Chemoselective Synthesis of α-Amino-α-cyanophosphonates by

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Chemoselective Synthesis of α‑Amino-α-cyanophosphonates by Reductive Gem-Cyanation−Phosphonylation of Secondary Amides Ting-Ting Chen, Ai-E Wang,*,†,‡ and Pei-Qiang Huang*,†,‡ †

Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, China ‡ State Key Laboratory of Applied Organic Chemistry Lanzhou University, Lanzhou 730000, China

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ABSTRACT: A novel approach to α-amino-α-cyanophosphonates has been developed. The method features a Tf2O-mediated reductive geminal cyanation/phosphonylation of secondary amides. Mild reaction conditions, high bond-forming efficiency, inexpensive readily available starting materials, and good to excellent yields with wide functional group compatibility constitute the main advantages of this method. The protocol can be run on a gram scale. α-Aminophosphonic acids are isosteres of α-amino acids in which the planar carboxyl group is replaced by a tetrahedral phosphonic acid moiety. α-Aminophosphonic acids and their phosphonate esters as well as phosphono peptides exhibit diverse biological activities and have found wide applications in the areas of biological and medicinal chemistry as well as agriculture.1 They have also been used as important synthetic intermediates2 and organocatalysts3 in organic synthesis. On the other hand, α-aminonitriles are common structural motifs found in many bioactive natural products and pharmaceutical agents.4,5c They are also versatile building blocks that can be readily converted to α-amino acids, αamino carbonyl compounds, vicinal diamines, β-amino alcohols, as well as a wide range of nitrogen heterocycles.5 Owing to the wide range of activity and importance of αaminophosphonic acids and α-aminonitriles, the preparation of trifunctional α-amino-α-cyanophosphonic acid derivatives 1 (Scheme 1), which combine both of the above characteristic structures, is therefore very attractive.

However, compared to the tremendous number of reports on the preparation of α-aminophosphonic acid derivatives6 and αaminonitriles,5a,c very few examples are known for the synthesis of α-amino-α-cyanophosphonic acid derivatives (Scheme 1).7 Moreover, all of those methods are based on specific multifunctional starting materials, and it takes three to four steps to prepare them. Consequently, the development of a general and efficient method for the synthesis of α-amino-αcyanophosphonic acids from simple and readily accessible starting materials is highly desirable. Amides are a class of readily available and stable compounds which are widespread in nature.8 Due to their low electrophilicity, breakthroughs for the chemoselective and direct conversion of amides into functional groups at lower oxidation states have not been achieved until recent years.9−17 In this respect, several groups have reported the reductive cyanation14 and alkylation/cyanation15 of amides for the synthesis of αamino nitriles (Scheme 2). Using Schwartz’s reagent, Zhao has developed a reductive phosphonylation of amides for the direct transformation of amides into α-aminophosphonates.16 In addition, our group has reported the reductive bisphosphonylation of amides for the synthesis of α-amino bisphosphonates.17 In this context, we envisioned that the reductive geminal cyanation/phosphonylation of amides, with a C−C bond and a C−P bond formed at the carbonyl carbon, would provide an attractive method for the efficient synthesis of α-amino-αcyanophosphonic acid derivatives. As part of our ongoing interest in developing new synthetic methods based on activation of amides with trifluoromethanesulfonic anhydride (Tf2O),12a,b,d−f,h,14e,g,17 we report herein the Tf2O-mediated

Scheme 1. Synthetic Routes to α-Amino-α-cyanophosphonic Acid Derivatives

Received: April 10, 2019

© XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.9b01257 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

