A cascade double 1,4-addition/intramolecular annulation strategy for expeditious assembly of unsymmetrical dibenzofurans

Existing synthetic routes for accessing dibenzofuran core have intrinsic regioselectivity, limiting the substitution patterns available in heteropolycyclic arene products. Here we report a double 1,4-conjugate addition/intramolecular annulation cascade reaction between propargylamines and two equivalents of imidazolium methylides that allows efficient access of structurally versatile dibenzofurans. This transition metal-free protocol proceeds smoothly under bench-top air atmosphere and offers easy manipulation of substituents on the dibenzofuran core, and also provides good-to-excellent product yields with good functional group tolerance, particularly the –Br and –Cl groups which are often incompatible with existing metal-catalyzed C–C and/or C–O bond ring-forming processes. It is worth noting that ladder-type π-systems with all-arene quarternary carbon structure can be straightforwardly generated upon simple late-stage functionalization.

Nevertheless, employing expensive transition metal catalysts and associated ligands, and particularly limited direct availability of substrate SM-1 with various substituents, would hamper their generality for synthesizing unsymmetrical dibenzofuran with wanted substitution patterns. Despite the advancement of transition metal-catalyzed strategy, direct functionalization of dibenzofuran molecule is also adoptable (Fig. 1c) 50 . However, the availability of pattern-desirable starting material SM-2 may not be straightforward, and in principle, the regioselectivity of electrophilic substitution is not favorable at the meta-position of arene to the oxygen atom in dibenzofurans. Recently, impressive synthetic method establishments were disclosed in which they do not require transition metal catalysts, for instance, the diazotization-comprised cyclization of ortho-(aryloxy)aniline promoted by visible light 51 or NaNO 2 /TFA; 52,53 the substrate-dependent arylation of phenols with bromonitroarenes; 54 the reaction of 2-aryl-3-nitrochromenes with pyridinium ylides; 55 and the three-component reaction between 2-hydroxy-β-nitrostyrenes, sulfur ylides, and alkynes for the synthesis of dibenzofuran acrylates 56,57 . ortho-Quinone methide (o-QM) is a versatile reagent for a variety of polycycle syntheses 58 . In particular, the alkynecontaining o-QM, namely alkynyl ortho-quinone methide (o-AQM) displays unique feature of possible exo-or endo-cyclization towards the alkynyl moiety [59][60][61][62][63][64][65][66] . In continuing our recent interest in investigating complex polycyclic structure assembly 67,68 and o-AQM chemistry [69][70][71] , we are intrigued whether the acyl carbene motif can be doubly incorporated to o-AQM in achieving the densely-substituted arene on one side of dibenzofuran framework.
Herein, we report a cascade reaction between propargylic amines and imidazolium methylides (Fig. 1d). This basepromoted protocol allows modular assembly of dibenzofurans with a complementary substitution pattern, and exhibits good functional group tolerance, particularly tolerating -Br and -Cl groups which offer potential for late-stage product modification via cross-coupling technology. It is worth noting that this method is operationally simple, as the reaction can be conveniently performed under bench-top air atmosphere, and is complementary to frequently Br-group-incompatible transition metal-catalyzed annulative C (Ar) −C (Ar') and C (Ar) −O bond construction reactions.

