Three-Component Coupling Reactions of Arynes for the Synthesis of Benzofurans and Coumarins

The domino three-component coupling reaction of arynes with DMF and active methylenes or methines was studied as a highly efficient method for preparing heterocycles. Coumarin derivative 5 was formed when diethyl malonate (2) or α-bromomalonate (3) were used as a C2-unit. In contrast, dihydrobenzofurans 7a and 7b were obtained by using α-chloroenolates generated from α-chloromalonates 4a and 4b and Et2Zn. The benzofuran 15a could be obtained by using ethyl iodoacetate (14) as a C1-unit. The one-pot conversion of dihydrobenzofurans 7a, 7b and 8a into benzofurans 15a and 15b was also studied. The direct synthesis of benzofuran 15b was achieved by using the active methine 18 having ketone and ester groups.


New Approach for the Domino Three-Component Coupling Process
The goal of our study on aryne chemistry is to develop the highly efficient domino reactions for preparing heterocycles. Therefore, we have designed a new approach involving two steps which are induced by the high reactivity related to the strain energy of aryne A and the four-membered intermeditate B (Scheme 1) [37].
The insertion of a highly strained aryne A, generated in situ from ortho-(trimethylsilyl)aryl triflate 1 and the fluoride ion [38], into the C=O of N,N-dimethylformamide (DMF) gives the moderately strained [2+2] adduct benzoxetene B, which would undergo isomerized into ortho-quinone methide C (Step 1). The sequential transformation can be achieved by the initial addition of nucleophiles to the transient intermediate C and the subsequent trapping process with electrophiles (Step 2). When nucleophile and electrophile belong to the same molecule as shown in Scheme 1, the use of C2-units (X-Y) leads to the products D and the use of C1-units (X) leads to the products E. Scheme 1. Three-component coupling reaction. Step 1: Insertion of aryne A into -bond of DMF

C1-units
For the synthesis of products D such as coumarin derivatives, we used enol F and enolate G having both nucleophilic and electrophilic sites, which were derived from malonate 2 and α-bromomalonate 3, respectively (Scheme 2). For the synthesis of products E such as dihydrobenzofurans and benzofurans, α-chloroenolate H having a nucleophilic and electrophilic carbon atom, derived from α-chloromalonate 4, was employed for trapping the unstable intermediate C.

Scheme 2.
Substrates for trapping the intermediate C.

The Synthesis of Coumarin Derivative
In organic synthesis, DMF can react as either an electrophilic or nucleophilic agent [39,40]. At first, we examined the reaction of 3-methoxy-2-(trimethylsilyl)phenyl triflate (1) as an aryne precursor with DMF and diethyl malonate (2) as a C2-unit (Table 1). It is well known that the active methylenes such as diethyl malonate (2) have an excellent reactivity toward arynes giving the σ-bond insertion products [41][42][43][44][45]. To suppress the competitive insertion of aryne into the C-C σ-bond of 2, DMF was employed as a solvent. We were gratified to observe the sufficient reactivity of active methylene 2 toward intermediate B in the absence of base. The effect of fluoride ion sources was studied. In the presence of CsF, treatment of triflate 1 with 2 in DMF at room temperature predominantly gave the desired coumarin 5 in 65% yield, accompanied by a trace amount of salicylaldehyde derivative 6 (entry 1). The replacement of CsF with anhydrous TBAF led to an increase in the chemical yield to give 5 in 86% yield (entry 2). In contrast, no reaction was observed when KF was employed (entry 3). Further investigations using α-bromomalonate 3 and organometallic reagents such as Et 2 Zn or Me 3 Al were performed ( Table 2). In the presence of Et 2 Zn, we initially allowed triflate 1 to react with 3 in DMF at room temperature for 12 h (entry 1). The desired coumarin 5 was obtained in 11% yield, accompanied by the recovered triflate 1 in 64%. Although the replacement of CsF with anhydrous TBAF led to an increase in the chemical yield, the new formation of dihydrobenzofuran 7a was observed (entry 2). The reaction did not take place when KF was employed (entry 3). Therefore, Me 3 Al was next employed (entries 4 and 5). In the presence of CsF, treatment of 1 with 3 in DMF predominantly gave the desired product 5 in 34% yield (entry 4). Improvement in the chemical yield of 5 was observed when anhydrous TBAF was used (entry 5). The chemical yield increased into 85%. In this transformation, a suitable combination of α-bromomalonate 3 and Me 3 Al led to the efficient generation of the debrominated metal enolate G, which reacted with intermediate C to give coumarin 5.

