Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Regio- and Stereoselective Hydrophosphorylation of Ynamides for the Synthesis of β‑Aminovinylphosphine Oxides Hai Huang,†,‡ Hongjun Zhu,‡ and Jun Yong Kang*,† †
Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, 4505 South Maryland Parkway, Las Vegas, Nevada 89154-4003, United States ‡ Department of Applied Chemistry, College of Chemistry and Molecular Engineering, Nanjing Tech University, No. 30 Puzhu Road (S), Nanjing 211816, People’s Republic of China S Supporting Information *
ABSTRACT: A metal-free hydrophosphorylation of ynamides with diaryl phosphine oxides has been developed. A highly E-selective and βregioselective hydrophosphorylation protocol has been established as a general method for the synthesis of diversely hydrophosphinylated products employing an in situ generated electrophilic phosphorus species. Deuterium incorporation experiments suggest that the amino phosphirenium intermediate undergoes a concerted ring-opening hydrolysis upon treatment with H2O to exclusively furnish βaminovinylphosphine oxides.
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Ynamide, a nitrogen-substituted alkyne, is a versatile functional group in organic synthesis and natural product synthesis.8 The functionalization of ynamides, such as an addition reaction, oxidation, cycloaddition reaction, and cycloisomerization, has significantly contributed to the synthesis of various nitrogen-containing compounds.8,9 The addition reaction of phosphorus species to ynamides produces synthetically and medicinally important β-aminovinylphosphorus compounds.10 In 2011, the Rabasso group disclosed a nickel-catalyzed hydrophosphonylation reaction of ynamides with dialkyl phosphites for the synthesis of β-aminovinylphosphonates (Scheme 2, a).11 In addition, Yamagishi and coworkers released a Cu-catalyzed hydrophosphinylation that is limited to only terminal ynamides (Scheme 2, b).12 However, to the best of our knowledge, hydrophosphorylation reaction of ynamides with diarylphosphine oxides under metal-free conditions has not been reported. Recently, Hirano and Miura developed an elegant strategy for the activation of Hphosphine oxides in which an electrophilic phosphorus species (P-species) generated from the diaryl phosphine oxides and Tf2O reacts with alkynes to generate phosphinative cyclization products, and an example of hydrophosphorylation of a symmetrical diphenylacetylene is described.13 Inspired by Hirano and Miura’s work as well as continued interest in the functionalization of ynamide,9 we investigated a metal-free hydrophosphorylation of ynamides. However, there are several challenges for the synthesis of β-aminovinylphosphine oxides with the unsymmetrical ynamide substrates, compared to the symmetrical diphenylacetylenes (Scheme 2, c): (1) βregioselectivity should be carefully controlled, (2) high
inylphosphorus compounds are versatile building blocks in synthetic, materials, and medicinal chemistry because of their unique structural features and biological activities.1 Over the past decades, various synthetic methods for vinylphosphorus compounds have been developed, including a transition-metal-catalyzed cross-coupling reaction of prefunctionalized alkenes,2 metal-promoted hydrophosphorylation reaction of alkynes,3 addition reaction of alkynylphosphorus compounds,4 phosphorus addition of allenes,5 and radical cyclization of alkynoates (Scheme 1).6 Among them, the Scheme 1. Methods for the Synthesis of Vinylphosphorus Compounds
