Practical Synthesis of Axially Chiral Dicarboxylates via Pd-Catalyzed External-CO-Free Carbonylation

Abstract

We have developed a safe and practical synthetic method for preparing axially chiral diphenyl dicarboxylates using Pd-catalyzed external-CO-free carbonylation with phenyl formate as a CO surrogate. Optimized conditions consisted of axially chiral [1,1′-binaphthalene]-2,2′-diyl ditriflate and its congeners, each easily prepared from commercially available enantiomerically pure diols, Pd(OAc)₂, 1,3-bis(diphenylphosphino)propane, ethyldiisopropylamine, and no solvent. To demonstrate the potential utility of these products, this method was conducted on gram-scale and the phenyl ester products were converted to other useful compounds, and both processes were carried out without difficulty.

Axially chiral compounds have found wide applications as ligands and organocatalysts in asymmetric organic reactions.^1–5) Their chiral backbones effectively construct an asymmetric environment around the molecules, enabling catalytic transformations, often with high enantioselectivity. A number of biaryl and spirocyclic chiral ligands are commercially available from multiple suppliers, and many recent papers mentioning the development of novel axially chiral ligands and organocatalysts indicate increasing demand and potential of axially chiral compounds for asymmetric catalysis.

In the search for highly effective chiral ligands and organocatalysts, [1,1′-binaphthalene]-2,2′-dicarboxylic acid and its derivatives such as esters are attractive axially chiral compounds.^6–9) However, most previous methods for the synthesis of the enantiomerically pure dicarboxylic acid and dicarboxylates required multiple tedious steps.^10–17) In addition, many of the methods include time-consuming optical resolution of racemic dicarboxylic acid. Therefore, it is desirable to develop more practical synthetic methods with fewer steps. Since enantiomerically pure 1,1′-bi-2-naphthol is readily available from many suppliers, it would be an efficient starting point in the synthesis of the targeted dicarboxylates (Chart 1). Recently, Hamashima and colleagues reported the synthesis of dicarboxylic acid from 1,1′-bi-2-naphthol via lithiation of [1,1′-binaphthalene]-2,2′-diyl diphosphate followed by carboxylation with carbon dioxide.¹⁸⁾ While this method affords dicarboxylic acid in high yield in two steps, the involvement of the strongly basic dilithiated intermediate might prove unmanageable with more complex substrates. As another route to [1,1′-binaphthalene]-2,2′-dicarboxylates from 1,1′-bi-2-naphthol, Takaya and colleagues previously reported the Pd-catalyzed alkoxycarbonylation of [1,1′-binaphthalene]-2,2′-diyl ditriflate using carbon monoxide (CO) gas.¹⁹⁾ Proving the utility of this pioneering work, many other researchers have used this method to obtain various derivatives.^20–23) While this method gives dicarboxylates in good yield under relatively mild, weakly basic conditions, use of the highly toxic CO gas is a major drawback.

Chart 1. [1,1′-Binaphthalene]-2,2′-dicarboxylates from 1,1′-Bi-2-naphthol

To circumvent the use of toxic CO gas, alternative methods using CO surrogates have attracted much attention in recent years.^24–27) We recently reported a series of external-CO-free carbonylation of haloarenes utilizing phenyl formate or other formic acid derivatives as CO surrogates.^28–32) These CO surrogates can generate CO under mild conditions in a closed reaction vessel, and this CO is consumed during carbonylation in a highly safe and efficient manner. We hypothesized that this external-CO-free carbonylation would be a powerful tool to directly afford not only [1,1′-binaphthalene]-2,2′-dicarboxylates, but also other axially chiral dicarboxylates from the corresponding ditriflates without handling toxic CO gas or strongly basic compounds. We report herein a practical synthetic method for various axially chiral dicarboxylates in an enantiomerically pure form using phenyl formate as a CO surrogate.