Results and discussion
Reaction optimization. Propargylic amine 1a and imidazolium salt 2a were chosen as the prototypical substrates for our initial reaction condition investigations (Table 1). Putting KOt-Bu in the reaction system allowed the formation of desired product 3aa Table 1 Optimization of reaction conditions a . Propargylic amine 1a and imidazolium salt 2a were used as the prototypical substrates for initial reaction condition investigations. . To our delight, mixing the commonly used bases provided better outcomes, particularly the KOt-Bu/K 2 CO 3 and KOt-Bu/KOH combinations (entries [8][9][10][11][12][13]. Further investigation of the base stoichiometry offered better product yields (entries [14][15][16]. Having the fruitful base combination, we next surveyed the regularly used solvents (entries 17-23). MeCN and DMF were found to be the best solvents of choice (entries 15 and 17). We intended to use MeCN for further screening owing to its operational simplicity. Room temperature conditions did not allow the reaction to proceed (entry 24). Further variation of reaction temperatures revealed that 80°C is the optimal condition (entries [25][26]. Extension of reaction time did not find beneficial to the product yield (entry 28). Thus, the optimal reaction conditions were found to be KOt-Bu/KOH in MeCN at 80°C for 3 h. It is worthy to note that this cascade reaction proceed-well under bench-top air atmosphere.
Substrate scope. With the optimized reaction conditions in hand, we next investigated the scope of propargylic amine with various substituents (Fig. 2). In general, the desired dibenzofurans were delivered in good-to-excellent yields. No significant electronic effect of the alkynyl arene moiety at the propargylic scaffold was found (products 3da, 3ea, 3fa, and 3ga). Similarly, the electronically-varied substituents (e.g., -Me and -Cl) at the paraposition of the phenolic moiety did not affect the product yields (products 3ea vs 3ha). Structure of 3ha was unambiguously characterized by single-crystal X-ray crystallography (see Supplementary Fig. 1 and Table 1, Supplementary Data 1 for CIF file). The -Br substituent at para-and ortho-position of the phenolic arene unit remained intact during the course of the reaction (products 3la, 3ma, 3na, and 3oa). This -Br group compatibility is of high attractiveness as this group can be further straightforwardly functionalized using established cross-coupling technology. In addition to halo-substituents, the steric bulky tertbutyl group at the ortho-phenolic-position was found to be tolerable towards the ring-forming process (product 3pa). Cyclohexenyl and thienyl units remained untouched in this cascade annulation and furnished the expected products 3ra and 3sa in 78% and 73% yields, respectively. The scope of the reaction was further tested using various benzoyl imidazolium methylide derivatives (Fig. 3). Essentially no steric influence of the arene at 2 was found and the desired products were afforded in good yields (products 3ab, 3ac, 3ad, and 3ae). Substrates bearing halo groups, e.g., fluoro, chloro, and bromo were successfully employed in this reaction, yielding the resulting products 3ag-3al in 77% to 90% yields. Highly electronwithdrawing substituent -CF 3 was compatible, affording the corresponding products 3am. With appropriate imidazolium methylide, the π-extended structure was able to be constructed in 92% yield (product 3an).
Mechanistic studies. A competition-study between two electronically different imidazolium methylides 2f and 2m were performed (Fig. 4). Two main products 3afm and 3am were isolated in 32% and 36% yields, respectively. This experiment clearly reflected that the electronically poor methylide 2m underwent deprotonation faster and thus subsequent 1,4-conjugate addition to o-AQM. The product of 3af was not detected essentially that further added to this mechanistic proposal.
A plausible reaction mechanism is proposed in Fig. 5. Synthetic transformations and applications. Pentacene has been successful in advancing organic material applications 72 . The high charge carrier mobility of acenes is believed to be originated from the highly ordered π-π-interaction stacking between adjacent  73 . Nevertheless, the stability of this pentacene towards practical application still has room for improvement. Recently, the ladder-type heteroacenes was reported to have both high charge mobility and stability under ambient conditions 74 . With regard to this impressive finding, we are interested to devise an investigation for assembling fluorene-containing spiro-laddertype heteroacenes 75 . The all-arene quaternary carbon unit would be useful for easy management of distinctive spatial arrangement of the π-system for desirable mobility-tuning 76,77 . To our delight, the initial attempt of using superacid-promoted synthetic strategy 78,79 was successful in delivering a spiro-ring-fused system (Fig. 6). In the presence of TfOH in toluene at room temperature, a series of spiro-ladder-type molecules 4aa, 4ca, and 4ia were able to be obtained in 91%, 94%, and 93% yields, respectively (Fig. 6). It is interesting to show that toluene served as both reagent and solvent for this transformation. Conversely, upon alternating the solvent to dichloromethane, the serendipitous products 5aa, 5af, 5ba, and 5oa were formed (the tertiary alcohol product 5aa was unambiguously confirmed by single-crystal X-ray crystallography, see Supplementary Fig. 2 and Table 2, Supplementary Data 2 for CIF file). These products indeed offer high opportunity for further functionalization via a simple -OH group transformation 80,81 , and thus allows rich entities for new material investigations.
In conclusion, we have succeeded in showing a doubly 1,4conjugate addition/annulation cascade process for facile access of structurally versatile dibenzofurans. This transition metal-free protocol proceeds smoothly under bench-top air atmosphere and realizes easy manipulation of substituents on one of the flankedarenes of dibenzofuran core. The present modular method  exhibits good product framework diversity and complexity, decent product yields, and allows good functional group tolerance, particularly the -Br and -Cl groups where they are often found impermissible in existing Pd-catalyzed aromatic C-C or C-O bond ring-forming processes. It is worthy to note that materially attractive spiro-ladder-type π-system with all-arene quaternary carbon feature can also be simply attained via a onestep subsequent functionalization.

