N-Triflylphosphorimidoyl Trichloride: A Versatile Reagent for the Synthesis of Strong Chiral Brønsted Acids

Abstract

A series of strong Brønsted acids has been synthesized in high yields using N-triflylphosphorimidoyl trichloride as reagent. The syntheses proceed efficiently with electron-rich, electron-deficient, and sterically hindered substrates.

Key words

N-triflylphosphorimidoyl trichloride - Brønsted acid - N-triflylphosphoramide - N-triflylthiophosphoramide - N,N′-bis(triflyl)phosphoramidimidate

Over the last decade, chiral phosphoric acid catalysts have attracted great attention because of their remarkable reactivity and ease of handling.[1] Since Akiyama and Terada had reported successful application of BINOL-derived phosphoric acids or their salts as catalysts in Mannich reactions, numerous catalyst variations have been developed by modifying the 3,3′-substituents of the BINOL backbone.[2] Furthermore, the Yamamoto group demonstrated that the activity of phosphoric acid catalysts can be enhanced by replacing the OH group with an N-triflyl group.[3] Due to the higher acidity of the resulting N-triflylphosphoramides, several groups successfully reported asymmetric reactions which could not be accomplished using the original phosphoric acids.[4] However, despite their utility, the synthesis of these catalysts requires a two-step procedure which involves a solvent change and a relatively long reaction time under heating.[3] [5] During our studies on the development of even stronger Brønsted acid catalysts, we recently reported a practical method to introduce N-triflyl groups to molecular structures using N-triflylphosphorimidoyl trichloride (1) as a reagent (Scheme [1]). We have prepared this substance in a solid-state reaction between phosphorous pentachloride (PCl₅) and trifluoromethansulfonylamide under reduced pressure.[6] When compound 1 was reacted with different BINOLs (2) in the presence of triethylamine or ­diisopropylethylamine in THF or toluene, intermediate 3 was formed within ten minutes. Adding 0.5 equivalent of ammonia or hexamethyldisilazane afforded the corresponding N-triflylphosphoramidimidate 4 in situ. With further heating under reflux, novel imidodiphosphorimidates (IDPi) 5 were obtained successively. On the basis of this observation, we wondered if it was possible to establish a new approach to Yamamoto catalysts, simply by hydrolyzing intermediate 3. Herein we report the fruition of these efforts with a general approach to various N-triflyl-substituted chiral Brønsted acids.

Scheme 1 Preparation of N-triflylphosphorimidoyl trichloride 1 and its application to the synthesis of imidodiphosphorimidates 5

Indeed, most BINOLs 2a–f, upon reaction with reagent 1 in dichloromethane and DIPEA, gave the corresponding intermediate 3 within 10 minutes. With sterically hindered BINOL 2g, the reaction took 1 hour until completion. Further reaction with water required only 10 minutes with chlorides 3a–f and 1 hour with compound 3g to furnish the corresponding acids. Products 6a–g were obtained in >80% yield regardless of the electronic or steric properties of the BINOL starting material (Table [1]).

Table 1 Substrate Scope of the Yamamoto-Type Brønsted Acid Synthesis^a

Entry	Product	Config.	R	Yield (%)
1	6a	S	Ph	98
2	6b	R	4-PhC6H4	97
3	6c	S	1-Naph	90
4	6d	R	2-Naph	96
5	6e	S	9-phenanthryl	89
6	6f	S	3,5-(CF3)2C6H3	97
7	6g	S	2,4,6-i-Pr3C6H2 b	82

^a Reactions were performed with 2 (1.0 equiv), 1 (1.1 equiv), and DIPEA (5.0 equiv) in CH₂Cl₂ (0.25 mL) for 10 min, and then H₂O (20 μL) was added to hydrolyze the intermediates 3.

^b In this case, substitution and hydrolysis reactions each took 1 h.

Scheme 2 Synthesis of N-triflylthiophosphoramides and N,N′-bis(triflyl)phosphoramidimidates

Next, we applied our method to synthesize other strong Brønsted acids (Scheme [2]). In 2008, the Yamamoto group exchanged the oxo group of their catalysts with a thio group. The resulting more acidic N-triflylthiophosphoramides successfully enabled catalytic enantioselective protonation reactions.[7] Later, our group exchanged the oxo group with an N-triflyl imino group expecting an even further increase in acidity.[8] In order to also obtain these two stronger acid motifs, intermediate 3 was reacted with H₂S or with triflamide, respectively. The target acids 7 and 8 were readily obtained within 20 minutes or 1 day, depending on the substrates.