hydrophosphorylation reaction of alkynes has emerged as a straightforward method with easy access to diverse alkyne substrates. However, precedent hydrophosphorylation reactions predominantly rely on the transition-metal catalysis (e.g., Ni, Rh, and Pd) and are limited to terminal alkynes.3,7 For example, the Han group recently reported a comprehensive study on the palladium-catalyzed hydrophosphorylation of alkynes with P(O)−H compounds in which the reactivity is still inclined to segregate to terminal alkynes.3a Therefore, efficient alternative protocols of hydrophosphorylation reaction, especially the metal-free approach, are highly desirable. © XXXX American Chemical Society
Received: April 4, 2018
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DOI: 10.1021/acs.orglett.8b01065 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
hand, there was no target product formed without the base (Table 1, entry 5). Next, the solvent screening showed that DCM is superior to other solvents such as THF, toluene, CH3CN, Et2O, and CHCl3 (Table 1, entries 6−10). Further control experiments revealed that a slight excess of electrophilic P-species (1.5 equiv) is needed for higher yields (Table 1, entries 11 and 12). With the optimized reaction conditions in hand, we explored the scope of the reaction described in Scheme 3. Ynamide 2b
Scheme 2. Examples of Hydrophosphonylation and Hydrophosphinylation of Ynamides
Scheme 3. Scope of Ynamidesa
stereoselectivity needs to be achieved, and (3) controlled chemoselectivity (hydrophosphorylation vs cyclization) should be addressed. Herein, we report a metal-free hydrophosphorylation reaction of ynamides with diaryl phosphine oxides for βaminovinylphosphine oxides using an in situ generated electrophilic P-species. To test our hypothesis of a stereoselective hydrophosphorylation of ynamides, we used diphenylphosphine oxide 1a and ynamide 2a as model substrates to optimize the reaction conditions, as shown in Table 1. Gratifyingly, the desired βTable 1. Optimization of the Reaction Conditionsa
entry
equiv (X)
base
solvent
3ab (%)
1 2 3 4 5 6 7 8 9 10 11 12
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.3 1.5
lutidine pyridine DMAP DABCO
DCM DCM DCM DCM DCM THF toluene CH3CN Et2O CHCl3 DCM DCM
61 48 49 30 NR
lutidine lutidine lutidine lutidine lutidine lutidine lutidine
a
Reaction conditions: 1a (0.3 mmol), Tf2O (0.3 mmol), and lutidine (0.3 mmol) in DCM (1.0 mL) for 10 min, then 2 (0.2 mmol) for 2 h. b Isolated yields. c3.0 mmol scale reaction.
with a methoxy substituent on a benzene ring provided the corresponding product 3b with 91% yield (Scheme 3). Alkylsubstituted ynamides (n-butyl, 2c; n-octyl, 2d) also furnished the target products 3c and 3d in 90% and 95% yields, respectively (Scheme 3). To investigate the influence of steric hindrance on the reaction with the oxazolidin-2-one ring, several ynamides 2e−g containing chiral auxiliaries were examined, and they provided the optically active β-aminovinylphosphine oxides 3e−g in moderate to high yields (56%− 90% yields). N-Sulfonylynamides 2h and 2i with an aryl or alkyl substituent were also proven to be suitable substrates, providing only the β-sulfaminovinylphosphine oxides 3h and 3i with 83% and 76% yields, respectively, without the potential phosphinative cyclization products 3ha and 3ia (Scheme 3).13 Additionally, N-aryl-N-sulfonylynamides 2j−l were also efficiently transformed to the desired products 3j−l in 72−78% yields, which suggests that the electronic effects of the N-aryl rings have a negligible influence on this hydrophosphorylation reaction. Finally, N-sulfonylynamides 2m and 2n with N-Ts groups were evaluated, and they also afforded the correspond-
21 37 19 79 99 (91)c
a
Reaction conditions: 1a (X equiv), Tf2O (X equiv), and base (X equiv) in solvent (1.0 mL) for 10 min, then 2a (0.2 mmol) for 2 h. b Yield was determined by 1H NMR on the crude reaction mixture using 1,3,5-trimethylbenzene as an internal standard. cIsolated yields.
