Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective Synthesis of α- and γ-Amino Quinolinyl Phosphonamides Using N‑Heterocyclic Phosphines (NHPs) Manasa Shetty,‡ Hai Huang,‡ 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 S Supporting Information *
ABSTRACT: A regioselective phosphonylation of quinolines for the synthesis of α-amino quinolinyl phosphonamides and γ-amino quinolinyl phosphonamides has been developed under mild reaction conditions. An NHP-thiourea enables selective synthesis of α-amino quinolinyl phosphonamides by a Reissert-type reaction, and an NHP-tosylamide affords γamino quinolinyl phosphonamides via a 1,4-conjugate addition reaction. The corresponding amino quinolinyl phosphonate adducts were obtained in moderate to excellent yields (up to 99% yield) and regioselectivities (up to 99:1) with good functional group tolerance. ver the past five decades, amino phosphonates have received much attention due to their diverse biological activities.1 They are defined as phosphorus analogues of naturally occurring amino acids a1a,2 (Figure 1), comprised of a
O
utilized for a direct phosphonylation of quinolines to construct amino quinolinyl phosphonate derivatives. For example, the Hamada group reported a base-promoted phosphonylation reaction of quaternary quinolinium salts with dialkyl or trialkyl phosphites in which a regioisomeric mixture of α-amino phosphonate and γ-amino phosphonate was generated (Scheme 1a).14 An acid-promoted dearomatization of quinolines using a silylated dimethyl phosphite via a tandem 1,4−1,2addition reaction was disclosed by the Stevens group (Scheme 1b).15 Recently, asymmetric organocatalyzed dearomatizations of quinolines and isoquinolines for the synthesis of chiral heterocyclic α-amino phosphonates were released by the Mancheño group (Scheme 1c) and the Mukherjee group, Scheme 1. Synthetic Routes toward Amino Quinolinyl Phosphonates
Figure 1. Several amino phosphonate derivatives.
biologically, pharmaceutically important N−C−P bond unit. Compounds with this scaffold offer broad applications in pharmacological activities such as enzyme activators3 or inhibitors4 and also physiological and pathological processes in biological systems.1a,5 In particular, amino phosphonate derivatives bearing a quinoline moiety play a vital role in medicinal chemistry as antitumor agents b,6 antimicrobial agents c,7 antioxidants,8 and protease inhibitors d9 (Figure 1). Also, transition metal complexes of quinoline phosphonates have demonstrated antitumor activities in vitro studies e10 (Figure 1). Multicomponent reaction (MCR) has emerged as an efficient synthetic tool for the synthesis of α-aminophosphonates employing amines, aldehydes, and dialkyl or trialkyl phosphites since its discovery by Kabachnick and Fields in 1952.11 This reaction proceeds via the formation of an imine intermediate in situ followed by a phospha-Mannich reaction,12 affording a N− C−P bond scaffold.13 Yet, the Reissert-type reaction has been © XXXX American Chemical Society
Received: December 7, 2017
A
DOI: 10.1021/acs.orglett.7b03829 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters respectively.16 Despite the recent advances in phosphonylation of quinolines by the dearomatization strategy, there are limitations such as the use of bases, strong acids, additives, special silylated phosphites, and more importantly the lack of regioselective phosphonylation of quinolines. Therefore, the development of a general, regioselective method of phosphonylation reaction to access amino quinolinyl phosphonates under mild reaction conditions is highly desirable in synthetic organic as well as medicinal chemistry. Recently, our study on N-heterocyclic phosphines (NHPs) demonstrated a strong nucleophilicity and bifunctionality of the NHPs toward various electrophile systems17 including iminium electrophiles17a generated in