Aroyl Fluorides as Bifunctional Reagents for Dearomatizing Fluoroaroylation of Benzofurans.

The 2,3-dihydrobenzofuran scaffold is widely found in natural products and biologically active compounds. Herein, dearomatizing 2,3-fluoroaroylation of benzofurans with aroyl fluorides as bifunctional reagents to access 2,3-difunctionalized dihydrobenzofurans is reported. The reaction that occurs by cooperative NHC/photoredox catalysis provides 3-aroyl-2-fluoro-2,3-dihydrobenzofurans with moderate to good yield and high diastereoselectivity. Cascades proceed via radical/radical cross-coupling of a benzofuran radical cation generated in the photoredox catalysis cycle with a neutral ketyl radical formed through the NHC catalysis cycle. The redox-neutral transformation exhibits broad substrate scope and high functional group compatibility. With anhydrides as bifunctional reagents, dearomatizing aroyloxyacylation of benzofurans is achieved and the strategy can also be applied to N-acylated indoles to afford 3-aroyl-2-fluoro-dihydroindoles.

2,3-Dihydrobenzofurans are core motifs that appear in biologically active compounds (Scheme a).[1,2] For example, DNA-PK inhibitors, CB2 receptor agonists, and furaquinocin A contain a functionalized 2,3-dihydrobenzofuran scaffold.[1−6] Therefore, it is important to develop methods to access such compounds.[7] Along these lines, benzofuran dearomatization is a straightforward route to 2,3-dihydrobenzofurans.[8] Known dearomatization strategies involve cycloaddition,[9−14] direct hydrogenation,[15,16] cyclopropanation,[17] radical cyclization,[18−20] and radical addition[21] among other reactions.[22−27] Halofunctionalizations have been used for benzofuran dearomatization.[28−30] However, a multistep operation for prior installation of substituents bearing nucleophilic moieties is generally required in these halofunctionalizations.

Scheme 1

Functionalized 2,3-Dihydrobenzofurans: Occurrence and Novel Synthetic Approach Using Aroyl Fluorides As Reagents via Redox Processes

The incorporation of fluorine atoms into organic compounds generally improves their metabolic stability and bioavailability.[31,32] In this context, the development of methods for construction of the C–F bond is of significance. In the past, aroyl fluorides have attracted considerable attention in chemistry.[33−35] They are valuable alternatives for the other aroyl halides or anhydrides due to their higher stability.[36] Accordingly, aroyl fluorides have been used as acylation reagents in ionic transformations.[37−39] Moreover, transition-metal catalyzed cross-coupling of aroyl fluorides has also been developed (Scheme b).[33−35,40−44] In general, aroyl fluorides mainly serve as “RCO” or “R” sources but reports on their use as fluorination reagents remain rare.[45−48] Notably, reactions where the aroyl fluoride acts as a bifunctional reagent[49] with the aroyl moiety and also the fluoride being incorporated into the product are very rare.[48]

Photoredox catalysis[50−68] has been used for arene functionalization. Along with reductive processes, established reactivity is the single electron transfer (SET) oxidation of the arene to give an arene radical cation that can be deprotonated at the α-position of an alkyl substituent to give a benzylic radical (Scheme c).[69−76] Alternatively, the arene radical cation can be trapped by a nucleophile to give a cyclohexadienyl radical.[77−81] However, the trapping of an arene radical cation with a C-radical to generate a cyclohexadienyl-type cation has rarely been reported.[82−84] This is challenging since both the arene radical cation and the C-radical are reactive intermediates and should be present in low concentrations. Successful examples use photoinduced[82,83] or electrochemical[84] electron transfer to generate a C-radical and an arene radical cation in close proximity that allows for efficient coupling.