Methods
General procedures for the synthesis of propargylamines 1. To a 25 mL roundbottom flask equipped with a magnetic stir bar were added pyrrolidine (1.2 mmol), aldehyde (1.0 mmol), acetylene (1.2 mmol), copper (I) iodide (10 mol%), and toluene (3 mL). The mixture was degassed and backfilled with nitrogen, and then stirred in an oil bath preheated to 100°C for 5 h (monitored by TLC). After the reaction completed (as determined using TLC), the reaction mixture was cooled to room temperature, diluted with CH 2 Cl 2 (10 mL), and filtered through a thin pad of silica gel. The filter cake was washed with CH 2 Cl 2 , and the combined filtrate was concentrated in a vacuum. The crude product was purified by flash column chromatography on silica gel to afford the corresponding propargylamines.
General procedure for the synthesis of imidazolium methylides 2. 1-Methyl-1H-imidazole (410 mg, 5.0 mmol) was added to 2-bromoethanones derivatives (5.0 mmol) in dry acetonitrile (5 mL). After stirring for 2 to 5 h at room temperature, the precipitate formed was filtered off and washed with acetonitrile to afford the desired imidazolium methylides 2, which can be used to next reaction without further purification. Other ylides used were synthesized according to these procedures.
General procedures for the synthesis of dibenzofurans 3. A mixture of propargylamines 1 (0.2 mmol), imidazolium methylides 2 (0.4 mmol), potassium tbutoxide (0.2 mmol), and potassium hydroxide (0.4 mmol) were added to a resealable screw-capped Schlenk tube under air atmosphere. Acetonitrile (2 mL) was then added. The tube sealed with a Teflon-coated cap and the resulting mixture was stirred in an oil bath preheated to 80°C for 3 h (monitored by TLC). Upon completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified using flash column chromatography with a silica gel (200-300 mesh), using ethyl acetate and petroleum ether (1:20, v/v) as the elution solvent to give desired products 3. For NMR spectra, see Supplementary .
10-Fold scale synthesis of compound 3aa. A mixture of 2-(3-phenyl-1-(pyrrolidin-1-yl)prop-2-yn-1-yl)phenol (1a) (2.0 mmol, 0.56 g), 1-methyl-3-(2-oxo-2phenylethyl)-1H-imidazol-3-ium bromide (2a) (4.0 mmol, 1.12 g), potassium tbutoxide (2.0 mmol, 0.22 g), and potassium hydroxide (4.0 mmol, 0.22 g) were added to a resealable screw-capped Schlenk tube. Acetonitrile (10 mL) was then added. The tube sealed with a Teflon-coated cap and the resulting mixture was stirred in an oil bath preheated to 80°C for 3 h (monitored by TLC). Upon completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified using flash column chromatography with a silica gel (200-300 mesh), using ethyl acetate and petroleum ether (1:20, v/v) as the elution solvent to give desired product 3aa in 75% yield. General procedures for the synthesis of compound 4. Dibenzofuran 3 (0.2 mmol) was mixed with TfOH (0.6 mmol) in a round bottom flask. Toluene (2 mL) was then added. The resulting mixture was stirred at room temperature (25°C) for 1 h (monitored by TLC). Upon completion of the reaction, the solvent was removed under reduced pressure. The residue was purified using flash column chromatography with a silica gel (200-300 mesh), using ethyl acetate and petroleum ether as the elution solvent to give desired product 4. For NMR spectra, see Supplementary Figures 75-80).
General procedures for the synthesis of compound 5. Dibenzofuran 3 (0.2 mmol) was mixed with TfOH (0.6 mmol) in a round bottom flask. Dichloromethane (2 mL) was then added. The resulting mixture was stirred at room temperature (25°C) for 2 h (monitored by TLC). Upon completion of the reaction, the solvent was removed under reduced pressure. The residue was purified using flash column chromatography with a silica gel (200-300 mesh), using ethyl acetate and petroleum ether as the elution solvent to give desired product 5. For NMR spectra, see Supplementary Figures 81-88).

Data availability
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