situ without the use of base and additives. Despite the many phospha-Mannich reactions of iminium electrophiles, a regioselective addition of phosphorus nucleophiles to quinolinium electrophiles to offer both α- and γamino quinolinyl phosphonates has not been previously developed. With the unique bifunctionality of the NHPs, we hypothesized that different Brønsted acid motifs on the NHPs may activate the quinolinium electrophiles through a different mode of ion-paring capability,18 leading to a regioselective phosphorus addition to the quinolinium salts. Herein, we report an NHP-promoted regioselective synthesis of α-amino quinolinyl phosphonates (α-AQPs) and γ-amino quinolinyl phosphonates (γ-AQPs) without the use of acids, bases, and additives under mild reaction conditions. To test our hypothesis, we first performed a one-pot reaction using equimolar amounts of NHP-thiourea 3a (1.0 equiv) and quinoline 1a (1.0 equiv) with ethyl chloroformate 2a (1.1 equiv) in CH2Cl2 at room temperature (Table 1). The reaction proceeds efficiently to afford 4a (α-AQPs) and 5a (γ-AQPs) in 83% yield with an 8:1 ratio (Table 1, entry 1). This high regioselectivity of the 1,2-addition over the potential competition of the 1,4-addition reaction is presumably associated with the Hbonding between the chloride anion and thiourea motif through an ion-paring process.16b,18 We next exploited the effects of
different Brønsted acids and the tether length between the NHP and Brønsted acid motif on this ion-paring event. Interestingly, NHP-thioureas 3b and 3c having three and four carbon-chain linkages (Table 1, entries 2−3), respectively, provided γ-AQP 5a as a major product. We attribute this selectivity reversal to the proximity interruption between the electrophilic α-position of the quinolinium and nucleophile of the NHP, resulting in the nucleophilic attack of the NHP favorably at the electrophilic γposition of the quinolinium. Modification of thiourea acidity using 3d and 3e has a similar effect on the selectivity, but they are inferior to the parent NHP-thiourea 3a (Table 1, entries 4−5). Both the one methyl-substituted thiourea 3f and an amide group 3g on the NHP have proven to form α-AQP 4a as a major product (Table 1, entries 6−7). To further study the role of Brønsted acids on the regioselectivity, NHP-ethanol 3h and NHP-tosylamide 3i were employed under the standard reaction conditions. However, without the H-bonding moiety, 3h provided 5a as a major product (Table 1, entry 8), showing the selectivity reversal. When the thiourea motif on the NHP was replaced with a tosylamide group 3i, we observed complete reversal in regioselectivity in the phosphonylation of quinoliniums, providing only γ-AQP 5a in 70% yield (Table 1, entry 9). Next, we sought to further optimize the reaction conditions for both 4a and 5a construction (Table 2). For the 4a formation, we Table 2. Optimization of Reaction Conditions for α-AQP and γ-AQPa
Table 1. Screening of Different NHPsa
entry
solvent
NHP
4a:5ab
yield (%)c
1 2 3 4 5 6 7 8d 9e 10e
CH2Cl2 CHCl3 DCE THF Et2O toluene CH3CN CH2Cl2 CH2Cl2 CH2Cl2
3a 3a 3a 3a 3a 3a 3a 3a 3a 3i
8:1 6:1 8:1 14:1 7:1 5:1 6:1 7:1 8:1 1:99
83 69 70 54 74 62 59 89 95 87
a
Reaction conditions: 1a (0.1 mmol), 2a ( 0.11 mmol), 3a (0.1 mmol), and solvent (0.5 mL) at rt for 24 h. bRatio was determined by 1 H NMR on the crude reaction mixture. cTotal isolated yield. d Reaction was carried out at 40 °C for 6 h. eReaction was carried out at 40 °C for 6 h using 1a (0.2 mmol), 2a (0.22 mmol), 3a (0.1 mmol) or 3i (0.1 mmol), and solvent (0.5 mL). entry
NHP
4a:5ab
yield (%)c
1 2 3 4 5 6 7 8 9
3a 3b 3c 3d 3e 3f 3g 3h 3i
8:1 1:4 1:3 6:1 4:1 6:1 6:1 1:3 1:99
83 74 83 67 30 86 86 58 70