Herein, we present dearomatizing 2,3-fluoroaroylation of benzofurans with aroyl fluorides as bifunctional reagents for both C–C and C–F bond formation via cooperative NHC/photoredox catalysis (Scheme d).[85−97] Reaction of an aroyl fluoride with an NHC catalyst will lead to an aroyl azolium ion that can be SET reduced by a photocatalyst (PC) to generate a ketyl radical.[91−96] Oxidation of benzofuran by the PC will give its radical cation that should cross-couple with the ketyl radical to give an oxocarbenium ion. Trapping by the F-anion and NHC fragmentation should lead to the fluoroaroylation product. Since the F-anion is a poor nucleophile and is present in low concentration only, we assumed that the radical cation/radical cross-coupling to be faster than trapping by the F-anion. Moreover, potential deprotonation of the benzofuran radical cation (for R = primary or secondary alkyl) has to be suppressed.

Initial experiments were conducted with 3-methylbenzofuran (1a) and benzoyl fluoride (2a). Optimization revealed that this reaction is best conducted in a 10:1 mixture of CH3CN/DMF, with K2HPO4 as base in the presence of Ir–F as the photocatalyst and the NHC catalyst A upon irradiation with a 5 W blue LED (λmax = 450 nm) at room temperature for 24 h to provide the racemic dihydrobenzofuran 3a in 70% isolated yield with high (15:1) trans-diastereoselectivity (Table , entry 1).[98] The relative configuration of the major isomer of 3a was assigned in analogy to compound 6 where an X-ray structure was obtained (see below). With Ru(bpy)3(PF6)2 or 9-mesityl-10-methylacridinium in place of Ir–F, 3a was not formed (entries 2 and 3). In CH3CN or in a mixture of CH3CN/acetone, the yield of 3a decreased (entries 4 and 5) and Cs2CO3 in place of K2HPO4 led to a reduced yield (entry 6). NHC catalyst screening showed the best result with the triazolium salt A, and no conversion or only a trace amount of 3a was observed with precatalysts B–D (entries 7–9). Control experiments demonstrated the necessity of visible light irradiation, the photocatalyst, and also the NHC catalyst (entries 10–12).

Table 1

Reaction Optimizationa

entry	variation from the standard condition	yield of 3a (%)b
1	none	73 (70)c
2	Ru(bpy)3(PF6)2 instead of Ir–F	ND
3	9-Mesityl-10-methylacridinium instead of Ir–F	ND
4	CH3CN instead of CH3CN/DMF	50
5	CH3CN/Acetone instead of CH3CN/DMF	61
6	Cs2CO3 instead of K2HPO4	40
7	NHC B instead of NHC A	2
8	NHC C instead of NHC A	35
9	NHC D instead of NHC A	ND
10	no light irradiation	ND
11	no NHC catalyst	ND
12	no photocatalyst	ND

Reaction conditions: 1a (0.1 mmol), 2a (0.4 mmol), NHC A (20 mol %), Ir–F (2 mol %), K2HPO4 (2.0 equiv), and CH3CN/DMF (1 mL/0.1 mL) under irradiation with 5 W blue LEDs for 24 h, 15:1 d.r.

Yields were determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard.

Isolated yield in brackets. ND = not detected.

With the optimized conditions identified, the generality of the protocol by first varying the benzofuran was explored (Scheme ). We found that various R1-substituents on the aromatic ring were tolerated and the dihydrobenzofurans 3b–3j were obtained with high trans-selectivity (8:1 to 30:1). Electronic effects at the C6-position are not pronounced and benzofurans bearing electron-donating (1b, 1c) as well as halo substituents (1d) worked well, affording 3b–d in 59–74% yields. However, lower yields were noted for C5-substituted systems. The methyl- and amide-substituted benzofurans 1e and 1f underwent dearomatizing fluoroaroylation in moderate yields with high diastereoselectivity (31–42%, 8:1–15:1 d.r.). For 1e, a complex mixture resulted and 3e was obtained in 31% yield. In contrast, benzofuran 1f reacted cleanly, but conversion was low and starting material was recovered. A low efficiency was also found for the 5-bromo derivative 1g (30%), where unreacted starting material was recovered. The disubstituted 1h and 1i engaged in the dearomatization to provide 3h and 3i in 60% and 32% yield. For 1i, the reaction was clean and the low yield is a result of a low conversion with recovery of 1i. Prolonging reaction time did not increase the conversion. The reason for the low conversion of 1f, 1g, and 1i is not understood. Back-electron transfer after benzofuran oxidation might play a role.[99]

Scheme 2

Substrate Scope: Variation of the Benzofuran

Reactions conducted on a 0.1 mmol scale for 24 h.

