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Synlett 2022; 33(18): 1837-1840
DOI: 10.1055/a-1892-4443
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Development and Applications of Novel Ligands/Catalysts and Mechanistic Studies on Catalysis

Palladium-Catalyzed Stereospecific Coupling of BINOL-bistriflates and Zinc Cyanide and Applications in the Synthesis of 1,1′-Binaphthyl-2,2′-bisoxazolines (BOXAX)

Zhan Dong
a   Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), and College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. of China
,
Dayou Zhong∗
a   Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), and College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. of China
,
Zi-Meng Li
a   Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), and College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. of China
,
Wei-Min Liu
a   Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), and College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. of China
,
Jing Zhao
a   Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), and College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. of China
,
Wen-Bo Liu∗
a   Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), and College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. of China
b   Wuhan University Shenzhen Research Institute, Shenzhen, Guangdong 518000, P. R. of China
› Author Affiliations

We thank the National Natural Science Foundation of China (21971198), the Natural Science Foundation of Hubei Province (2020CFA036), the Fundamental Research Funds for the Central Universities (2042021kf0193), and Guangdong Basic and Applied Basic Research Foundation (2022A1515012614) for financial support.
› Further Information
 
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Abstract

A palladium-catalyzed synthesis of enantiopure [1,1′-binaphthalene]-2,2′-dicarbonitriles from BINOL-bistriflates and zinc cyanide is reported. This cross-coupling reaction employs a 0.1–5 mol% catalyst loading, and is scalable and stereospecific. The synthetic applications of this reaction are demonstrated by product derivatizations and the synthesis of [1,1′-binaphthalene]-2,2′-bisoxazolines (BOXAX).


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Key words

atropchiral compounds - palladium - cyanation - cross-coupling - stereospecific - chiral ligand

Atropchiral compounds are ubiquitous in the areas of natural products, pharmaceuticals, and asymmetric catalysis.[1] [2] In particular, 1,1′-binaphthalene is one of the most important axially chiral scaffolds, being widely used as catalysts/ligands and chirality induction units in helical materials.[3–5] As a result of their ready availability and configurational stability toward racemization, enantiopure 1,1′-bi-2-naphthol (BINOL) derivatives, most commonly BINOL-bistriflates 1, are often used as starting materials to access 1,1′-binaphthalene-based ligands or their precursors.[6]

[1,1′-Binaphthalene]-2,2′-dicarbonitriles 2 are easily converted into the corresponding dicarboxylic acids,[7] dialdehydes,[7] diamines,[8] bisoxazolines,[9] etc., allowing the downstream synthesis of C 2-symmetric ligands.[10] The development of synthetic approaches to 2a is appealing, however, only limited examples have been revealed (Scheme [1]).[10d] , [11] [12] [13] For instance, Putala’s group have reported a Pd-catalyzed cross-coupling of zinc cyanide and (S)-2,2′-dihalogeno-1,1′-binaphthalenes, achieving a 94% yield (eq. 1).[7] Hagiwara’s group have also demonstrated the synthesis of 2a from [1,1′-binaphthalene]-2,2′-dicarboxylic acid through amide formation and dehydration (eq. 2).[10d] [12a] Recently, Kang and co-workers reported an elegant t BuONO–AlCl3 system for the synthesis of dinitrile 2a from enantioenriched 2,2′-dimethyl-1,1′-binaphthalene (eq. 3).[12b] [c] However, the substrates employed in these methods require multiple-step syntheses, which is tedious and time consuming, especially for large-scale preparations. Moreover, the erosion of the enantioselectivity during the above-mentioned transformations, even slightly (e.g., from >96% to 92% ee, eq. 1, and from >99% to 93% ee), would be problematic for the synthesis of enantiopure chiral ligands. Therefore, the development of a stereospecific method capable of straightforwardly converting BINOL-bistriflates into [1,1′-binaphthalene]-2,2′-dicarbonitriles is of practical importance in terms of cost effectiveness. It should be noted that Ikariya et al. reported a nickel-catalyzed stereospecific cyanation of BINOL-bistriflates, albeit toxic potassium cyanide was employed (eq. 4).[8a] Herein, we report a palladium-catalyzed cross-coupling of BINOL-bistriflates 1 and zinc cyanide to construct axially chiral dinitriles 2.[8b] This stereospecific method features a low catalyst loading, uses a less toxic cyanide source, and can be performed on multigram scale.