found that a subsequent screening of polar and nonpolar solvents did not improve the product yield (Table 2, entries 1−7) but improved regioselectivity was observed with THF solvent with a moderate yield (Table 2, entry 4). When the reaction was run at 40 °C in CH2Cl2, it was completed in 6 h with an 89% yield of 4a (Table 2, entry 8). Further improvement of the product yield was achieved with a slight excess of 1a and 2a without affecting the regioselectivity, providing a 95% yield of 4a with an 8:1 ratio of the regioisomers (Table 2, entry 9). For the optimization of 5a formation, NHP-tosylamide 3i was employed under the same reaction conditions of 4a construction, and this reaction provided exclusively γ-AQP 5a in 87% yield with excellent regioselectivity (Table 2, entry 10). Further screening of different
a
Reaction conditions: 1a (0.1 mmol), 2a (0.11 mmol), 3a (0.1 mmol), and solvent (0.5 mL) at rt for 24 h. bRatio was determined by 1H NMR on the crude reaction mixture. cTotal isolated yield. B
DOI: 10.1021/acs.orglett.7b03829 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
electron-withdrawing groups (Ph, F, Cl, Br) (1f−1i) on the quinoline moiety yielded the γ-AQPs as major products (5d−5i). In general, quinolines with electron-donating groups exhibited higher regioselectivity than those of electron-withdrawing groups. We also witnessed the same dual functionalization of 6hydroxy quinoline 1j to yield 6-ethylcarbonate γ-AQP 5j in 62% yield with excellent regioselectivity. Additionally, other functional groups such as aldehyde 1k, methyl acrylate 1l, and phenylacetylene 1m on the quinoline moiety afforded the desired 1,4-adducts (5k−5m) in 55−73% yields with high regioselectivity. To develop an alternative mild procedure to an existing phosphonylation reaction of isoquinolines,16b NHP 3a was chosen as a phosphonylation reagent for the phosphonylation of isoquinoline 1n, and this reaction provided α-AQP 6 in 96% yield in an atropisomeric 1:1 mixture (Scheme 4, eq a). We further
solvents did not increase the product yield and the selectivity of 5a (see Supporting Information, Table S1). Having the optimized reaction conditions in hand, we explored the scope of the reaction with different quinoline derivatives and chloroformates using the NHP-thiourea 3a (Scheme 2). Various chloroformates 2a−2c delivered the desired Scheme 2. Scope of Quinolines and Chloroformates Using NHP-Thiourea 3aa
Scheme 4. Phosphonylation of Other Substrates
a Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), 3a (0.1 mmol), and CH2Cl2 (0.5 mL) at 40 °C for 6 h. bTotal isolated yield. cRatio was determined by 1H NMR on the crude reaction mixture. d2a (0.4 mmol) was used.
α-AQPs (4a−4c) in 95−99% yields with good regioselectivity. Not only the quinoline derivatives containing electron-donating groups (Me, MeO) (1d, 1e) but also those with electronwithdrawing groups (Ph, F, Cl, Br) (1f−1i) efficiently afforded the corresponding α-AQPs (4d−4i) with moderate to excellent yields and high regioselectiviy. Interestingly, when 6-hydroxy substituted quinoline 1j was employed, a dual functionalization occurred, affording 6-ethylcarbonate α-AQP 4j instead of 6hydroxy α-AQP. Other functional groups such as aldehyde, methyl acrylate, and phenylacetylene on quinoline derivatives (1k−1m) were also well tolerated and yielded the target products (4k−4m) with high regioselectivity. Next, the reactivity of the NHP-tosylamide 3i was studied (Scheme 3). Screening of various chloroformates (2a−2c) afforded the corresponding γ-AQPs as major products (5a−5c) in 73−98% yields with moderate to excellent regioselectivity. Both electron-donating groups (Me, MeO) (1d, 1e) and
explored this synthetic protocol to synthesize a diphosphonylated adduct of the quinoline substrate under mild reaction conditions.15,19 We were delighted to see that our NHP-thiourea 3a could also function as a diphosphonylation reagent (Scheme 4, eq b), in which the 1-methylquinolin-1-ium iodide 1o was used as an electrophile to give a double addition product 7 in 46% yield. To demonstrate synthetic transformation of the phosphonylation products, 4a and 5a were subjected to an oxidation reaction (Scheme 5). For example, an epoxidation reaction of 4a Scheme 5. Synthetic Transformations
