Chiral Quaternary Ammonium Salt Derived from Dehydroabietylamine: Synthesis and Application to Alkynylation of Isatin Derivatives Catalyzed by Silver

: Abietic acid and its derivatives have broadly been used in ﬁne chemicals and are renewable resources. Its inherent chiral rigid tricyclic phenanthrene skeleton is unique. Its utilities in asymmetric catalysis remain to be explored. A series new amide-type chiral quaternary ammoniums bearing dehydroabietylamine were designed, and prepared by two convenient steps. Acylation of dehydroabietylamine with bromoacetyl chloride afforded amide holding bromoacetyl group in higher yields using triethyl amine as base. Subsequent quaternization reaction gave the desired amide-type chiral quaternary ammoniums. The new chiral quaternary ammoniums can be used as phase-transfer catalyst (PTC) for the transition metal-catalysed alkynylation of isatin derivatives. and in to good respectively. including ﬂuoro-, and smoothly reacted with aromatic alkynes containing a wide range of functionalities to give the corresponding products 7 in good to high yields. The results indicated that the electronic property and steric hindrance on the or aromatic alkynes had a slight effect on the reaction.


Design and Synthesis of Chiral Dehydroabietylamine Quaternary Ammoniums
We envisaged that new chiral dehydroabietylamine quaternary ammonium derivatives should be conveniently prepared by short steps. Thus, five dehydroabietylamine quaternary ammonium salts were derived from chain or cyclic tertiary amines ( Figure 2).

Metal-Catalysed Alkynylation of Isatin Derivatives in the Presence of Chiral Quaternary Ammoniums
Our investigation began with the addition of phenylacetylene 6a to isatin derivative 5a (Table 1). Initially, the reaction was carried out by using 5 mol % of AgOAc and 5.5 mol% 1a as catalyst and K2CO3 as base in THF. The desired product can be obtained in a 68% yield without enantioselectivity at 50 °C (Table 1, entry 1). Investigations into the effects of dehydroabietylamine quaternary ammonium derivatives suggested that marginal enantioselectivities were observed when 1d and 1e were used (Table 1, entries 2-5). The same enantioselectivity was obtained but the yield was slightly reduced when toluene was used as a solvent (Table 1, entry 6). Examination into the effects of metal catalyst precursors suggested that AgOAc was the best choice, although AgOTf, CuOTf and CuI were suitable catalysts for the present reaction (Table 1, entries 7-10). The reaction was very sluggish at room temperature (Table 1, entry 11). When 5b was used as substrate, the enantioselectivity was increased to 6%ee (Table 1, entries [12][13]. When 5c was used as substrate, the screening of solvents suggested that the solvents have a distinct influence on catalytic activity (Table 1, entries [14][15][16][17][18][19][20][21][22]. Mesitylene gave best result with respect to the enantioselectivity, whereas, THF, toluene, DMSO, and MeOH gave worse results  The synthesis of dehydroabietylamine quaternary ammonium derivatives is shown in Scheme 1. Amidation reaction between bromoacetyl chloride 3 and commercially available dehydroabietylamine 2 produces bromide 4 in 85% yields using triethyl amine as base in CH2Cl2. The quaternization reaction bromide 4 with triethyl amine, 1-methylpiperidine, 1-methylpyrrolidine, N, N, N', N'-tetramethyl-1,3-propanediamine, triethylene diamine (DABCO) gave the corresponding quaternary ammonium derivatives in high yields, respectively. Scheme 1. Synthesis of chiral dehydroabietylamine quaternary ammonium derivatives.