Zoom Image
Scheme 1 Previously reported methods and our protocol for the synthesis of [1,1′-binaphthalene]-2,2′-dicarbonitriles

Our study began with an investigation of the palladium-catalyzed cyanation reaction conditions using [1,1′-binaphthalene]-2,2′-diyl bis(trifluoromethanesulfonate) (1a) as a model substrate (see Tables S1–S3 in the Supporting Information). As highlighted in Table [1], the catalyst derived from Pd(OAc)2 (10 mol%) and 1,3-bis(diphenylphosphino)propane (dppp) (20 mol%) in DMF furnished the desired product 2a in an excellent yield with complete retention of the configuration (entry 1, >95% yield, ee >99%). The reaction using the monophosphine PPh3 resulted in a decreased yield (entry 2, 88%). Next, bisphosphine ligands, including dppf, dppm, XantPhos, (rac)-BINAP, dppe, etc., were investigated (entries 3–5 and Table S1). Although all these ligands provided perfect stereoselectivity, the yield was not improved in comparison with dppp; however, XantPhos delivered a similar result. Interestingly, nickel catalysts also enabled the cross-coupling reaction, albeit affording low yields (entries 6 and 7).[8a] On decreasing the catalyst loading from 10 mol% to 0.1 mol%, no decline in the yield was observed (entry 8). Further investigations led to identification of the optimum reaction conditions as follows: Pd(OAc)2 (0.1 mol%), dppp (0.2 mol%), Zn(CN)2 (1.5 equiv) in DMF at 120 ℃ (entry 9).

Table 1 Reaction Optimization for the Palladium-Catalyzed Cyanidation of 1a a

Entry

Variation from the above conditions

Yield (%)b

ee (%)c

1

none

>95

>99

2

PPh3 instead of dppp

88

>99

3

XantPhos instead of dppp

95

>99

4

(rac)-BINAP instead of dppp

73

>99

5

dppe instead of dppp

78

>99

6d

Ni(dppp)Cl2 instead of Pd(OAc)2

38

>99

7d

Ni(dppe)Cl2 instead of Pd(OAc)2

33

>99

8

Pd(OAc)2 (0.1 mol%), dppp (0.2 mol%)

>95

>99

9e

Pd(OAc)2 (0.1 mol%), dppp (0.2 mol%)

>95

>99

a The reactions were conducted with 1a (0.5 mmol), Pd(OAc)2 (10 mol%), ligand (20 mol% for bisphosphine ligands and 40 mol% for monophosphine ligands) and Zn(CN)2 (2.5 mmol) in DMF (1 mL) at 120 °C for 48 h; dppp = 1,3-bis(diphenylphosphino)propane, XantPhos = (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane), (rac)-BINAP = 2,2′-bis(diphenylphosphaneyl)-1,1′-binaphthalene, dppe = 1,2-bis(diphenylphosphino)ethane.

b Isolated yield of 2a.

c Determined by HPLC (Chiralpak AD-H).

d Without any ligand.

e Zn(CN)2 (1.5 equiv) was used.

With optimum reaction conditions established, we next investigated the substrate scope by employing an array of substituted BINOL-bistriflates (Scheme [2]). It should be noted that the catalyst loading varied from 0.1–5 mol% depending on the substrates, as detailed in Scheme [2]. Bistriflates with 6,6′-dimethyl (1b) and difluoro (1c) substituents on the BINOL skeleton provided the corresponding dinitriles 2b and 2c in 94% and 97% yields, respectively. 6,6′-Diaryl and diheteroaryl substituents, including phenyl, p-methylphenyl, 2-furanyl, 2-thienyl, and 3-thienyl were subjected to the reaction conditions, and the corresponding products 2d–h were obtained in excellent yields of 92–98%. We then turned our attention to the steric effect of the substrates. The reactions with 3,3′-dimethyl (1i) and 3,3′-difluoro (1j) substituents were sluggish, but we were able to isolate the corresponding products 2i and 2j in 94% and 76% yields by increasing the catalyst loading to 5 mol% and the temperature to 140 °C, whilst also prolonging the reaction time. Unfortunately, 3,3′-diphenyl-substituted BINOL bistriflate 1k was not tolerated by this method. Finally, octahydro[1,1′-binaphthalene]-2,2′-diyl bistriflate 1l was a feasible substrate, providing product 2l in 95% yield.