In summary, we have established a simple and practical route to synthesize strong chiral Brønsted acids. The method is effective for the preparation of N-triflylphosphor­amides with electron-deficient, electron-rich, and sterically demanding substrates.[9] Furthermore, both of N-triflylthiophosphoramides and N,N′-bis(triflyl)phosphoramidimidates were prepared in high yields within one day. Further use of reagent 1 in catalyst development is currently underway in our laboratory.

Acknowledgment

We thank the technicians of our group and the analytical departments of the institute for support of this work. Funding from the Max-Planck-Society, the European Research Council (Advanced Grant CHAOS) and the DFG (Leibniz Award to BL) is gratefully acknowledged. This work is part of the Cluster of Excellence RESOLV (EXC 1069) funded by DFG.

• References and Notes

• 1a Akiyama T. Chem. Rev. 2007; 107: 5744
• 1b Terada M. Synthesis 2010; 1929
• 1c Kampen D. Reisinger CM. List B. Top Curr. Chem. 2010; 291: 395
• 1d Asymmetric Organocatalysis Workbench Edition . List B. Maruoka K. Thieme; Stuttgart: 2012
• 1e Parmar D. Sugiono E. Raja S. Rueping M. Chem. Rev. 2014; 114: 9047
• 1f Akiyama T. Mori K. Chem. Rev. 2015; 115: 9277
• 2a Akiyama T. Itoh J. Yokota K. Fuchibe K. Angew. Chem. Int. Ed. 2004; 43: 1566
• 2b Uraguchi D. Terada M. J. Am. Chem. Soc. 2004; 126: 5356

See also:
• 2c Hatano M. Moriyama K. Maki T. Ishihara K. Angew. Chem. Int. Ed. 2010; 49: 3823
• 2d Klussmann M. Ratjen L. Hoffmann S. Wakchaure V. Goddard R. List B. Synlett 2010; 2189
• 2e Terada M. Kanomata K. Synlett 2011; 1255
• 2f Mao Z. Mo F. Lin X. Synlett 2016; 27: 546
• 2g Tay J.-H. Nagorny P. Synlett 2016; 27: 551
• 2h Lai Z. Sun J. Synlett 2016; 27: 555
• 2i Lebée C. Blanchard F. Masson G. Synlett 2016; 27: 559
• 2j Qin L. Wang P. Zhang Y. Ren Z. Zhang X. Da C.-S. Synlett 2016; 27: 571
• 2k Jiang F. Zhang Y.-C. Yang X. Zhu Q.-N. Shi F. Synlett 2016; 27: 575
• 2l Kanomata K. Terada M. Synlett 2016; 27: 581
• 2m Zhou Y. Liu X.-W. Gu Q. You S.-L. Synlett 2016; 27: 586
• 2n Monaco MR. Properzi R. List B. Synlett 2016; 27: 591
• 2o Monaco MR. Pupo G. List B. Synlett 2016; 27: 1027
• 3 Nakashima D. Yamamoto H. J. Am. Chem. Soc. 2006; 128: 9626
• 4a Enders D. Narine AA. Toulgoat F. Bisschops T. Angew. Chem. Int. Ed. 2008; 47: 5661
• 4b Rueping M. Nachtsheim BJ. Moreth SA. Bolte M. Angew. Chem. Int. Ed. 2008; 47: 593
• 4c Rueping M. Theissmann T. Kuenkel A. Koenigs RM. Angew. Chem. Int. Ed. 2008; 47: 6798
• 4d Zeng M. Kang Q. He Q.-L. You S.-L. Adv. Synth. Catal. 2008; 350: 2169
• 4e Lee S. Kim S. Tetrahedron Lett. 2009; 50: 3345
• 4f Enders D. Seppelt M. Beck T. Adv. Synth. Catal. 2010; 352: 1413
• 4g Guan H. Wang H. Huang D. Shi Y. Tetrahedron 2012; 68: 2728
• 4h Guo B. Schwarzwalder G. Njardarson JT. Angew. Chem. Int. Ed. 2012; 51: 5675
• 4i Han Z.-Y. Chen D.-F. Wang Y.-Y. Guo R. Wang P.-S. Wang C. Gong L.-Z. J. Am. Chem. Soc. 2012; 134: 6532
• 4j Borovika A. Nagorny P. Tetrahedron 2013; 69: 5719
• 4k Cui Y. Villafane LA. Clausen DJ. Floreancig PE. Tetrahedron 2013; 69: 7618
• 4l Enders D. Rembiak A. Seppelt M. Tetrahedron Lett. 2013; 54: 470
• 4m Wang P.-S. Li K.-N. Zhou X.-L. Wu X. Han Z.-Y. Guo R. Gong L.-Z. Chem. Eur. J. 2013; 19: 6234
• 4n Hong X. Küçük HB. Maji MS. Yang Y.-F. Rueping M. Houk KN. J. Am. Chem. Soc. 2014; 136: 13769
• 4o Kong L. Han X. Jiao P. Chem. Commun. 2014; 50: 14113
• 4p Li N. Chen D.-F. Wang P.-S. Han Z.-Y. Gong L.-Z. Synthesis 2014; 46: 1355
• 4q Wu X. Li M.-L. Wang P.-S. J. Org. Chem. 2014; 79: 419
• 4r Lin J.-S. Yu P. Huang L. Zhang P. Tan B. Liu X.-Y. Angew. Chem. Int. Ed. 2015; 54: 7847
• 4s Liu J. Zhou L. Wang C. Liang D. Li Z. Zou Y. Wang Q. Goeke A. Chem. Eur. J. 2016; 22: 6258