Using 2 × 45 W blue LEDs.

Reactions conducted for 72 h.

1-Methylnaphtho[2,1-b]furan 1j was converted to 3j with a high yield and high diastereoselectivity (74%, 20:1 d.r.). The influence of the R2-substituent was investigated, and the ethyl 1k, phenethyl 1l, acetoxyethyl 1m, isobutyl 1n, pentyl 1o, and cyclohexyl 1p derivatives all worked rather well to deliver 3k–3p with moderate to good yields and high diastereoselectivity (47–69%, 13:1–20:1 d.r.).

Next, we studied the scope with respect to the aroyl fluoride by using 1j as the reaction partner (Scheme ). Fluorides bearing electron-donating (e.g., Me, MeO) or electron-withdrawing (e.g., F, Cl, I, OCF3, CN) substituents at the para-position of the phenyl ring are tolerated, and 3q–3w were isolated in 30–77% yields with high diastereoselectivity. Moreover, aroyl fluorides with methyl, methoxy, fluoro, chloro, and bromo substituents at the meta-position of the phenyl ring engaged in the reaction to provide 3x–3ab in 37–82% yields (13:1–25:1 d.r.). Hence, no clear trend regarding electronic effects could be deduced. The reaction of the 3,4-dimethylated benzoyl fluoride proceeded efficiently to give 3ac (85%), and 2-naphthoyl fluoride was also compatible providing 3ad in 62% yield and excellent diastereoselectivity (>20:1). Pleasingly, heteroaroyl fluorides such as the 2-furyl and 2-thienyl derivatives worked well to afford 3ae and 3af (50% and 68%, >20:1 d.r.).

Scheme 3

Substrate Scope: Varying the Aroyl Fluoride

Reactions conducted on a 0.1 mmol scale for 24 h.

Using 2 × 45 W blue LEDs

In order to explore the potential of the methodology, dearomatizing indole 2,3-difunctionalization was tested (Scheme a). Pleasingly, N-acetyl and N-benzoyl substituted indoles 4a and 4b reacted under slightly modified conditions using 4CzlPN as the PC (5 mol %) with 2a to give the fluorodihydroindoles 5a and 5b in moderate yield and excellent diastereoselectivity. 5-Methyl and 5-methoxy N-acetyl-indole also reacted well, but the corresponding fluorinated indoles were unstable and could not be isolated. The 5-bromo and 6-fluoro N-acetyl-indole reacted with very low efficiency to the corresponding unstable products that were not isolable. Moreover, a larger scale reaction of 1j with 2a was conducted without compromising the yield (Scheme b). Next, various follow-up transformations were carried out to document the value of the products. Treatment of 3j with hydroxylamine hydrochloride afforded the oxime 6 in 57% yield along with 10% of the cyclized 2-isoxazoline 7 (Scheme c). The relative configuration in 6 was assigned by X-ray structure analysis. We found that 6 fully cyclizes to 7 in the presence of p-TsOH (4 equiv) (Scheme c). Reduction of 3j with NaBH4 provided quantitatively the alcohol 8 as a 1:1 diastereoisomeric mixture (Scheme d).

Scheme 4

Indole Dearomatization and Synthetic Applications

5 (0.1 mmol), 2a (0.4 mmol), NHC A (20 mol %), 4-CzlPN (5 mol %), K2HPO4 (2.0 equiv), and CH3CN/DMF (1 mL/0.1 mL) under irradiation with 2 × 45 W blue LEDs for 24 h.

1j (1.0 mmol), 2a (4.0 mmol), NHC A (20 mol %), Ir–F (2 mol %), K2HPO4 (2.0 equiv), and CH3CN/DMF (10.0 mL/1.0 mL) under irradiation with 2 × 45 W blue LEDs for 24 h.

