Enantioselective Boronate Additions to N-Acyl Quinoliniums Catalyzed by Tartaric Acid

Abstract

Tartaric acid catalyzes the asymmetric addition of vinylboronates to N-acyl quinoliniums, affording highly enantioenriched dihydroquinolines. The catalyst serves to activate the boronate through a ligand-exchange reaction and generates the N-acyl quinolinium in situ from the stable quinoline-derived N,O-acetal.

Nucleophilic addition to quinolines is an effective method to synthesize dihydroquinolines; useful synthons in the construction of biologically active alkaloids. ¹ Shibasaki reported the first catalytic, enantioselective addition to quinoline, a Reissert-type reaction with trimethylsilylcyanide and a bifunctional phosphine-BINOLate catalyst. ² Alexakis performed a direct lithiation of quinolines in the presence of a chiral diether catalyst.³ Recently, Takemoto reported a Petasis-type reaction of quinolines with boronic acids and a bifunctional thiourea catalyst. ⁴ All of these reaction require an in situ formation of an N-acyl quinolinium generated by the addition of a chloroformate to the quinoline electrophile. We hoped to utilize 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinolines (EEDQs) as stable N-acyl quinolinium precursors to avoid the use of chloroformates.⁵ Although EEDQs are reactive partners in Petasis-like reactions, ⁶ only one enantioselective transformation of EEDQs has been reported.^6c Herein, we report the use of tartaric acid as a catalyst to perform highly enantioselective additions of boronates to N-acyl quinoliniums to form chiral dihydroquinolines.

Many of the seminal developments of asymmetric synthesis and catalysis utilize tartaric acid derivatives as chiral auxiliaries or catalysts.⁷ The Sharpless asymmetric epoxidation,⁸ asymmetric allylborations,⁹ and asymmetric Diels-Alder reactions¹⁰ are just a few examples of highly utilized transformations employing the tartaric acid motif. Surprisingly, tartaric acid itself has found little use as an organocatalyst despite its ubiquitous nature and densely functionalized structure.¹¹ Instead, the role of tartaric acid in asymmetric synthesis is most often as a resolving agent.¹²

We began our studies using a Lewis acid-Brønsted acid catalyst system of 10 mol % tartramide 4 and 5 mol % Yb(OTf)₃, which was previously successful in catalyzing the addition of boronates to 2H-chromene acetals.¹³ The commercially available EEDQ 1 and diethyl styrylboronate 2 afforded the desired product 3 in 24% yield and 54:46 er under these conditions (Table 1, entry 1). Switching to tartaric acid 5 and 10 mol % Yb(OTf)₃ gave a similar result (entry 2); however, omitting the Lewis acid co-catalyst led to increased enantioselectivity (entries 3 and 4). To increase catalyst turnover, protic additives were employed in the reaction (entries 5-7), and it was found one equivalent of CF₃CH₂OH increased yield to 46% with a concomitant increase in enantioselectivity of 81:19 er (entry 8).¹⁴ Use of 10 equivalents of CF₃CH₂OH gave 73% yield of 3 and 83:17 er (entry 11). Other tartaric acid-derived catalysts, such as the CAB-type catalyst 6 and diethyl tartrate 7 were tested, but these catalysts did not perform well (entries 9 and 10). Takemoto and co-workers observed that the enantioselectivity of their reaction depended on the type of carbamate.⁴ Under the tartaric acid catalyzed conditions, methyl and benzyl substituted carbamates gave slightly lower selectivities and yields relative to the ethyl carbamate (entries 12 and 13). The larger, phenyl-substituted carbamate proved to be the least effective N-acyl quinolinium precursor in this reaction (entry 14).

Table 1.

Asymmetric Addition of Boronates to EEDQs.^a

entry	R	catalyst	additive (equiv)	solvent	yieldb	erc
1	Et	4	Yb(OTf)3 (0.05)	EtOAc	24%	54:46
2	Et	5	Yb(OTf)3 (0.1)	EtOAc	13%	56:44
3	Et	5	–	EtOAc	21%	69:31
4	Et	5	–	CH3CN	31%	75:25
5	Et	5	EtOH (1.0)	CH3CN	21%	74:26
6	Et	5	PhOH (1.0)	CH3CN	27%	80:20
7	Et	5	AcOH (1.0)	CH3CN	10%	75:25
8	Et	5	CF3CH2OH (1.0)	CH3CN	46%	81:19
9	Et	6	CF3CH2OH (1.0)	CH3CN	8%	62:38
10	Et	7	CF3CH2OH (1.0)	CH3CN	18%	50:50
11	Et	5	CF3CH2OH (10.0)	CH3CN	73%	83:17
12	CH3	5	CF3CH2OH (10.0)	CH3CN	59%	77:23
13	Bn	5	CF3CH2OH (10.0)	CH3CN	36%	72:28
14	Ph	5	CF3CH2OH (10.0)	CH3CN	12%	65:35

^aReactions were run with 0.20 mmol 1, 0.4 mmol 2, 10 mol % catalyst, and additive in solvent (1.0 mL) for 16 h at room temperature under Ar, followed by flash chromatography on silica gel.