aminovinylphosphine oxide 3a was isolated in 61% yield with excellent regio- and stereoselectivity when lutidine was employed as a base (Table 1, entry 1). It is noteworthy to mention that this reaction procedure provides only E-βaminovinylphosphine oxide. Other bases such as pyridine, DMAP, and DABCO were inferior to pyridine, yielding the product in 30−49% yields (Table 1, entries 2−4). On the other B
DOI: 10.1021/acs.orglett.8b01065 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters ing β-sulfaminovinylphosphine oxides 3m and 3n in 85% and 88% yields, respectively (Scheme 3). It is noteworthy to mention that a large-scale reaction (3.0 mmol) was performed without sacrificing product yields (Scheme 3, 3a, 93%). Next, we evaluated the substrate scope of phosphine oxides using an aliphatic ynamide 2c, and the outcomes are shown in Scheme 4. Diverse diarylphosphine oxides 1b−d with different
Scheme 6. Proposed Mechanism
Scheme 4. Scope of Phosphine Oxidesa
Tf2O and base.13,14 Then, the intermediate A undergoes a [2 + 1] cycloaddition reaction with ynamide 2 to form amino phosphirenium intermediate B.9a,c−e,15 Finally, the phosphirenium cation B is converted to β-aminovinylphosphine oxide product 3 via a ring-opening hydrolysis of the intermediate C upon treatment with H2O during the workup procedure. Presumably due to a partial negative charge at the α-carbon of the amide withdrawing group C, a high regioselectivity is observed. In summary, we have developed a highly regio- and stereoselective hydrophosphorylation reaction of ynamides with diarylphosphine oxides. The electrophilic P-species in situ generated from diarylphosphine oxides with Tf2O/lutidine has been applied for a metal-free hydrophosphorylation of ynamides to form β-aminovinylphosphorus compounds with high functional group tolerance under mild reaction conditions. The deuterium incorporation experiments suggest that a concerted ring-opening hydrolysis process is responsible for high regio- and stereoselectivity of the β-aminovinylphosphine oxides. Further studies on efficient synthetic transformations for P−C bond formation employing the P-species are underway and will be reported in due course.
a
Reaction conditions: 1 (0.3 mmol), Tf2O (0.3 mmol), and lutidine (0.3 mmol) in DCM (1.0 mL) for 10 min, then 2c (0.2 mmol) for 2 h. NG = no target product given. bIsolated yield.
substituents such as methyl, fluoro, and chloro groups were well tolerated, affording the corresponding β-aminovinylphosphine oxides 4a−c in high yields (87−91%). Highly conjugated and polyaromatic phosphine oxides were also proven to be suitable substrates for this synthetic transformation to provide βaminovinylphosphine oxides 4d and 4e (Scheme 4). However, ortho-substituted diarylphosphine oxide failed to give the βaminovinylphosphine oxide product 4f, probably due to steric hindrance (Scheme 4, 4f). The reaction of dibutylphosphine oxide gave an unidentified mixture (Scheme 4, 4g). To gain insight into the reaction mechanism of this transformation, deuterium incorporation experiments were conducted (Scheme 5). Ynamide 2a was treated with
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01065. Experimental details (PDF) Spectral data of all new compounds (PDF)
Scheme 5. Deuterium Incorporation Experiment
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
diphenylphosphine oxide 1a, Tf2O, and lutidine under the standard reaction conditions. After 2 h, the reaction mixture was quenched by D2O and NaHCO3 at room temperature. The target product 3a-D was isolated in 88% yield, and 1H NMR analysis showed more than 78% deuterium incorporation at the α-position of the vinylphosphine oxide product 3a-D (Scheme 5). On the basis of experimental observation and our previous work, a rational mechanism of regio- and stereoselective hydrophosphorylation reaction of ynamide is described in Scheme 6. The electrophilic P-species A could be in situ generated from diaryl phosphine oxide 1 in the presence of
ORCID
Hongjun Zhu: 0000-0002-8227-6064 Jun Yong Kang: 0000-0002-7178-2981 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the University of Nevada, Las Vegas. Maciej Kukula at SCAAC is acknowledged for mass spectra data. C
DOI: 10.1021/acs.orglett.8b01065 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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J.; Pascual, S.; Trocóniz, G. F. d. J. Org. Chem. 2008, 73, 4568−4574. (c) Doherty, S.; Knight, J. G.; Bell, A. L.; El-Menabawey, S.; Vogels, C. M.; Decken, A.; Westcott, S. A. Tetrahedron: Asymmetry 2009, 20, 1437−1444. (d) Budzisz, E.; Nawrot, E.; Malecka, M. Arch. Pharm. 2001, 334, 381−387. (e) Rochdi, A.; Taourirte, M.; Lazrek, H. B.; Barascut, J. L.; Imbach, J. L. Molecules 2000, 5, 1139−1145. (11) Fadel, A.; Legrand, F.; Evano, G.; Rabasso, N. Adv. Synth. Catal. 2011, 353, 263−267. (12) Kinbara, A.; Sato, M.; Yumita, K.; Yamagishi, T. Tetrahedron 2017, 73, 1705−1710. (13) Unoh, Y.; Hirano, K.; Miura, M. J. Am. Chem. Soc. 2017, 139, 6106−6109. (14) Yuan, T.; Huang, S.; Cai, C.; Lu, G.-p. Org. Biomol. Chem. 2018, 16, 30−33. (15) (a) Breslow, R.; Deuring, L. A. Tetrahedron Lett. 1984, 25, 1345−1348. (b) Marinetti, A.; Mathey, F. J. Am. Chem. Soc. 1985, 107, 4700−4706. (c) Mathey, F. Chem. Rev. 1990, 90, 997−1025.