Hydroxylamine hydrochloride (5.0 equiv), NaOAc (10.0 equiv), EtOH, 70 °C; p-TsOH (4.0 equiv), Toluene, 70 °C.

NaBH4 (2.0 equiv), MeOH/THF (1:1), 0 °C.

To elucidate the mechanism, control experiments were performed (Scheme ). When adding a stoichiometric amount of TEMPO, complete suppression of the dearomatization was noted and benzofuran was recovered (Scheme a). Reaction of the acylazolium ion 9 and benzofuran 1j in the presence of NEt3·3HF (1 equiv) without the NHC and K2HPO4 afforded 3j (Scheme b). This result demonstrated that acyl azoliums of type 2a-I are competent intermediates. In addition, Stern–Volmer quenching experiments revealed that benzofuran 1j could efficiently quench the excited photocatalyst while acylazolium ion 9 did not quench the excited state of the PC (see Supporting Information). Importantly, running the reaction of 1j with 2a with a chiral NHC provided 3j in 53% yield with 30% ee and complete diastereoselectivity (Scheme c). This experiment indicated that the radical C–C coupling as the enantiodetermining step may occur prior to C–F bond formation. Although another reaction pathway involving C–F bond formation prior to C–C coupling might be possible and cannot be totally ruled out, the fact that moderate enantioselectivity was observed when chiral NHC catalyst was used in the reaction argues in favor of a preferential occurrence of radical cross-coupling. On basis of these experiments and previous reports,[91−96,100] a mechanism is proposed in Scheme d. Upon visible light irradiation, benzofuran 1a (E1/2= 1.28 V vs SCE) is oxidized to its radical cation 1a-1 by photoexcited Ir(III)*. On the other hand, the reaction of 2a with the NHC gives the acyl azolium ion 2a-I (E1/2= −1.29 V vs SCE),[91] which is reduced by Ir(II) (E1/2(P/P•–) = −1.37 V vs SCE) to regenerate Ir(III) with the formation of the persistent ketyl radical 2a-II.[91−96,100] Subsequent cross-coupling of 2a-II with the radical cation 1a-I leads to the oxocarbenium ion 1a-II. Diastereoselective trapping of this carbenium ion by the F-anion trans to the bulky alcoholate moiety and NHC fragmentation provide 3a closing the NHC catalysis cycle. Alternatively, NHC fragmentation can occur prior the trapping of the oxocarbenium ion by the F-anion.

Scheme 5

Mechanistic Studies

Finally, symmetrical anhydrides were tested as bifunctional reagents for the dearomatizing aroyloxyacylation of benzofurans (Scheme ). Under slightly modified conditions (CH3CN in place of CH3CN/DMF), the symmetric anhydrides 10a–10c were converted with moderate to good yield and excellent diastereoselectivity to 11a–11c (46–64%, > 20:1 d.r.). The relative configuration of 11c was assigned by X-ray structure analysis. Repeating the reaction of 1j with 10a using a chiral NHC afforded 11a in 39% ee indicating that a similar mechanism as with the aroyl fluorides is operative.

Scheme 6

Dearomatizing Benzofuran Functionalization with Anhydrides

1j (0.1 mmol), 10 (0.2 mmol), NHC A (20 mol %), Ir–F (2 mol %), K2HPO4 (2.0 equiv), and CH3CN/DMF (1.0 mL/0.1 mL) under irradiation with 2 × 45 W blue LEDs for 24 h.

In summary, fluoroaroylation of benzofurans via cooperative NHC and photoredox catalysis has been achieved. Aroyl fluorides were shown to react as bifunctional reagents to incorporate both the aroyl moiety and also the fluoride into the product. The mild photocatalytic protocol shows a broad scope and high functional group tolerance. Of note, N-acyl indoles were found to be eligible substrates for the 2,3-difunctionalizing dearomatization. The synthetic value was further demonstrated by follow up transformations. Along with aroyl fluorides, anhydrides also serve as bifunctional reagents for benzofuran dearomatization. Mechanistic studies reveal that these transformations proceed via a rare radical/radical cation cross-coupling reaction as a key step.