Scheme 3. Scope of Quinolines and Chloroformates Using NHP-Tosylamide 3ia
and 5a proceeded smoothly with m-chloroperbenzoic acid20 in the presence of NaHCO3, providing 8a (Scheme 5, eq a) and 8b (Scheme 5, eq b) in 88% and 97% yields, respectively. With the experimental results and previous reports,17b,c a plausible reaction mechanism for the formation of α-AQP and γAQP is depicted in Scheme 6. A mixture of quinoline 1a and chloroformate 2a generates a quinolinium salt I, which promptly reacts with the NHP-thiourea 3a to furnish diazaphosphonium intermediate IIIa via the Reissert-type reaction probably due to a preferred ion-paring capability16b,18,21 between the chloride anion and thiourea moiety IIa. Then, the intermediate IIIa undergoes an intramolecular nucleophilic substitution reaction initiated by the anionic thiourea moiety17a to provide the desired α-AQP 4a and a thiazolidine byproduct IVa22 (Scheme 6,
a
Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), 3i (0.1 mmol), and CH2Cl2 (0.5 mL) at 40 °C for 6 h. bTotal isolated yield. cRatio was determined by 1H NMR on the crude reaction mixture. d2a (0.4 mmol) was used. C
DOI: 10.1021/acs.orglett.7b03829 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
(c) Hudson, H. R.; Kukhar, V. P. Aminophosphonic and aminophosphinic acids: chemistry and biological activity; John Wiley & Sons: Chichester, U.K., 2000. (d) Kukhar, V. P.; Soloshonok, V. A.; Solodenko, V. A. Phosphorus, Sulfur Silicon Relat. Elem. 1994, 92, 239. (2) Wuggenig, F.; Schweifer, A.; Mereiter, K.; Hammerschmidt, F. Eur. J. Org. Chem. 2011, 2011, 1870. (3) Yellapu, N. K.; Kilaru, R. B.; Chamarthi, N.; Pvgk, S.; Matcha, B. Comput. Biol. Chem. 2017, 68, 118. (4) (a) Lejczak, B.; Kafarski, P.; Zygmunt, J. Biochemistry 1989, 28, 3549. (b) Sienczyk, M.; Oleksyszyn, J. Curr. Med. Chem. 2009, 16, 1673. (c) Beers, S. A.; Schwender, C. F.; Loughney, D. A.; Malloy, E.; Demarest, K.; Jordan, J. Bioorg. Med. Chem. 1996, 4, 1693. (5) (a) Lejczak, B.; Kafarski, P. Top. Heterocycl. Chem. 2009, 20, 31. (b) Naydenova, E. D.; Todorov, P. T.; Troev, K. D. Amino Acids 2010, 38, 23. (6) (a) Zhu, X.-F.; Zhang, J.; Sun, S.; Guo, Y.-C.; Cao, S.-X.; Zhao, Y.-F. Chin. Chem. Lett. 2017, 28, 1514. (b) Wang, B.; Miao, Z. W.; Wang, J.; Chen, R. Y.; Zhang, X. D. Amino Acids 2008, 35, 463. (7) (a) Ali, T. E.; Abdel-Aziz, S. A.; El-Edfawy, S. M.; Mohamed, E.-H. A.; Abdel-Kariem, S. M. Synth. Commun. 2014, 44, 3610. (b) Kategaonkar, A. H.; Sonar, S. S.; Sapkal, S. B.; Gawali, V. U.; Shingate, B. B.; Shingare, M. S. Phosphorus, Sulfur Silicon Relat. Elem. 2010, 185, 2113. (8) Tesmar, A.; Ferenc, W.; Wyrzykowski, D.; Sikorski, A.; InkielewiczStępniak, I.; Osypiuk, D.; Drzeżdżon, J.; Jacewicz, D.; Chmurzyński, L. Polyhedron 2017, 133, 75. (9) Bhattacharya, A. K.; Rana, K. C.; Raut, D. S.; Mhaindarkar, V. P.; Khan, M. I. Org. Biomol. Chem. 2011, 9, 5407. (10) (a) Juribašić, M.; Bellotto, L.; Traldi, P.; Tušek-Božić, L. J. Am. Soc. Mass Spectrom. 2011, 22, 1815. (b) Tušek-Božić, L.; Juribašić, M.; Traldi, P.; Scarcia, V.; Furlani, A. Polyhedron 2008, 27, 1317. (c) TušekBožić, L.; Juribašić, M.; Scarcia, V.; Furlani, A. Polyhedron 2010, 29, 2527. (d) Tusek-Bozic, L.; Matijasic, I.; Bocelli, G.; Calestani, G.; Furlani, A.; Scarcia, V.; Papaioannou, A. J. Chem. Soc., Dalton Trans. 1991, 195. (11) (a) Fields, E. K. J. Am. Chem. Soc. 1952, 74, 1528. (b) Kabachnik, M.; Medved, T. Dokl. Akad. Nauk SSSR 1952, 83, 689. (12) Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 1979, 81. (13) Dodda, R.; Zhao, C.-G. Org. Lett. 2007, 9, 165. (14) Takeuchi, I.; Shinata, Y.; Hamada, Y. Heterocycles 1985, 23, 1635. (15) De Blieck, A.; Masschelein, K. G. R.; Dhaene, F.; RozyckaSokolowska, E.; Marciniak, B.; Drabowicz, J.; Stevens, C. V. Chem. Commun. 