We first optimized the reaction conditions for Pd-catalyzed phenoxycarbonylation of (R)-[1,1′-binaphthalene]-2,2′-diyl ditriflate (1), which was easily prepared from enantiomerically pure (R)-1,1′-bi-2-naphthol,³³⁾ using phenyl formate as a CO surrogate, as shown in Table 1. Following Takaya’s procedure with CO gas,¹⁹⁾ we chose Pd(OAc)₂ as a Pd source, 1,3-bis(diphenylphosphino)propane (DPPP) as a ligand, ethyldiisopropylamine as a base, and dimethyl sulfoxide (DMSO) as a solvent. However, only a trace amount of the desired phenyl ester 2 was obtained under the external-CO-free conditions (entry 1). Solvent screening (entries 2–5) yielded N,N-dimethylformamide (DMF) as the solvent of choice (entry 5), though a certain amount of monocarbonylated by-product 3 was still present. A review of other phosphine ligands at slightly raised temperatures (entries 6–11) showed that DPPP was the best ligand.³⁴⁾ Notably, subtle differences in the ligand structure significantly influenced the outcome of the reaction. Xantphos and tri(tert-butyl)phosphine, which were effective in the aryloxycarbonylation of haloarenes,^28,29,31,32) were both not suitable for the reaction of 1 with phenyl formate, probably owing to steric repulsion between the substrate and the substituents of these ligands. Decreasing of the amount of DPPP improved the yield (entries 12, 13), probably because of the suppression of excess ligation to the Pd center. We also tested other bases (entries 14–20); bulky amines such as ethyldiisopropylamine (entry 12) and 2,2,6,6-tetramethylpiperidine (TMP) (entry 16) were found to be most effective. This tendency is similar to that found in Takaya’s studies.¹⁹⁾ Further studies revealed that the yield could be improved by removing the solvent (entry 21), increasing the amounts of phenyl formate and base, raising the temperature to 120°C (entry 22), and increasing the reaction time (entry 23). It was confirmed that no racemization occurred during this carbonylation: enantiomeric purity of 2 obtained from ditriflate 1 (>99% ee) was measured to be >99% ee by chiral HPLC.

Table 1. Optimization of Reaction Conditions for Carbonylation

Entry	Solvent	Ligand (mol%)	Base (equiv)	X (equiv)	Temp. (°C)	Yield (%)
						2	3
1	DMSO	DPPP (25)	iPr2NEt (5)	4	80	Trace	Trace
2	Toluene	DPPP (25)	iPr2NEt (5)	4	80	17	26
3	DCE	DPPP (25)	iPr2NEt (5)	4	80	3	2
4	CH3CN	DPPP (25)	iPr2NEt (5)	4	80	15	72
5	DMF	DPPP (25)	iPr2NEt (5)	4	80	32	45
6	DMF	DPPP (25)	iPr2NEt (5)	4	100	47	17
7	DMF	DPPE (25)	iPr2NEt (5)	4	100	Trace	33
8	DMF	DPPB (25)	iPr2NEt (5)	4	100	Trace	Trace
9	DMF	Xantphos (25)	iPr2NEt (5)	4	100	6	50
10	DMF	PCy3 (50)	iPr2NEt (5)	4	100	Trace	Trace
11	DMF	P(t-Bu)3·HBF4 (50)	iPr2NEt (5)	4	100	Trace	Trace
12	DMF	DPPP (15)	iPr2NEt (5)	4	100	65	Trace
13	DMF	DPPP (10)	iPr2NEt (5)	4	100	56	10
14	DMF	DPPP (15)	NMI (5)	4	100	6	Trace
15	DMF	DPPP (15)	NBu3 (5)	4	100	47	14
16	DMF	DPPP (15)	TMP (5)	4	100	62	6
17	DMF	DPPP (15)	DABCO (5)	4	100	34	28
18	DMF	DPPP (15)	DBU (5)	4	100	Trace	4
19	DMF	DPPP (15)	NaHCO3 (5)	4	100	45	Trace
20	DMF	DPPP (15)	Cs2CO3 (5)	4	100	8	Trace
21	—a)	DPPP (15)	iPr2NEt (5)	4	100	69	18
22	—a)	DPPP (15)	iPr2NEt (12)	8	120	79	0
23b)	—a)	DPPP (15)	iPr2NEt (12)	8	120	80	0