REFERENCES
(1) (a) Minami, T.; Motoyoshiya, J. Synthesis 1992, 1992, 333−349. (b) Dembitsky, V. M.; Al Quntar, A. A. A.; Haj-Yehia, A.; Srebnik, M. Mini-Rev. Org. Chem. 2005, 2, 91−109. (c) Liu, Z.; MacRitchie, N.; Pyne, S.; Pyne, N. J.; Bittman, R. Bioorg. Med. Chem. 2013, 21, 2503− 2510. (d) Tonelli, F.; Lim, K. G.; Loveridge, C.; Long, J.; Pitson, S. M.; Tigyi, G.; Bittman, R.; Pyne, S.; Pyne, N. J. Cell. Signalling 2010, 22, 1536−1542. (e) Harnden, M. R.; Parkin, A.; Parratt, M. J.; Perkins, R. M. J. Med. Chem. 1993, 36, 1343−1355. (f) Lazrek, H. B.; Rochdi, A.; Khaider, H.; Barascut, J. L.; Imbach, J. L.; Balzarini, J.; Witvrouw, M.; Pannecouque, C.; De Clercq, E. Tetrahedron 1998, 54, 3807−3816. (g) Parvole, J.; Jannasch, P. Macromolecules 2008, 41, 3893−3903. (h) Sato, T.; Hasegawa, M.; Seno, M.; Hirano, T. J. Appl. Polym. Sci. 2008, 109, 3746−3752. (i) Pike, R. M.; Cohen, R. A. J. Polym. Sci. 1960, 44, 531−538. (j) Magnusson, C. D.; Liu, D.; Chen, E. Y. X.; Kelland, M. A. Energy Fuels 2015, 29, 2336−2341. (k) Lanzinger, D.; Salzinger, S.; Soller, B. S.; Rieger, B. Ind. Eng. Chem. Res. 2015, 54, 1703−1712. (l) Banks, M.; Ebdon, J. R.; Johnson, M. Polymer 1994, 35, 3470−3473. (m) Luangtriratana, P.; Kandola, B. K.; Ebdon, J. R. Prog. Org. Coat. 2015, 78, 73−82. (n) Gonzalez-Nogal, A. M.; Cuadrado, P.; Sarmentero, M. A. Tetrahedron 2010, 66, 9610−9619. (o) Cheruku, P.; Paptchikhine, A.; Church, T. L.; Andersson, P. G. J. Am. Chem. Soc. 2009, 131, 8285−8289. (p) Lazrek, H. B.; Rochdi, A.; Khaider, H.; Barascut, J. L.; Imbach, J. L.; Balzarini, J.; Witvrouw, M.; Pannecouque, C.; De Clercq, E. Tetrahedron 1998, 54, 3807−3816. (2) (a) Liu, L.; Wang, Y.; Zeng, Z.; Xu, P.; Gao, Y.; Yin, Y.; Zhao, Y. Adv. Synth. Catal. 2013, 355, 659−666. (b) Liao, L.-L.; Gui, Y.-Y.; Zhang, X.-B.; Shen, G.; Liu, H.-D.; Zhou, W.-J.; Li, J.; Yu, D.-G. Org. Lett. 2017, 19, 3735−3738. (c) Wu, Y.; Liu, L.; Yan, K.; Xu, P.; Gao, Y.; Zhao, Y. J. Org. Chem. 2014, 79, 8118−8127. (d) Tang, L.; Wen, L.; Sun, T.; Zhang, D.; Yang, Z.; Feng, C.; Wang, Z. Asian J. Org. Chem. 2017, 6, 1683−1692. (3) (a) Chen, T.; Zhao, C.