2010, 46, 258. (16) (a) Fischer, T.; Duong, Q.-N.; García Mancheño, O. Chem. - Eur. J. 2017, 23, 5983. (b) Ray Choudhury, A.; Mukherjee, S. Chem. Sci. 2016, 7, 6940. (17) (a) Mulla, K.; Kang, J. Y. J. Org. Chem. 2016, 81, 4550. (b) Molleti, N.; Kang, J. Y. Org. Lett. 2017, 19, 958. (c) Molleti, N.; Bjornberg, C.; Kang, J. Y. Org. Biomol. Chem. 2016, 14, 10695. (d) Huang, H.; Palmas, J.; Kang, J. Y. J. Org. Chem. 2016, 81, 11932. (e) Molleti, N.; Yong Kang, J. Org. Biomol. Chem. 2016, 14, 8952. (f) Huang, H.; Kang, J. Y. Org. Lett. 2016, 18, 4372. (g) Mulla, K.; Aleshire, K. L.; Forster, P. M.; Kang, J. Y. J. Org. Chem. 2016, 81, 77. (h) Huang, H.; Kang, J. Y. J. Org. Chem. 2017, 82, 6604. (i) Huang, H.; Kang, J. Y. Org. Lett. 2017, 19, 544. (18) Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2013, 52, 534. (19) (a) Zhang, Q.; Wei, D.; Cui, X.; Zhang, D.; Wang, H.; Wu, Y. Tetrahedron 2015, 71, 6087. (b) De Blieck, A.; Catak, S.; Debrouwer, W.; Drabowicz, J.; Hemelsoet, K.; Verstraelen, T.; Waroquier, M.; Van Speybroeck, V.; Stevens, C. V. Eur. J. Org. Chem. 2013, 2013, 1058. (20) (a) Robinson, M. W. C.; Pillinger, K. S.; Mabbett, I.; Timms, D. A.; Graham, A. E. Tetrahedron 2010, 66, 8377. (b) Robinson, M. W. C.; Davies, A. M.; Buckle, R.; Mabbett, I.; Taylor, S. H.; Graham, A. E. Org. Biomol. Chem. 2009, 7, 2559. (21) (a) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404. (b) Wasa, M.; Liu, R. Y.; Roche, S. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2014, 136, 12872. (22) Sommen, G. L.; Linden, A.; Heimgartner, H. Eur. J. Org. Chem. 2005, 2005, 3128. (23) (a) Das, B.; Krishnaiah, M.; Laxminarayana, K. J. Chem. Res. 2007, 2007, 82. (b) Wu, J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2000, 65, 1344.
Scheme 6. A Plausible Reaction Mechanism
pathway A). On the other hand, the quinolinium salt I in the presence of 3i is converted to a diazaphosphonium intermediate IIIb via a 1,4-conjugate addition reaction activated by H-bonding between a carbonyl oxygen of the quinolinium and a tosylamide group IIb, in which an unpaired free chloride anion is available in the reaction media (Scheme 6, pathway B). The free chloride anion serves as an internal nucleophile to transform the diazaphosphonium IIIb to γ-AQP adduct 5a and a 2-chloroethyl tosylamide byproduct IVb23 via an intermolecular nucleophilic substitution reaction. In summary, a reagent-controlled phosphonylation reaction of quinolines for the synthesis of biologically significant amino quinolinyl phosphonates using bifunctional NHPs has been developed. Importantly, by modifying the Brønsted acid motif on NHPs, this phosphonylation reaction enables regioselective synthesis of α-AQPs and γ-AQPs. This transformation tolerates a wide array of quinolines and chloroformates, delivering the target adducts in moderate to excellent yields ( 53−99%) under catalyst- and additive-free reaction conditions. Further investigation of enantioselective synthesis of the N−C−P bond scaffold on quinoline derivatives is underway.
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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.7b03829. Experimental details (PDF) Spectral data of all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jun Yong Kang: 0000-0002-7178-2981 Author Contributions ‡
M.S. and H.H. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by University of Nevada Las Vegas (Doctoral Graduate Research Assistant Award). Maciej Kukula at SCAAC is acknowledged for mass spectra data.
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REFERENCES
(1) (a) Mucha, A.; Kafarski, P.; Berlicki, Ł. J. Med. Chem. 2011, 54, 5955. (b) Horiguchi, M.; Kandatstu, M. Nature 1959, 184, 901. D
DOI: 10.1021/acs.orglett.7b03829 Org. Lett. XXXX, XXX, XXX−XXX