^bYield of isolated product.

^cEnantiomeric ratios determined by HPLC analysis using a chiral stationary phase.

Interestingly, increasing the Lewis basicity of the solvent resulted in increased enantioselectivity and yield.¹⁵ Ethereal solvents THF and Et₂O gave lower yields and selectivities than CH₃CN (Table 2, entries 1 and 2). Reactions run in DMF, tetramethylurea (TMU), and 1,3-dimethyl-2-imidazolidinone (DMI) gave low yields but enantioselectivity between 76:24 - 83:17 er (entries 3-5). Strongly coordinating solvents, such as 1,3-dimethyl-tetrahydropyrimidin-2-(1H)-one (DMPU), N-methylpyrrolidinone (NMP) and hexamethylphosphoramide (HMPA) gave the best selectivity with HMPA, affording dihydroquinoline 3 in 96:4 er (entries 6-8). Increasing the amount of tartaric acid to 20 mol % and lowering the temperature of the reaction increased yields to 63% (entry 9 and 10). Finally, a change to the slightly less acidic CCl₃CH₂OH additive at −10 ° C provided the optimal reaction conditions and produced dihydroquinoline 3 in 96:4 er and 82% yield (entry 12).

Table 2.

Lewis Basic Solvents for the Asymmetric Addition of Boronates to EEDQs.^a

entry	mol % 5	additive	solvent	temp (°C)	yieldb	erc
1	10	CF3CH2OH	THF	20	48%	69:31
2	10	CF3CH2OH	Et2O	20	34%	57:43
3	10	CF3CH2OH	DMF	20	9%	83:17
4	10	CF3CH2OH	TMU	20	15%	76:24
5	10	CF3CH2OH	DMI	20	8%	82:18
6	10	CF3CH2OH	DMPU	20	32%	92:8
7	10	CF3CH2OH	NMP	20	27%	92:8
8	10	CF3CH2OH	HMPA	20	32%	96:4
9	20	CF3CH2OH	HMPA	20	49%	95:5
10	20	CF3CH2OH	HMPA	−10	63%	93:7
11	20	CCl3CH2OH	HMPA	−10	61%	96:4
12	20	CCl3CH2OH	HMPAd	−10	82%	96:4

^aReactions were run with 0.20 mmol 1, 0.3 mmol 2, 0.02 – 0.04 mmol 5, and 2.0 mmol additive in solvent (1.0 mL) for 16 h at room temperature under Ar, followed by aqueous work-up and flash chromatography on silica gel.

^bYield of isolated product.

^cEnantiomeric ratios determined by HPLC analysis using a chiral stationary phase.

^dRun for 48 h.

A substrate table was generated under the optimized reaction conditions using HMPA and NMP as solvent. First, we examined the effect of substitution at the 6-position of EEDQ. Electron-donating groups on EEDQ gave good yields and selectivities in NMP at low temperatures (Table 3, entries 1 and 2), while electron-poor EEDQs required slightly higher temperatures in HMPA (entries 3 and 4). The amido-substituted EEDQ afforded the dihydroquinoline 3f in 71% yield and 91:9 er (entry 5). The higher reactivity of the electron-rich N-acyl quinolinium precursors indicates the importance of stabilizing the positive charge on the electrophilic iminium during the rate-determining step. This trend of reactivity was also observed in the tartaramide-catalyzed additions of boronates to oxocarbeniums.^[13]

Table 3.