The Synthesis of Dihydrobenzofurans
We next investigated the domino reaction for the synthesis of dihydrobenzofurans ( Table 3). The key issue of this transformation is the efficient generation of α-halogenated enolate as a C1-unit. However, as mentioned above, the debromination took place when α-bromomalonate 3 and organometallic reagents were employed. In remarked contrast to α-bromomalonate 3, we found that the use of α-chloromalonates 4a,b and Et 2 Zn led to the generation of desired α-halogenated enolates H (Scheme 4). Thus, a combination of α-chloromalonates 4a,b and Et 2 Zn was checked under the different reaction conditions for the synthesis of dihydrobenzofurans. Table 3. Reaction of aryne precursor 1 with DMF and 4a,b.

Scheme 4.
Generation of enolates and reaction pathway.
In the presence of anhydrous TBAF, treatment of triflate 1 with 4a in DMF at room temperature gave the desired product 7a in 21% yield, accompanied by 64% yield of undesired dihydrobenzofuran 8a (entry 1). The undesired dihydrobenzofuran 8a having a hydroxy group would be formed as a result of hydrolysis of intermediates B or C with contamining water. The isolated yield of 7a increased to 66% yield by changing the reaction temperature (entry 2). The formation of undesired product 8a was not observed when CsF was employed (entries 3 and 4). In particular, improvement in the chemical yield of 7a was observed, when 1.2 equivalents of triflate 1 was reacted with 1.0 equivalent of 4a in DMF (entry 4). Similar trend was observed in the reaction using α-chloromalonate 4b (entries 6 and 7).
In the presence of CsF and Et 2 Zn, treatment of triflate 1 (1.2 equiv) with 4b (1.0 equiv) in DMF at −40 °C to room temperature for 12 h gave the desired dihydrobenzofuran 7b in 89% yield (entry 7).
In this transformation, α-chloroenolates H are effectively generated from α-chloromalonates 4a,b and Et 2 Zn (Scheme 4). These α-halogenated enolates H work as not only a nucleophile to attack to the intermediate C but also an electrophile to trap intramolecularly the intermediate anion J to give the desired dihydrobenzofurans 7a,b.
The reactivity of α-chloromalonate 4a toward arynes was also investigated (Scheme 5). In the presence of CsF, the direct reaction of triflate 1 with 4a was carried out in CH 3 CN without DMF. As expected, the σ-bond insertion product 9 was obtained in 52% yield. Scheme 5. Reaction of 1 with 4a.
As mentioned above, the competitive insertion of aryne into the C-C σ-bond of 4a was not observed in the domino three-component coupling reaction of bulky triflate 1. Decreasing the steric hindrance around the triple bond of aryne induced the direct insertion of aryne into α-chloromalonate 4a. When sterically less hindered triflate 10 was employ as an aryne precursor, the σ-bond insertion product 12 was obtained in 51% yield (Scheme 6). To suppress the competitive insertion of aryne into 4a, the concentration was evaluted. Under the high diluted concentration (0.02 M solution of 10 in DMF), the σ-bond insertion was mostly suppressed to afford the desired dihydrobenzofuran 11 in 65% yield, accompanied by 14% yield of dihydrobenzofuran 13 having a hydroxy group. Scheme 6. Reaction of 10 with DMF and 4a.

The Synthesis of Benzofurans
With these results in mind, the synthesis of benzofurans was next studied (Table 4). At first, ethyl iodoacetate 14 was employed as a C1-unit. The reaction of triflate 1 with 14 was run in DMF in the presence of 3.0 equivalents of TBAF (entry 1). However, the simple O-alkylated product 16 was formed in 28% yield, accompanied by salicylaldehyde derivative 6 in 45% yield. The similar trend was observed when CsF was used (entry 2). The reaction temperature had an impact on the chemical transformation (entry 3). The desired benzofuran 15a was obtained in 40% yield, when reaction was run at 100 °C. The use of Et 2 Zn or Me 3 Al as additive was not effective for this reaction (entries 4 and 5). To understand the reaction pathway, the formation of benzofuran 15a from the simple O-alkylated product 16 was studied (Scheme 7). As expected, benzofuran 15a was obtained in 32% yield, after being stirred at room temperature for 12 h followed by heated at 100 °C for 12 h. Thus, benzofuran 15a could be obtained from O-alkylated product 16.