As shown in Table 2, under the optimized conditions, a variety of secondary amides underwent reductive geminal cyanation/ phosphonylation with TMSCN and diethyl phosphite to give the corresponding α-amino-α-cyanophosphonates in good isolated yields. The electronic properties of aroyl amides do not have an obvious influence on the reaction. High yields were obtained for benzamides bearing electron-donating (1b, 1d, 1e) or electron-withdrawing (1j−o) groups at the para position of the phenyl ring (84−98% yields). The steric effects of the substituents seem to have some influence. A slight decrease in yields was observed for benzamides 2c and 2h, which have substituents at the ortho position of the ring (71% and 82% yields, respectively). The reaction is widely functional group tolerant and highly chemoselective. Consistent with the observations by Charette,11b−d not only halogen (1f−i), nitro (1k), cyano (1l), and azo (1m) groups but also ester (1o) and ketone (1n) groups are largely compatible with this Tf2Omediated process to furnish the desired α-amino-α-cyanophosphonates in high yields. 2-Naphthamide 2p was also a suitable substrate for the reaction. The N-substituents on the secondary aroyl amides could vary from isopropyl to other sec-alkyl (1q−s) and n-alkyl (1t−y) substituents and benzyl (1z) or allyl (1aa) groups, and some functional groups such as ether (1s and 1u), ester (1v), and halogen (1w and 1x) groups are tolerated. Interestingly, for N(4-bromobutyl)benzamide 2y, the tandem cyanation/phosphonylation and cyclization occurred to afford the α-amino-αcyanophosphonate 1y. The introduction of an N-tert-butyl and N-phenyl group to the secondary amide, however, completely abolished product formation (1ab and 1ac). Furthermore, the branched nonenolizable pivalamide 2ad is also a suitable substrate for the reaction. No desired product was obtained for enolizable alkanamides. Instead of imidoyl cyanide, enamine derivative was formed after reaction with TMSCN. Besides diethyl phosphite, reductive geminal cyanation/ phosphonylation of amides with different phosphites was also studied. The reaction with dimethyl phosphite and diisopropyl phosphite gave the expected products 1ae and 1af in 92% and 85% yield, respectively, while no product was obtained for ditert-butyl and diphenyl phosphite (1ag and 1ah). Diphenylphosphine oxide is inert for the reaction (1ai). To explore the practical utility of this transformation in organic synthesis, a gram-scale preparation of α-amino-αcyanophosphonate 1z from amides 2z (1.06 g, 5.00 mmol) was performed, which furnished the desired product 2z in 80% yield. It is worth mentioning that most of the products obtained are stable compounds, which can be purified by flash chromatography and kept stable even after storage at room temperature for one year, except for ortho-substituted 1c and 1h, which are labile. Interestingly, 1w and 1x, which are prone to form aziridiniums,19 are also stable. In conclusion, we have developed a novel and general method for the preparation of α-amino-α-cyanophosphonates. The method features a Tf2O-mediated reductive geminal cyanation/ phosphonylation of secondary amides. The reaction is mild, efficient, and tolerant of a wide range of functional groups, providing the corresponding α-amino-α-cyanophosphonates in good to excellent yields. Further applications of this method are currently underway in our laboratory.

Scheme 2. Reported Methods for the Direct Conversion of Amides to α-Aminonitriles and α-Aminophosphonates and Our Proposal for the Synthesis of α-Amino-αcyanophosphonates from Amides

reductive geminal cyanation/phosphonylation of secondary amides for the preparation of α-amino-α-cyanophosphonates. The initial investigation began with the reaction of Tf2Oactivated N-isopropylbenzamide 2a with TMSCN and diethyl phosphite (Table 1). When a solution of amide 2a (1.0 equiv) Table 1. Reaction Optimization on Reductive Geminal Cyanation/Phosphonylation of Secondary Amidesa

entry

phosphite (equiv)

base

temp (°C)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12

2.0 2.0 2.0 2.0 2.0 2.0 1.5 1.3 1.3 1.1 1.3 1.3

None None None DBU (2.0 equiv) K2CO3 (2.0 equiv) Na2CO3 (2.0 equiv) K2CO3 (2.0 equiv) K2CO3 (2.0 equiv) Na2CO3 (2.0 equiv) K2CO3 (2.0 equiv) K2CO3 (1.8 equiv) K2CO3 (1.5 equiv)

0 to rt rt 45 rt rt rt rt rt rt rt rt rt

81 (73c) 81 55 90 96 (90c) 96 (89c) 96 (92c) 95 (92c) 93 (85c) 94 (88c) 95 (90c) 93 (88c)

a Reaction conditions: amide 2a (0.50 mmol), Tf2O (0.55 mmol), 2F-Pyr (0.60 mmol), CH2Cl2 (0.2 M), 0 °C, 10 min; TMSCN (0.60 mmol), 0 °C to rt, 3 h; HPO(OEt)2, 10 h. bDetermined by 1H NMR with 1,3,5-trimethoxybenzene as internal standard. cIsolated yield.