Tartaric Acid-Catalyzed Addition of Boronates to EEDQs.^a

entry	product	solvent	temp (°C)	yieldb	erc
1	3b: R1=CH3, R2=C6H5	NMP	−10	81%	94:6
2	3c: R1=OCH3, R2=C6H5	NMP	−20	74%	94:6
3	3d: R1=Cl, R2=C6H5	HMPA	4	89%	95:5
4	3e: R1=NO2, R2=C6H5	HMPA	4	73%	92:8
5d	3f: R1=AcNH, R2=C6H5	NMP	−10	71%	91:9
6e	3g: R1=H, R2=4-CH3OC6H4	HMPA	−10	87%	94:6
7	3h: R1=H, R2=4-ClC6H4	HMPA	−10	86%	92:8
8	3i: R1=H, R2=3-C4H3S	HMPA	−10	83%	96:4
9	3j: R1=H, R2=3,4-CH2O2C6H4	HMPA	−20	73%	92:8
10	3k: R1=H, R2=2-Naphthyl	NMP	4	70%	92:8
11	3l: R1=H, R2=3-FC6H4	HMPA	4	77%	95:5
12	3m: R1=Cl, R2=4-CH3OC6H4	HMPA	−20	82%	95:5
13	3n: R1=OCH3, R2=4-CH3OC6H4	NMP	−20	81%	92:8
14	3o: R1=OCH3, R2=3-FC6H4	NMP	4	73%	88:12

^aReactions were run with 0.2 mmol EEDQ, 0.3 mmol boronate, 0.04 mmol 5 and 2.0 mmol Cl₃CH₂OH in NMP or HMPA (0.4 mL) for 48 h under Ar, followed by aqueous work-up and flash chromatography on silica gel.

^bYield of isolated product.

^cEnantiomeric ratios determined by HPLC analysis using a chiral stationary phase.

^dEntries 5, 10, 11, and 14 were run for 72 h.

^eEntries 6 and 8 were run for 24 h.

Next, we expanded the scope of the reaction using functionalized vinylboronates. Electron-donating groups on the boronate gave good results using HMPA with selectivities of >92:8 er (entries 6 and 9). Electron-withdrawing boronates were also good partners in the reaction, with a chlorine-substituted boronate affording product 3h in 86% yield and 92.5:7.5 er (entry 7). The fluorine substituted boronate reacted slowly and was warmed to 4°C to afford 3l in 95:5 er (entry 11). The thiophene-derived boronate gave 3i in excellent selectivity of 96.5:3.5 er (entry 8). Difunctionalized products 3m – 3o were synthesized in good yields and selectivity, and the reaction appears tolerant of a variety of functionalization on both the boronate and EEDQ (entries 12-14).

Mechanism studies were undertaken to ascertain the role of the tartaric acid catalyst during the course of the reaction. Although double exchange reaction occurs between catalyst 5 and boronate 2 the fate of the catalyst after the reaction with the quinolinium remained unclear. To understand whether the tartaric acid would remain free in solution or bound to boron a series of experiments were conducted. Triethyl borate and tartaric acid 5 were mixed in HMPA for 5 min, and an aliquot of the solution was injected into the ESI-MS (Scheme 1a). Monomeric borate 8 was not observed in the reaction, although it is probably a fleeting intermediate in the reaction. Instead a mass was observed for the dimeric tartaric acid adduct 9, a previously reported tetracoordinated boron “ate” structure. ¹⁶ To determine whether boron “ate” 9 is catalytically viable, the complex was formed in situ and used in the reaction (Scheme 1b). Using 10 mol % 9 under the optimized reaction conditions, dihydroquinoline 3 was formed with similar selectivity and yield as the original reaction conditions.

Scheme 1.

Catalyst resting state, borate 9.

Our proposed catalytic cycle relies on the tetracoordinated boron “ate” 9 as the resting state of the catalyst (Scheme 2). The dimeric borate 9 undergoes a disproportionation with boronate 2 to form the activated alkenyl dioxaborolane 10. This exchange is likely facilitated by the protic Cl₃CH₂OH additive.¹⁶ Next, activated dioxaborolane 10 reacts with N,O-acetal 1 to form the N-acyl quinolinium and boron “ate” intermediate 11. Nucleophilic addition of the alkenyl group to the iminium proceeds enantioselectively to furnish dihydroquinoline 3 and regenerate complex 9.

Scheme 2.

Proposed catalytic cycle.

In summary, we have developed a nucleophilic boronate addition reaction to stable EEDQs to form chiral dihydroquinolines catalyzed by simple, inexpensive tartaric acid. The reaction proceeds with high enantioselectivity, good yield and excellent functional group tolerance. Mechanism studies indicated that the tartaric acid activates the boronate via a double-exchange reaction, and following the first catalytic cycle the catalyst resting state is a tetracoordinated boron “ate.” While often overlooked as a catalyst in favor of its many derivatives, tartaric acid was found to be a competent diol-exchange catalyst and the optimal catalyst in this particular reaction. Further studies into the application of tartaric acid in organocatalysis are ongoing.