-Q.; Han, L.-B. J. Am. Chem. Soc. 2018, 140, 3139−3155. (b) Han, L.-B.; Tanaka, M. J. Am. Chem. Soc. 1996, 118, 1571−1572. (c) Zhao, C.-Q.; Han, L.-B.; Goto, M.; Tanaka, M. Angew. Chem., Int. Ed. 2001, 40, 1929−1932. (d) Trostyanskaya, I. G.; Beletskaya, I. P. Tetrahedron 2014, 70, 2556−2562. (4) (a) Braga, A. L.; Vargas, F. c.; Zeni, G.; Silveira, C. C.; de Andrade, L. H. Tetrahedron Lett. 2002, 43, 4399−4402. (b) Aziz Quntar, A. A.; Srebnik, M. Org. Lett. 2001, 3, 1379−1381. (c) Quntar, A. A. A. A.; Dembitsky, V. M.; Srebnik, M. Org. Lett. 2003, 5, 357− 359. (d) Quntar, A. A. A.; Srebnik, M. Chem. Commun. 2003, 58−59. (5) (a) Mulla, K.; Aleshire, K. L.; Forster, P. M.; Kang, J. Y. J. Org. Chem. 2016, 81, 77−88. (b) Buono, G.; Llinas, J. R. J. Am. Chem. Soc. 1981, 103, 4532−4540. (c) Fürmeier, S.; Lau, M. L.; Lie Ken Jie, M. S. F.; Lützen, A.; Metzger, J. O. Eur. J. Org. Chem. 2003, 2003, 4874− 4878. (6) Mi, X.; Wang, C.; Huang, M.; Zhang, J.; Wu, Y.; Wu, Y. Org. Lett. 2014, 16, 3356−3359. (7) Itazaki, M.; Katsube, S.; Kamitani, M.; Nakazawa, H. Chem. Commun. 2016, 52, 3163−3166. (8) (a) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840−2859. (b) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560−578. (c) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064−5106. (d) Pan, F.; Shu, C.; Ye, L.-W. Org. Biomol. Chem. 2016, 14, 9456− 9465. (9) (a) Huang, H.; Zhu, X.; He, G.; Liu, Q.; Fan, J.; Zhu, H. Org. Lett. 2015, 17, 2510−2513. (b) Huang, H.; He, G.; Zhu, G.; Zhu, X.; Qiu, S.; Zhu, H. J. Org. Chem. 2015, 80, 3480−3487. (c) Huang, H.; Fan, J.; He, G.; Yang, Z.; Jin, X.; Liu, Q.; Zhu, H. Chem. - Eur. J. 2016, 22, 2532−2538. (d) Huang, H.; Tang, L.; Liu, Q.; Xi, Y.; He, G.; Zhu, H. Chem. Commun. 2016, 52, 5605−5608. (e) Huang, H.; Tang, L.; Han, X.; He, G.; Xi, Y.; Zhu, H. Chem. Commun. 2016, 52, 4321−4324. (f) Tang, L.; Huang, H.; Xi, Y.; He, G.; Zhu, H. Org. Biomol. Chem. 2017, 15, 2923−2930. (10) (a) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899−932. (b) Palacios, F.; Retana, A. M. O. d.; Oyarzabal, D
DOI: 10.1021/acs.orglett.8b01065 Org. Lett. XXXX, XXX, XXX−XXX