and 2-F-Pyr. (1.2 equiv) in CH2Cl2 was treated successively with Tf2O (1.1 equiv, 0 °C, 10 min), TMSCN (1.2 equiv, 0 °C to rt, 3 h), and HPO(OEt)2 (2.0 equiv, 0 °C to rt, 10 h), the expected αamino-α-cyanophosphonate product 1a was isolated in a yield of 73% (entry 1). Addition of HPO(OEt)2 in the presence of organic/inorganic bases (2.0 equiv) improved the yield in most cases (entries 4−6, see the SI for details), probably due to the influence of the base on the tautomerism, favoring the phosphite form.18 The highest yields were obtained with K2CO3 and Na2CO3, providing product 1a in 90% and 89% isolated yield, respectively (entries 5 and 6). Further optimization showed that K2CO3 was the optimal base, in the presence of which the amount of diethyl phosphite can be decreased to 1.3 equiv without much influence on the yield (entry 8). B

DOI: 10.1021/acs.orglett.9b01257 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 2. Substrate Scopes for Reductive Geminal Cyanation/Phosphonylation of Secondary Amidesa

a Reaction conditions: amide (0.50 mmol), Tf2O (0.55 mmol), 2-F-Pyr (0.60 mmol), CH2Cl2 (0.2 M), 0 °C, 10 min; TMSCN (0.60 mmol), 0 °C to rt, 3 h; HPO(OR)2 (0.65 mmol), K2CO3 (1.0 mmol), 10 h. bMolecular ion peaks were not observed in their HRMS spectra, while [M − HCN]+ peaks appeared as the most intensive ones. (See the SI for details). cRun on 5.0 mmol scale.

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DOI: 10.1021/acs.orglett.9b01257 Org. Lett. XXXX, XXX, XXX−XXX

