20 mol% CoI₂/8/ZnI₂/Bu₄NBH₄; condition B: 120/20 mol% ZnI₂/Bu₄NBH₄, see Supporting Information.

^bIsolated yields.

The utility of acetylated 2′-hydroxychalcones in [4+2] cycloadditions was further established by the total synthesis of nicolaioidesin C (4)⁶ (Scheme 1). Acetylated chalcone 39 was prepared in four steps¹² (74% overall yield) from commercially available 2′,6′-dihydroxy-4′-methoxyacetophenone. Diels-Alder cycloaddition of 39 and myrcene 23, followed by saponification, afforded 4 as a single regioisomer in 52% yield. A 15% yield of 4 was observed in the corresponding reaction conducted without cobalt.¹²

Scheme 1.

Synthesis of nicolaioidesin C

Our finding that cycloadditions are observed with Bu₄NBH₄/ZnI₂¹⁵ in conjunction with literature reports documenting electron transfer from Bu₄NBH₄ to acceptor substrates¹⁶ suggests that radical anions¹⁷ may be involved in the catalysis. As shown in Scheme 2, coordination of ZnI₂ to 2′-hydroxychalcone 5 may afford complex 40. Preliminary cyclic voltammetry studies¹² indicate that 5 in the presence of ZnI₂ (CH₂Cl₂) shows two new irreversible reduction peaks (E_p,c −0.59 V, 0.36 V vs. SCE, respectively) compared to 5 alone (E_p,c −1.25 V vs. SCE). The apparent shift in the halfwave reduction potentials to less negative values is expected to parallel the promotion of electron transfer, and may be attributed to carbonyl activation by ZnI₂. In the presence of electron donors such as Co(I)^11a or borohydride, 40 may undergo metal ion-promoted single electron transfer¹⁸ to generate a chalcone radical anion 41.¹⁹ Regioselective addition of 41 to isoprene²⁰ should afford a stabilized, allylic radical 42a which may undergo ring-closing cyclization to produce ketyl intermediate 43. Subsequent single electron transfer between 43 and another complex 40 may afford cycloadduct 16 and radical anion 41, thereby restarting the catalytic cycle.

Scheme 2.

Generalized Mechanism for [4+2] Cycloadditions

In summary, we have developed [4+2] cycloadditions of highly electron rich 2′-hydroxychalcones and dienes using catalyst systems composed of electron donor (Co(I) or BH₄⁻) and a Lewis acid (ZnI₂). Mechanistic studies and further applications towards the syntheses of other natural product targets are currently in progress and will be reported in due course.