ORGANIC LETTERS
Fluoroalkyl r,β-Unsaturated Imines. Valuable Synthetic Intermediates from Primary Fluorinated Enamine Phosphonates
2002 Vol. 4, No. 5 769-772
Francisco Palacios,* Sergio Pascual, Julen Oyarzabal, and Ana M. Ochoa de Retana Departamento de Quı´mica Orga´ nica I, Facultad de Farmacia, UniVersidad del Paı´s Vasco, Apartado 450, 01080 Vitoria, Spain
[email protected] Received December 18, 2001
ABSTRACT
A simple method for the preparation of fluoroalkyl allylamines or r,β-unsaturated ketones by an olefination reaction of primary enamine phosphonates and aldehydes, followed by selective reduction with hydrides or hydrolysis, is reported. Fluorinated β-amino nitriles are also obtained by an olefination reaction of primary enamine phosphonates with aldehydes and subsequent addition of metalated acetonitrile.
Enamines have attracted a great deal of attention in recent years because of their range of applications.1,2 However, primary enamines, despite their potential interest as synthons in organic synthesis, have been less extensively studied, due to the fact that they are unstable unless conjugated with an electron-withdrawing group on the β-carbon atom.3 In this context, we describe new methods for the preparation of phosphorus-substituted nitrogen heterocycles from phosphorylated enamines,4 as well as the synthesis of primary enamines5 derived from phosphazenes and phosphonates and (1) Rappoport, Z. The Chemistry of Enamines. The Chemistry of Functional Groups; Patai, S., Rappoport, Z., Eds.; J. Wiley: Chichester, 1994. (2) (a) Palacios, F.; Aparicio, D.; Garcı´a, J.; Rodrı´guez, E. Eur. J. Org. Chem. 1998, 1413. (b) Palacios, F.; Aparicio, D.; Garcı´a, J. Tetrahedron 1996, 52, 9609. (c) Palacios, F.; Aparicio, D.; Garcı´a, J.; Rodrı´guez, E.; Ferna´ndez, A. Tetrahedron 2001, 56, 3131. (3) Erker, G.; Riedel, M.; Koch, S.; Jo¨edicke, T.; Wu¨erthwein, E. U. J. Org. Chem. 1995, 60, 5284. (4) (a) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Ezpeleta, J. M. J. Org. Chem. 2000, 65, 3213. (b) Palacios, F.; Pagalday, J.; Piquet, V.; Dahan, F.; Bacereido, A.; Bertrand, G. J. Org. Chem. 1997, 62, 292. (c) Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J. Tetrahedron 1999, 55, 5947. 10.1021/ol017254p CCC: $22.00 Published on Web 02/08/2002
© 2002 American Chemical Society
their synthetic use for the preparation of functionalized acyclic compounds6a and phosphorus-containing heterocycles.6b,c The development of efficient and mild methods for organofluorine compound synthesis represents a broad area in organic chemistry since the incorporation of a fluorinecontaining group into an organic molecule dramatically alters its physical, chemical, and biological properties.7 Among them, special interest has been focused on developing synthetic methods for the preparation of fluorinated building blocks since they are used for the efficient and/or selective preparation of fluorine-containing molecules with biological (5) (a) Barluenga, J.; Lo´pez, F.; Palacios, F.; Cano, F. H.; Foces, M. C. J. Chem Soc., Perkin Trans. I 1988, 2329. (b) Palacios, F.; Oyarzabal, J.; Ochoa de Retana, A. M. Tetrahedron Lett. 1996, 37, 4577. (6) (a) Lo´pez, F.; Pela´ez, E.; Palacios, F.; Barluenga, J.; Garcı´a, J.; Tejerina, B.; Garcı´a, A. J. Org. Chem. 1994, 59, 1984. (b) Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J. Tetrahedron 1999, 55, 3091. (c) Barluenga, J.; Lo´pez, F.; Palacios, F. Chem. Commun. 1985, 1681. (7) (a) Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishnan, S., Eds.; Wiley: New York, 1991. (b) Organofluorine Compounds: Chemistry and Applications; Hiyama, T., Ed.; Springer: Berlin, 2000.