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(8) The Amide Linkage: Structural Significance in Chemistry, Biochemistry and Materials Science; Greenberg, A., Breneman, C. M., Liebman, J. F., Eds.; Wiley: New York, 2003. (9) For reviews, see: (a) Seebach, D. Angew. Chem., Int. Ed. 2011, 50, 96. (b) Pace, V.; Holzer, W. Aust. J. Chem. 2013, 66, 507. (c) Pace, V.; Holzer, W.; Olofsson, B. Adv. Synth. Catal. 2014, 356, 3697. (d) Sato, T.; Chida, N. Org. Biomol. Chem. 2014, 12, 3147. (e) Kaiser, D.; Maulide, N. J. Org. Chem. 2016, 81, 4421. (f) Sato, T.; Yoritate, M.; Tajima, H.; Chida, N. Org. Biomol. Chem. 2018, 16, 3864. (g) Kaiser, D.; Bauer, A.; Lemmerer, M.; Maulide, N. Chem. Soc. Rev. 2018, 47, 7899. (h) Huang, P.-Q. Huaxue Xuebao 2018, 76, 357. (10) For pioneering works, see (a) Ghosez, L.; Haveaux, B.; Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1969, 8, 454. (b) Marchand-Brynaert, J.; Ghosez, L. J. Am. Chem. Soc. 1972, 94, 2869. (c) Falmagne, J.-B.; Escudero, J.; Taleb-Sahraoui, S.; Ghosez, L. Angew. Chem., Int. Ed. Engl. 1981, 20, 879. (d) Sisti, N. J.; Fowler, F. W.; Grierson, D. S. Synlett 1991, 1991, 816. (e) Charette, A. B.; Grenon, M. Can. J. Chem. 2001, 79, 1694. (11) For recent selected examples, see: (a) Movassaghi, M.; Hill, M.; Ahmad, O. K. J. Am. Chem. Soc. 2007, 129, 10096. (b) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18. (c) Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817. (d) Bechara, W. S.; Pelletier, G.; Charette, A. B. Nat. Chem. 2012, 4, 228. (e) Oda, Y.; Sato, T.; Chida, N. Org. Lett. 2012, 14, 950. (f) Pelletier, G.; Charette, A. B. Org. Lett. 2013, 15, 2290. (g) Mewald, M.; Medley, J. W.; Movassaghi, M. Angew. Chem., Int. Ed. 2014, 53, 11634. (h) Cyr, P.; Régnier, S.; Bechara, W. S.; Charette, A. B. Org. Lett. 2015, 17, 3386. (i) Romanens, A.; Bélanger, G. Org. Lett. 2015, 17, 322. (j) White, K. L.; Mewald, M.; Movassaghi, M. J. Org. Chem. 2015, 80, 7403. (k) Gregory, A. W.; Chambers, A.; Hawkins, A.; Jakubec, P.; Dixon, D. Chem. - Eur. J. 2015, 21, 111. (l) Xie, L.-G.; Dixon, D. J. Chem. Sci. 2017, 8, 7492. (m) Yoritate, M.; Takahashi, Y.; Tajima, H.; Ogihara, C.; Yokoyama, T.; Soda, Y.; Oishi, T.; Sato, T.; Chida, N. J. Am. Chem. Soc. 2017, 139, 18386. (n) Tona, V.; Maryasin, B.; de la Torre, A.; Sprachmann, J.; González, L.; Maulide, N. Org. Lett. 2017, 19, 2662. (o) Xie, L.-G.; Dixon, D. J. Nat. Commun. 2018, 9, 2841. (p) Hiraoka, S.; Matsumoto, T.; Matsuzaka, K.; Sato, T.; Chida, N. Angew. Chem., Int. Ed. 2019, 58, 4381. (q) Ielo, L.; Touqeer, S.; Roller, A.; Langer, T.; Holzer, W.; Pace, V. Angew. Chem., Int. Ed. 2019, 58, 2479. (12) For selected contributions from our group, see: (a) Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang, Y.; Huang, P.-Q. Angew. Chem., Int. Ed. 2010, 49, 3037. (b) Xiao, K.-J.; Wang, A.-E; Huang, P.-Q. Angew. Chem., Int. Ed. 2012, 51, 8314. (c) Huang, P.-Q.; Ou, W.; Han, F. Chem. Commun. 2016, 52, 11967. (d) Zheng, J.-F.; Hu, X.-N.; Xu, Z.; Cai, D.C.; Shen, T.-L.; Huang, P.-Q. J. Org. Chem. 2017, 82, 9693. (e) Wang, A.-E; Yu, C.-C.; Chen, T.-T.; Liu, Y.-P.; Huang, P.-Q. Org. Lett. 2018, 20, 999. (f) Chen, H.; Ye, J.-L.; Huang, P.-Q. Org. Chem. Front. 2018, 5, 943. (g) Hu, X.-N.; Shen, T.-L.; Cai, D.-C.; Zheng, J.-F.; Huang, P.-Q. Org. Chem. Front. 2018, 5, 2051. (h) Huang, Y.-H.; Wang, S.-R.; Wu, D.-P.; Huang, P.-Q. Org. Lett. 2019, 21, 1681. (13) For umpolung of the α-position of amides, see: (a) Kaiser, D.; de la Torre, A.; Shaaban, S.; Maulide, N. Angew. Chem., Int. Ed. 2017, 56, 5921. (b) de la Torre, A.; Kaiser, D.; Maulide, N. J. Am. Chem. Soc. 2017, 139, 6578. (c) Kaiser, D.; Teskey, C. J.; Adler, P.; Maulide, N. J. Am. Chem. Soc. 2017, 139, 16040. (14) (a) Xia, Q.; Ganem, B. Org. Lett. 2001, 3, 485. (b) Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Angew. Chem., Int. Ed. 2010, 49, 6369. (c) Nakajima, M.; Oda, Y.; Wada, T.; Minamikawa, R.; Shirokane, K.; Sato, T.; Chida, N. Chem. - Eur. J. 2014, 20, 17565. (d) Nakajima, M.; Sato, T.; Chida, N. Org. Lett. 2015, 17, 1696. (e) Huang, P.-Q.; Huang, Y.-H.; Xiao, K.-J.; Wang, Y.; Xia, X. E. J. Org. Chem. 2015, 80, 2861. (f) Fuentes de Arriba, Á . L.; Lenci, E.; Sonawane, M.; Formery, O.; Dixon, D. Angew. Chem., Int. Ed. 2017, 56, 3655. (g) Gao, Y.-J.; Xiao, Z.H.; Liu, L.-X.; Huang, P.-Q. Youji Huaxue 2017, 37, 1189. (h) Takahashi, Y.; Yoshii, R.; Sato, T.; Chida, N. Org. Lett. 2018, 20, 5705. (i) Trillo, P.; Slagbrand, T.; Adolfsson, H. Angew. Chem., Int. Ed. 2018, 57, 12347. (j) Ou, W.; Han, F.; Hu, X.-N.; Chen, H.; Huang, P.Q. Angew. Chem., Int. Ed. 2018, 57, 11354. (k) Yamamoto, S.; Komiya,

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01257. Experimental procedure, product characterization data, and 1H/13C/31P NMR spectra of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Ai-E Wang: 0000-0002-6891-4840 Pei-Qiang Huang: 0000-0003-3230-0457 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support of this work from the National Key R&D Program of China (Grant No. 2017YFA0207302), the National Natural Science Foundation of China (Nos. 21672176 and 21332007), the PCSIRT of Ministry of Education, and the Natural Science Foundation of Fujian Province of China (No. 2014J01062) is gratefully acknowledged.