Scheme 7. Conversion of 16 into 15a.
For the formation of benzofuran 15a, two possible reaction pathways are shown in Scheme 8. As a direct pathway, benzofuran 15a is assumed to be obtained from ortho-quinone methide C and

Scheme 8. Two reaction pathways.
As an alternative approach for synthesis of benzofurans, we tried to establish the conversion of dihydrobenzofurans 7a and 7b into benzofurans 15a and 15b (Scheme 9). When dihydrobenzofuran 7a was treated with 2.5 equivalents of EtMgBr followed by SiO 2 , the disered benzofuran 15a was obtained in 77% yield without the isolation of adduct 17a. Similarly, benzofuran 15b was formed form dihydrobenzofuran 7b. These transformations would proceed via the retro-aldol type reaction of adducts 17a and 17b followed by the elimination of a dimethylamino group. Conversion of 7a,b into 15a Next, we directed our attention into the direct one-pot synthesis of benzofuran 15b (Scheme 10). For this purpose, the active methine 18 having ketone and ester groups was used, since ketone moiety would selectively react with Et 2 Zn, leading to the retro-aldol type process. In the presence of CsF, triflate 1 and methine 18 in DMF were treated with Et 2 Zn (1.0 equiv + 0.5 equiv) at −60 °C to room temperature for 12 h. As expected, the desired benzofuran 15b having an ester group was directly generated via the addition of an ethyl anion to a ketone group of dihydrobenzofuran O, the retro-aldol type reaction of intermediate P and the elimination of a dimethylamino group of anion Q.

Scheme 10. Direct one-pot synthesis of benzofuran 15b.
Finally, we investigated the transformation of dihydrobenzofuran 8a having a hydroxy group into benzofuran 15a (Scheme 11) [46]. As a starting substrate, the preparation of dihydrobenzofuran 8a was initially studied. When the domino reaction of triflate 1 with α-bromomalonate 3 and DMF was carried out in the presence of water (1.0 equiv), the desired dihydrobenzofuran 8a was obtained in 77% yield instead of dihydrobenzofuran 7a having a dimethylamino group. For the synthesis of benzofuran 15a, we next allowed dihydrobenzofuran 8a to react with several bases ( Table 5). Treatment of dihydrobenzofuran 8a with 1.0 equivalent of NaH in DMF at room temperature gave the desired benzofuran 15a in 83% yield (entry 1). Probably, this transformation proceeds via the decarboxylation of cyclic intermediate R. In contrast, benzofuran 15a was not obtained when LiHMDS was employed in THF at −40 °C (entry 2). Interestingly, the replacement of LiHMDS with NaHMDS led to the formation of 15a (entry 3). The isolated yield of 15a dramatically increased to 96% yield by replacing NaHMDS with KHMDS (entry 4).

Scheme 11.
Preparation of 8a and transformation of 8a into 15a.

General
Melting points were taken on a Yanaco MP-J3 and are uncorrected. Infrared spectra were measured on a JASCO FT/IR-4100. 1 H-NMR spectra were measured on a JEOL ECX-400 PSK (400 MHz) or Varian NMRS 600 (600 MHz). 13 C-NMR spectra were measured on a JEOL ECX-400 PSK (101 MHz) or Varian NMRS 600 (151 MHz) with CDCl 3 as an internal standard (77.0 ppm). High resolution mass spectra were obtained by use of a Hitachi M-4100 GC/MS spectrometer or Thermo Fisher Scientific Exactive LC/MS spectrometer. For silica gel column chromatography, SiliCycle Inc. SiliaFlash F60 was used. The anhydrous TBAF was prepared from TBAF·3H 2 O by heating the hydrate at 40 °C for 6 h, at 60 °C for 12 h, at 80 °C for 6 h, and then at 120 °C for 12 h under reduced pressure [47]. The prepared anhydrous TBAF was used as a solution by addition of appropriate solvent such as DMF.

Typical Procedure for Conversion of Dihydrobenzofurans into Benzofurans
To a solution of 7a (40.0 mg, 0.12 mmol) in THF (2.4 mL) was added EtMgBr (1.0 M in THF, 300 µL, 0.30 mmol) under argon atmosphere at −40 °C. After being stirred at −40 °C to room temperature for 3 h, the reaction mixture was diluted with saturated NH 4 Cl and then extracted with AcOEt. The organic phase was dried over Na 2 SO 4 and concentrated at reduced pressure to give quantitatively the crude adduct 17a, which was used for next reaction without further purification. To a solution of 17a (35.2 mg, 0.10 mmol) in AcOEt (1.0 mL) was added silica gel (0.50 g) under the atmosphere at room temperature. After being stirred for 12 h, the reaction mixture was concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography (EtOAc/hexane = 1:10-1:3) afforded the product 15a (16.9 mg, 77%).

Conclusions
We have demonstrated that the domino three-component coupling reaction of arynes with DMF and active methylenes or methines gave various heterocycles such as coumarin derivatives, dihydrobenzofurans and benzofurans.