activity and commercial applications.8 A recent publication9 reporting the preparation of trifluoromethylated allylic amines from R,β-unsaturated N-tert-butanesulfinimines prompts us to report our own results concerning the synthetic use of fluorinated R,β-unsaturated imines obtained by an olefination reaction of primary enamines with aldehydes for the preparation of R-monofluoromethyl, R-trifluoromethyl, and R-perfluoroalkyl allylamines and functionalized allylamines derived from fluorinated β-amino nitriles as well as for the synthesis of R,β-unsaturated ketones. Fluorinated primary enamines, despite their potential interest as synthons in organic synthesis for the construction of more complex fluoro-containing acyclic and cyclic compounds, have not received much attention recently, probably owing to the lack of general methods of synthesis of these compounds. As far as we know, only examples of β-fluoro primary enamines,10a R,β-fluoro-substituted primary enamines,10b and three types of R-fluoro-substituted primary enamines containing a sulfinyl,11a an alkoxycarbonyl,11b and a carbonyl group11c have been reported, and one example of preparation of a fluorinated primary enamine containing a phosphonate group by reaction of 1,2,3,3,3-pentafluoropropenyl phosphonates with ammonia has been described.11d The presence of phosphorus substituents in these substrates could favor the isolation and stabilization of the primary enamine3 and increase the synthetic value of these compounds because they may be used as building blocks for the stereoselective carbon-carbon double bond construction;12 moreover, phosphorus substituents could regulate important biological functions and increase the biological activity of these compounds, in a similar way to that reported for pharmaceuticals.13 Continuing with our interest in the design of new phosphorus-substituted building blocks, we report here an easy and selective synthesis of primary β-enamino phosphonates 1 (Scheme 1) through simple addition of fluoroalkyl
Scheme 1
nitriles to metalated alkyl phosphonates, as well as their use as versatile tools for the formation of fluoro-containing derivatives. We first explored the preparation of the (Z)-primary β-enamino phosphonates 1. These enamines are easily obtained,14 in a selective fashion, through R-lithiation of diethyl alkylphosphonates 2 (R1 ) H, CH3) followed by (8) (a) Enantiocontrolled Synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and Biomedical Targets; Soloshonok, V. A., Ed.; Wiley: New York, 1999. (b) Fluorine-Containing Amino Acids: Synthesis and Applications, Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: New York, 1995. (9) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3, 2847. (10) (a) Hojo, M.; Masuda, M.; Okada, E. Tetrahedron Lett. 1989, 45, 6173. (b) Doussot, P.; Portella, Ch. J. Org. Chem. 1993, 58, 6675. 770
Scheme 2
reaction with fluoroalkyl nitriles15 3 and aqueous workup, in a manner similar to that previously reported for other phosphorus derivatives5 (Scheme 2, Table 1). Spectroscopic
Table 1. Synthesis of Primary Enamino Phosphonates 1 compd
R1
RF
base
yield, %a
1a 1b 1c 1d 1e
H H H CH3 H
CF3 C2F5 C7F15 CF3 CH2F
MeLi MeLi LDA MeLi LDA
81 85 87 42 79
a
Yields refer to isolated compounds.