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DEDICATION This work is dedicated in honor of the 90th birthday of Professor Qing-Yun Chen. REFERENCES

(1) For reviews on the biological activity of α-aminophosphonic acid derivatives, see: (a) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 193. (b) Aminophosphonic and aminophosphinic acids: chemistry and biological activity; Kukhar, V. P., Hudson, H. R., Eds.; John Wiley & Sons: Chichester, 2000. (c) Sieńczyk, M.; Oleksyszyn, J. Curr. Med. Chem. 2009, 16, 1673. (d) Orsini, F.; Sello, G.; Sisti, M. Curr. Med. Chem. 2010, 17, 264. (e) Mucha, A.; Kafarski, P.; Berlicki, Ł. J. Med. Chem. 2011, 54, 5955. (2) (a) Van Speybroeck, V.; Moonen, K.; Hemelsoet, K.; Stevens, C. V.; Waroquier, M. J. Am. Chem. Soc. 2006, 128, 8468. (b) Moonen, K.; Dieltiens, N.; Stevens, C. V. J. Org. Chem. 2006, 71, 4006. (c) Dieltiens, N.; Moonen, K.; Stevens, C. V. Chem. - Eur. J. 2007, 13, 203. (3) (a) Dinér, P.; Amedjkouh, M. Org. Biomol. Chem. 2006, 4, 2091. (b) Tao, Q.; Tang, G.; Lin, K.; Zhao, Y.-F. Chirality 2008, 20, 833. (c) Malmgren, M.; Granander, J.; Amedjkouh, M. Tetrahedron: Asymmetry 2008, 19, 1934. (4) (a) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597. (b) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53, 7902. (5) (a) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359. (b) Otto, N.; Opatz, T. Chem. - Eur. J. 2014, 20, 13064. (c) Kouznetsov, V. V.; Puerto Galvis, C. E. Tetrahedron 2018, 74, 773. (6) For reviews on the synthesis of quaternary α-aminophosphonates: (a) Ordóñez, M.; Sayago, F. J.; Cativiela, C. Tetrahedron 2012, 68, 6369. (b) Bera, K.; Namboothiri, I. N. N. Asian J. Org. Chem. 2014, 3, 1234. (7) (a) Costisella, B.; Gross, H. Tetrahedron 1982, 38, 139. (b) Minami, T.; Tokumasu, S.; Mimasu, R.; Hirao, I. Chem. Lett. 1985, 14, 1099. (c) Fahmy, A. A.; Ismail, N. A.; Hafez, T. S. Phosphorus, Sulfur Silicon Relat. Elem. 1992, 66, 201. (d) Simon, J.; Neidlein, R. Synthesis 2000, 2000, 1101. (e) Vicario, J.; Ezpeleta, J. M.; Palacios, F. Adv. Synth. Catal. 2012, 354, 2641. (f) Kuźnik, A.; Mazurkiewicz, R.; Zieba, M.; Erfurt, K. Tetrahedron Lett. 2018, 59, 3307. D

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Organic Letters Y.; Kobayashi, A.; Minamikawa, R.; Oishi, T.; Sato, T.; Chida, N. Org. Lett. 2019, 21, 1868. (15) (a) Vincent, G.; Guillot, R.; Kouklovsky, C. Angew. Chem., Int. Ed. 2011, 50, 1350. (b) Yanagita, Y.; Nakamura, H.; Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Chem. - Eur. J. 2013, 19, 678. (c) Jäkel, M.; Qu, J.; Schnitzer, T.; Helmchen, G. Chem. - Eur. J. 2013, 19, 16746. (16) Gao, Y.; Huang, Z.; Zhuang, R.; Xu, J.; Zhang, P.; Tang, G.; Zhao, Y. Org. Lett. 2013, 15, 4214. (17) Wang, A.-E; Chang, Z.; Sun, W.-T.; Huang, P.-Q. Org. Lett. 2015, 17, 732. (18) Springs, B.; Haake, P. J. Org. Chem. 1977, 42, 472. (19) Métro, T.-X.; Duthion, B.; Gomez Pardo, D.; Cossy, J. Chem. Soc. Rev. 2010, 39, 89.

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DOI: 10.1021/acs.orglett.9b01257 Org. Lett. XXXX, XXX, XXX−XXX