Metal-Catalysed Alkynylation of Isatin Derivatives in the Presence of Chiral Quaternary Ammoniums
Our investigation began with the addition of phenylacetylene 6a to isatin derivative 5a (Table 1). Initially, the reaction was carried out by using 5 mol % of AgOAc and 5.5 mol% 1a as catalyst and K2CO3 as base in THF. The desired product can be obtained in a 68% yield without enantioselectivity at 50 °C (Table 1, entry 1). Investigations into the effects of dehydroabietylamine quaternary ammonium derivatives suggested that marginal enantioselectivities were observed when 1d and 1e were used (Table 1, entries 2-5). The same enantioselectivity was obtained but the yield was slightly reduced when toluene was used as a solvent (

Metal-Catalysed Alkynylation of Isatin Derivatives in the Presence of Chiral Quaternary Ammoniums
Our investigation began with the addition of phenylacetylene 6a to isatin derivative 5a (Table 1). Initially, the reaction was carried out by using 5 mol % of AgOAc and 5.5 mol% 1a as catalyst and K 2 CO 3 as base in THF. The desired product can be obtained in a 68% yield without enantioselectivity at 50 • C ( Table 1, entry 1). Investigations into the effects of dehydroabietylamine quaternary ammonium derivatives suggested that marginal enantioselectivities were observed when 1d and 1e were used (Table 1, entries 2-5). The same enantioselectivity was obtained but the yield was slightly reduced when toluene was used as a solvent ( (entries [14][15][16][17][18][19][20][21]. Investigations into the effects of bases suggested that all of the examined inorganic base carbonates were suitable bases for the present reaction (Table 1, entries [22][23][24][25][26]. Finally, in the absence of AgOAc, no desired compound was observed, suggesting that metal catalyst played an important role in the transformation [101] (Table  1, entry 26).

Scope for Addition of Alkynes to Isatin Derivatives
Next, studies on the expansion of the substrate scopes were then carried out using the relative optimal reaction conditions (Table 1, entry 21). As shown in Scheme 2, the different substituents and substitution patterns of the isatin and aryl acetylene were all tolerated. The 1-n-Butyl-4-ethynylbenzene was successfully added to 5c to give the corresponding product 7cb in a moderate yield and 6%ee. The reaction of 5c with 1-ethynyl-4-methoxybenzene and 1-ethynyl-4-ethoxybenzene, holding a strong electron-donating substituent, gave the desired products 7cc and 7cd in good yield with 3%ee and 9%ee, respectively. Aryl acetylene-bearing, electron-withdrawing substituents, including fluoro-and chloro-groups, were tested for the present reaction, and the desired products (7ce and 7cf) were obtained in good to high yields with 2%ee and 3%ee. The reaction of isatin derivative 5d holding methyl with phenylacetylene 6a and 1-ethynyl-3-fluorobenzene 6f gave the desired products, 7da and 7df, in good yields with 3%ee. The alkynylation of isatin derivative 5e tolerating electron-donating substituents with phenylacetylene 6a, 1-ethyl-4-ethynylbenzene 6g, and 1-ethynyl-3-fluorobenzene 6f gave the desired products, 7ea, 7eg, and 7df, in moderate to good yields, respectively. Isatin derivatives (5f, 5g, and 5h) with electron-withdrawing substituents, including fluoro-, bromo-, and chloro-groups, smoothly reacted with aromatic alkynes containing a wide range of functionalities to give the corresponding products 7 in good to high yields. The results indicated that the electronic property and steric hindrance on the isatins or aromatic alkynes had a slight effect on the reaction.
respectively. Aryl acetylene-bearing, electron-withdrawing substituents, including fluoro-and chloro-groups, were tested for the present reaction, and the desired products (7ce and 7cf) were obtained in good to high yields with 2%ee and 3%ee. The reaction of isatin derivative 5d holding methyl with phenylacetylene 6a and 1-ethynyl-3-fluorobenzene 6f gave the desired products, 7da and 7df, in good yields with 3%ee. The alkynylation of isatin derivative 5e tolerating electron-donating substituents with phenylacetylene 6a, 1-ethyl-4-ethynylbenzene 6g, and 1-ethynyl-3-fluorobenzene 6f gave the desired products, 7ea, 7eg, and 7df, in moderate to good yields, respectively. Isatin derivatives (5f, 5g, and 5h) with electron-withdrawing substituents, including fluoro-, bromo-, and chlorogroups, smoothly reacted with aromatic alkynes containing a wide range of functionalities to give the corresponding products 7 in good to high yields. The results indicated that the electronic property and steric hindrance on the isatins or aromatic alkynes had a slight effect on the reaction. The ee was determined by chiral HPLC analysis.