a) Under neat condition. b) 36 h. DCE: 1,2-dichloroethane, DPPP: 1,3-bis(diphenylphosphino)propane, DPPE: 1,2-bis(diphenylphosphino)ethane, DPPB: 1,4-bis(diphenylphosphino)butane, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, NMI: N-methylimidazole, TMP: 2,2,6,6-tetramethylpiperidine, DABCO: 1,4-diazabicyclo[2.2.2]octane, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

Under the optimized conditions (Table 1, entry 23), various enantiomerically pure ditriflates bearing axial chirality were examined for phenoxycarbonylation (Table 2). Substituents at the 6 and 6′ positions of the 2,2′-binaphthyl scaffold did not adversely affect the carbonylation reaction; they instead afforded the desired dicarboxylates 4–7 in good yield. Notably, base-sensitive ester moieties tolerated the reaction conditions to give 7. The only exception was the derivative bearing nitro groups (for compound 8). The reaction proceeded smoothly with a partially saturated substrate to give 9 in high yield. Unfortunately, ditriflate with methyl groups on the 3 and 3′ positions failed to afford product 10. Instead, the monophenoxycarbonylated compound was obtained in modest yield. This carbonylation method was also applicable to the synthesis of spirocyclic dicarboxylate 11, which was produced in good yield. Methyl-substituted biphenyl 12, albeit in racemic form, was also synthesized by this phenoxycarbonylation.

Table 2. Substrate Scope of Carbonylation

^a Monophenoxycarbonylated product was obtained in 47% yield. ^b A racemic substrate was used.

The reaction was tested on gram-scale to evaluate its practicality (Chart 2). To our delight, more than 1 g of 2 was obtained in a single reaction which was conducted in a simple two-necked flask equipped with an empty balloon without any difficulties.

Chart 2. Gram-Scale Synthesis of 2

Owing to their relative electrophilicity when compared with alkyl esters, the phenyl ester groups could be easily derivatized to other functional groups using nucleophiles (Chart 3). Hydrolysis of 2 afforded dicarboxylic acid 13, and reduction using lithium aluminum hydride gave diol 14 in high yield. Bis(2-(trimethylsilyl)ethyl) ester 15, a useful protected analogue of dicarboxylic acid,^8,35) was obtained via ester exchange. Moreover, 2 was converted into diamide 16 in good yield.

Chart 3. Derivatization of Diphenyl Ester Product 2

In summary, a novel and practical synthetic method to produce axially chiral dicarboxylates was developed using Pd-catalyzed external-CO-free carbonylation with phenyl formate as a CO surrogate. Binaphthyl and other ditriflates, which were readily prepared from the corresponding enantiomerically pure diols, were directly converted to dicarboxylates, and they can be used as potential intermediates of chiral ligands and organocatalysts. Without using a strong base or CO gas from a cylinder, the reaction can be conducted in a safe and practical manner. Furthermore, gram-scale synthesis of dicarboxylates and subsequent derivatization are readily feasible. Since various axially chiral diols are commercially available in the enantiomerically pure form, the present reaction can offer a general, rapid access to axially chiral dicarboxylates that would help accelerate the development of more efficient asymmetric transformations.

Acknowledgments

We are grateful to Professor Masato Koreeda (University of Michigan) for helpful discussion. This work was supported by JSPS KAKENHI (15H04634 to K.M., 15K18834 to H.K.), and by a Grant for The Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and Japan Agency for Medical Research and Development (AMED).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials (detailed experimental procedure, physical data, and NMR spectra of isolated products).

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