See also:
• 4t Hatano M. Ishihara H. Goto Y. Ishihara K. Synlett 2016; 27: 564
• 5 Rueping M. Nachtsheim BJ. Koenigs RM. Ieawsuwan W. Chem. Eur. J. 2010; 16: 13116
• 6a Kaib PS. J. Schreyer L. Lee S. Properzi R. List B. Angew. Chem. Int. Ed. 2016; 55: 13200
• 6b Xie Y. Cheng GJ. Lee S. Kaib PS. J. Thiel W. List B. J. Am. Chem. Soc. 2016; 138: 14538
• 6c Lee S. Kaib PS. J. List B. J. Am. Chem. Soc. 2017; 139: 2156
• 7a Cheon CH. Yamamoto H. J. Am. Chem. Soc. 2008; 130: 9246
• 7b Cheon CH. Yamamoto H. Org. Lett. 2010; 12: 2476
• 7c Yokosaka T. Kanehira T. Nakayama H. Nemoto T. Hamada Y. Tetrahedron 2014; 70: 2151
• 7d Sai M. Yamamoto H. J. Am. Chem. Soc. 2015; 137: 7091
• 8 Kaib PS. J. List B. Synlett 2016; 27: 156
• 9 General Procedure: In a flame-dried vial under Ar, the corresponding (S)- or (R)-BINOL (1.0 equiv) was dissolved in anhyd CH₂Cl₂ (0.20 M). TfNPCl₃ (1.1 equiv) and DIPEA (5.0 equiv) were added and the mixture was stirred for 10 min at ambient temperature. After the full consumption of the starting material (as indicated by TLC), the second nucleophile was added (20 μL for H₂O, 2.0 equiv for H₂S and TfNH₂). After an additional 10 min of stirring, the reaction mixture was dried over Na₂SO₄, filtered, concentrated, and purified by column chromatography on silica gel to afford the desired product as a salt. Acidification in CH₂Cl₂ with HCl (3.0 M) followed by drying under reduced pressure afforded the desired product as a free acid.
• 10 Spectroscopic Data of (S)-6a: ¹H NMR (501 MHz, CD₂Cl₂): δ = 8.14 (s, 1 H), 8.09 (s, 1 H), 8.05 (dd, J = 8.4, 1.1 Hz, 1 H), 8.00 (dd, J = 8.2, 1.1 Hz, 1 H), 7.67–7.72 (m, 2 H), 7.60 (ddt, J = 10.4, 6.0, 1.9 Hz, 3 H), 7.48 (dd, J = 8.4, 7.0 Hz, 2 H), 7.39 (m, 7 H), 7.29 (dd, J = 8.6, 1.1 Hz, 1 H), 7.22 (ddd, J = 8.4, 6.7, 1.3 Hz, 1 H). ¹³C NMR (126 MHz, CD₂Cl₂): δ = 143.53 (d, J = 11.7 Hz), 142.73 (d, J = 9.4 Hz), 136.01, 135.98, 133.55, 133.53, 133.36, 133.34, 131.96, 131.93, 131.83, 131.80, 130.00, 129.71, 128.54, 128.53, 128.47, 128.11, 128.09, 127.87, 126.95, 126.94, 126.79, 126.69, 126.62, 126.38, 122.21 (d, J = 2.0 Hz), 122.19 (d, J = 3.0 Hz), 118.71 (qd, J = 322.1, 1.6 Hz). ¹⁹F NMR (471 MHz, CD₂Cl₂): δ = –77.8. ³¹P NMR (203 MHz, CD₂Cl₂): δ = –5.8. HRMS (ESI): m/z [M – H⁺] calcd for C₃₃H₂₀F₃NO₅PS: 630.0757; found: 630.0759.