data are consistent with the proposed structure. Only one signal was observed in 31P and 19F NMR for each compound 1, and in 13C NMR a vicinal 13C-31P coupling constant (3JPC) in the range of 25-30 Hz shows that the fluoro-substituted alkyl group (RF) and the phosphorus atom in enamines 1 are trans related.16 Formation of primary enamines 1 can be (11) (a) Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Neille, S. V.; Zanda, M.; Cavicchio, G.; Crucianelli, M. J. Org. Chem. 1996, 61, 3375. (b) Lee, L. F.; Howe, R. K. J. Org. Chem. 1984, 49, 4780. (c) Luo, B. H.; Guan, H. P.; Hu, C. M. Synlett 1997, 1261. (d) Von Allwo¨rden, U.; Ro¨schenthaler, G. V. Chem. Zeitg. 1988, 112, 69. (12) (a) Kolodiazhnyi, O. I. Phosphorus Ylides; Wiley-VCH: Weinhein, 1999. (b) Johnson, A. W.; Kaska, W. C.; Ostoja Starzewski, K. A.; Dixon, D. A. Ylides and Imines of Phosphorus; J. Wiley: New York, 1993. (13) Toy, A. D. F.; Walsh, E. N. Phosphorus Chemistry in EVeryday LiVing; American Chemical Society: Washington DC, 1987. (14) General procedure for the preparation of enamines 1: A solution of methyl-phosphonic acid diethyl ester 2 (R1 ) H) (760 mg, 5 mmol) in THF (10 mL) was added to a solution of MeLi (1.6 M in Et2O) (3.12 mL, 5 mmol) in THF (15 mL) at -78 °C under an N2 atmosphere. The mixture was stirred for 1 h at -78 °C. Then, CF3CN was bubbled into the solution. The reaction was allowed to warm to room temperature. The resulting mixture was washed three times with water (20 mL), extracted with CH2Cl2, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was purified by chromatography using silica gel (hexane/ ethyl acetate) to give pure 1a (1.00 g, 4.05 mmol). (15) Some of these nitriles are toxic and must be careful handled. (16) (a) Palacios, F.; Aparicio, D.; de los Santos, J. M. Tetrahedron 1994, 50, 12727. (b) Duncan, M.; Gallager, M. J. Org. Magn. Reson. 1981, 15, 37. Org. Lett., Vol. 4, No. 5, 2002
assumed to proceed via protonation of enamino intermediates 5, formed by prototropic tautomerization of imines 4 (Scheme 2). The scope of the reaction was not limited to R-trifluoromethyl-enamines 1a,d (RF ) CF3), since perfluoroalkyl- 1b,c (RF ) CnF2n+1, n ) 2, 7) and R-monofluoromethyl-enamines 1e (RF ) CH2F) were also prepared. Fluorinated allylamines and R,β-unsaturated fluoralkyl ketones represent an important class of compounds in organic synthesis17a and in medicinal chemistry.17b,18 In this context, secondary trifluoromethyl allylamines have been prepared by Lewis acid-catalyzed addition of acetylenes to trifluoroacetaldehyde N,N-aminals,19a by vinylmagnesium bromide addition to N-acyl imines derived from trifluoroacetaldehyde generated in situ,19b or by nucleophilic trifluoromethylation of N-tosyl aldimine,19c while R,β-unsaturated fluoroalkyl ketones have been prepared from esters,20a,b enamines,20c-e tellurides,20f or R-acetylenic trifluoromethyl ketones.20g,h With this in mind, we thought that fluorinated allylamines and unsaturated ketones could be prepared from fluoroalkylsubstituted primary enamino phosphonates 1. Reaction of primary enamines 1 with butyllithium, followed by addition of aromatic and heteroaromatic aldehydes, and subsequent treatment of the reaction mixture with NaBH4 in methanol gave primary fluoroalkyl allylamines 6a-f (Scheme 3, Table 2) in a stereoselective fashion and in good
Scheme 3a
(a) i. Base, -78 °C; ii. RFCN; (b) H2O; (c) BuLi, 0 °C; (d) R2CHO; (e) NaBH4, MeOH, -78 °C; (f) H3O+; (g) MeCN, BuLi, -78 °C. a
yields.21 Vicinal 3JHH coupling constants in the range of 1617 Hz between the vinylic protons of 6a-d are consistent with the E configuration of the carbon-carbon double bond. Formation of compounds 6 can be explained by Horner(17) (a) Nenajdenko, V. G.; Sanin, A. V.; Balenkova, E. S. Russ. Chem. ReV. 1999, 68, 437. (b) Yoshimatsu, M.; Hibino, M. Chem. Pharm. Bull. 2000, 48, 1395. (18) Ohba, T.; Ikeda, E.; Wakeyama, J.; Takei, H. Bioorg. Med. Chem. Lett. 1996, 6, 219. (19) (a) Xu, Y.; Dolbier, W. R. J. Org. Chem. 2000, 65, 2134. (b) Weygand, F.; Steglich, W.; Oettmeir, W.; Maierhofer, A.; Loy, R. S. Angew. Chem., Int. Ed. Engl. 1966, 5, 600. (c) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett 2001, 77. Org. Lett., Vol. 4, No. 5, 2002
Table 2. Preparation of Fluorinated Carbonyl Compounds and Allylic Amines compd
R1
R2
RF
yield, %a
6a 6b 6c 6d 6e 6f 8a 8b 8c 8d 8e 8f
H H H H CH3 CH3 H H H H H CH3
p-Me-Ph Ph-CHdCH p-Me-Ph p-F-Ph 2-Fur p-Me-Ph p-Me-Ph p-Me-Ph p-F-Ph R2 ) c-C6H11 Ph-CHdCH 2-Fur
CF3 CF3 C2F5 CH2F CF3 CF3 CF3 C2F5 CH2F CF3 C7F15 CF3
65 54 73 57b 53 71 76 82 56b 83 81 62
a Yields refer to isolated compounds. phosphonate 2.