Zoom Image
Scheme 2 Substrate scope. The reactions were conducted with 1 (0.5 mmol), Pd(OAc)2 (0.1 mol%), dppp (0.2 mol%) and Zn(CN)2 (1.5 equiv) in DMF (1 mL) at 120 °C for 48 h. a Pd(OAc)2 (0.5 mol%). b Pd(OAc)2 (1.0 mol%). c Reaction time: 24 h. d Pd(OAc)2 (5 mol%) and dppp (10 mol%) were used. e Reaction time: 56 h.

A scale-up reaction and downstream transformations were carried out to demonstrate the utility of this strategy (Scheme [3]). With a 2.0 mol% catalyst loading, the gram-scale reaction of 1a delivered 6.70 g of 2a in quantitative yield. Selective reduction of the cyano groups of 2a formed the corresponding aldehyde 3a in 90% yield, whilst hydration of 2a provided the corresponding amide 4a in 78% yield.[14] A nickel-catalyzed [2+2+2] cycloaddition of 2a and dimethyl 2,2-di(but-2-yn-1-yl)malonate resulted in the formation of bispyridine 5a in 45% yield.[15]

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Scheme 3 A gram-scale reaction and downstream transformations of 2a

Axially chiral C 2-symmetric bisoxazolines have previously been reported as bidentate ligands in stereoselective transition-metal catalysis.[16] We therefore sought to further showcase the application of our strategy by synthesizing a variety of enantiomerically pure 1,1′-binaphthyl-2,2′-bisoxazolines (BOXAX) using 2a as a key substrate (Scheme [4]). To our delight, the single-step condensation of dinitrile 2a with different amino alcohols promoted by zinc triflate formed the desired bisoxazolines 6 in yields of 34–82%. Thus, our protocol offers an efficient and practical alternative to the present synthetic approaches toward BOXAX ligands.

Zoom Image
Scheme 4 Applications for synthesis of 1,1′-binaphthyl-2,2′-bisoxazolines (BOXAX). The reactions were conducted with 2a (1.0 mmol), amino alcohol (5.0 equiv) and Zn(OTf)2 (5.0 equiv) in PhCl at 140 °C for 4 d.

In conclusion, we have developed a palladium-catalyzed cross-coupling of BINOL-bistriflates and zinc cyanide for the synthesis of [1,1′-binaphthalene]-2,2′-dicarbonitrile derivatives. This method features low loading catalyst, readily available starting materials, and stereospecific selectivity enabling complete retention of the axial chirality. The application of this strategy is showcased by derivatizations of the nitrile functional group and the synthesis of BOXAX ligands. Given its scalability and efficiency, we anticipate that this cross-coupling reaction will provide more opportunities for the development of novel chiral ligands.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The Core Research Facilities of CCMS (WHU) are acknowledged for providing access to analytical equipment.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1892-4443.
  • Supporting Information

Corresponding Authors

Dayou Zhong
Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), and College of Chemistry and Molecular Sciences, Wuhan University
Wuhan 430072
P. R. of China   

Wen-Bo Liu
Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), and College of Chemistry and Molecular Sciences, Wuhan University
Wuhan 430072
P. R. of China   

Publication History

Received: 10 May 2022

Accepted after revision: 05 July 2022

Accepted Manuscript online:
05 July 2022

Article published online:
28 July 2022

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Zoom Image
Scheme 1 Previously reported methods and our protocol for the synthesis of [1,1′-binaphthalene]-2,2′-dicarbonitriles
Zoom Image
Scheme 2 Substrate scope. The reactions were conducted with 1 (0.5 mmol), Pd(OAc)2 (0.1 mol%), dppp (0.2 mol%) and Zn(CN)2 (1.5 equiv) in DMF (1 mL) at 120 °C for 48 h. a Pd(OAc)2 (0.5 mol%). b Pd(OAc)2 (1.0 mol%). c Reaction time: 24 h. d Pd(OAc)2 (5 mol%) and dppp (10 mol%) were used. e Reaction time: 56 h.
Zoom Image
Scheme 3 A gram-scale reaction and downstream transformations of 2a
Zoom Image
Scheme 4 Applications for synthesis of 1,1′-binaphthyl-2,2′-bisoxazolines (BOXAX). The reactions were conducted with 2a (1.0 mmol), amino alcohol (5.0 equiv) and Zn(OTf)2 (5.0 equiv) in PhCl at 140 °C for 4 d.