Mechanism for Ag-Catalysed Alkynylation of Isatin Derivatives
On the basis of the experimental results as well as literature's working hypothesis [47,77], we propose the mechanism of the present Ag catalysed alkynylation of isatin derivatives, as shown in Scheme 3. We speculated that a silver alkynilide is formed by the coordination of terminal alkyne 6 with Ag(I) and deprotonation, which can produce a

Mechanism for Ag-Catalysed Alkynylation of Isatin Derivatives
On the basis of the experimental results as well as literature's working hypothesis [47,77], we propose the mechanism of the present Ag catalysed alkynylation of isatin derivatives, as shown in Scheme 3. We speculated that a silver alkynilide is formed by the coordination of terminal alkyne 6 with Ag(I) and deprotonation, which can produce a silver alkynilide ion pair intermediate A with chiral quaternary ammoniums catalyst (Q + Br − ). The nucleophilic addition of the silver alkynilide intermediate A to isatin 5 affords the desired product 7. Comparison with Maruoka's chiral quaternary ammoniums catalyst holding binaphthyl framework, a lower enantioselectivity was observed, which may be causeded by the asymmetric center of the catalyst being far away from the nitrogen atom. The future focus will be to further modify the structure of the chiral quaternary ammonium salt containing dehydroabietylamine to improve the enantioselectivity.

methyl) acetamide 4
To a solution of dehydroabietylamine (2.850 g, 10.0 mmol) and triethylamine (1.525 g, 15.0 mmol) in dry dichloromethane (20 mL) at 0 °C under nitrogen atmosphere, was added dropwise a solution of bromoacetyl chloride (2.340 g, 15.0 mmol) in dry dichloromethane (10 mL). After the completion of addition, the reaction mixture was stirred at room temperature overnight and poured into saturated NaHCO3 solution. The aqueous layer was extracted with dichloromethane (2 × 25 mL) and the combined organic phases were washed with brine solution, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography to give the product 4, 3.440 g, 85%. 1 13

General Information
The 1 H and 13 C NMR data were acquired on a Bruker AV-400 and/or AV-600 MHz spectrometer (Billerica, MA, USA). HRMS data were obtained from Agilent 6520 Q-TOF LC/MS (Santa Clara, CA, USA). Commercial reagents were purchased and used without further purification. THF and toluene were distilled over benzophenone ketyl under nitrogen. DMF and MeOH were distilled over CaH 2 under nitrogen. Dioxane was distilled over LiAlH 4 under nitrogen.

General Procedure for the Synthesis of Chiral Dehydroabietylamine Quaternary Ammoniums 1
To a reaction tube were added above bromide 4 (445 mg, 1.1 mmol), CH 3 CN (3 mL), and tertial amine (1 mmol 1a, 1b, 1c; 0.5 mmol 1d, 1e). The mixture was stirred at 60 • C overnight. After being cooled to room temperature, AcOEt (10 mL) was added and the resulting solid was washed with AcOEt several times to give the quaternary ammonium salt.

General Procedure for Addition of Alkynes to Isatin Derivatives
Under an atmosphere of N 2 , a reaction tube was charged with isatin (0.20 mmol), AgOAc (0.01 mmol), quaternary ammonium salt (0.011 mmol), base (0.40 mmol). Then, mesitylene (2.0 mL) and alkyne (0.40 mmol) were added successively to the tube. The mixture was stirred at given temperature for 12 h. The mixture was directly purified through silica gel column chromatography to give the product 7.

Conclusions
In summary, a series of new amide-type chiral quaternary ammoniums bearing dehydroabietylamine were prepared by acylation of dehydroabietylamine with bromoacetyl chloride in higher yields using triethyl amine as base and subsequent quaternization reaction with tertial amines and/or tertial diamines. To some extent enantioselectivities were observed when using them as phase-transfer catalyst for the transition-metal catalytic alkynylation of isatin derivatives. Their chiral recognition ability or application in the others' asymmetric transformation will be examined.