b
“One pot” procedure from
Emmons olefination reaction of enamines 1 to give Nunsubstituted 1-azadienes 7, followed by subsequent selective hydride reduction of the imine carbon-nitrogen double bond of unstable heterodienes 7. From a preparative point of view, it is noteworthy that the synthesis of allylamines 6 does not require the isolation and purification of enamines 1 and that they can be obtained in a “one pot” reaction from phosphonates 2, when after the addition of base and fluronitriles 3 a subsequent addition of aldehydes and hydride is carried out (Table 2). Therefore, this procedure is quite general and highly selective, affording exclusively the E stereoisomer not only of R-trifluoromethyl allylamines 6a,b,e,f (RF ) CF3) but also of perfluoroalkyl 6c (RF ) C2F5) and of R-monofluoromethyl allylamines 6d (RF ) CH2F). These fluorinated allylamines 6 can be used as building blocks for the preparation of fluorine-containing R-amino aldehyde, R-amino ketone, and R-amino acids by an oxidative cleavage reaction of the carbon-carbon double bond. These results prompted us to extend this reaction to the preparation of R,β-unsaturated ketones 8. Treatment of primary enamines 1 with butyllithium, followed by addition (20) (a) Singh, R. P.; Ca, G. F.; Kichmeier, R. L.; Sheeve, J. M. J. Org. Chem. 1999, 64, 483. (b) Wiedemann, W.; Heiner, T.; Mloston, G.; Prakash, G. K. S.; Olah, G. A. Angew. Chem., Int. Ed. 1998, 37, 820. (c) Andrew, R. J.; Mellor, J. M. Tetrahedron 2000, 56, 7261. (d) Sanin, A. V.; Nenajdenko, V. G.; Smolko, K.; Denisenko, D. I.; Balenkova, E. S. Synthesis 1999, 842. (e) Huang, W. S.; Yuan, C. Y. J. Chem. Soc., Perkin Trans. 1 1995, 741. (f) Mo, X. S.; Huang, Y. Z. Synlett 1995, 180. (g) Xu, Y.; Dolbier, W. R. Tetrahedron Lett. 1998, 39, 9151. (h) Linderman, R. J.; Jamois, E. A.; Tennyson, S. D. J. Org. Chem. 1995, 59, 957. (21) General procedure for the preparation of allylamines 6: Butyllithium (1.6 M in hexanes) (3.12 mL, 5 mmol) was added to a solution of fluorinated enaminophosphonate 1a (1.23 g, 5 mmol) in THF (15 mL) at 0 °C under an N2 atmosphere. The mixture was stirred for 1 h at the same temperature. Then, a solution of p-methylbenzaldehyde (600 mg, 5 mmol) in THF (15 mL) was added and the reaction was stirred at room temperature until TLC showed the disappearance of 1a. The reaction was cooled to -78 °C; NaBH4 (386 mg, 10 mmol) and MeOH (25 mL) were added. After 1 h at -78 °C, the mixture was warmed to rt, 3% HCl (15 mL) was added, and stirring was continued for 1 h. The mixture was made alkaline (pH 12) with NaOH pellets and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over anhydrous MgSO4 and filtered, and the solvent was evaporated under vacuum. The crude product was purified by chromatography using silica gel (hexane/ethyl acetate) to give pure 6a (699 mg, 3.25 mmol). 771
of aldehydes and acid hydrolysis (H2SO4 5 M), afforded a stereoselective synthesis of R,β-unsaturated ketones 8a-f (Scheme 3), obtained only as the E isomers (see Table 2). Formation of compounds 8 can be explained by a HornerEmmons olefination reaction of enamines 1, followed by hydrolysis of the N-unsubstituted 1-azadienes 7. Ketones 8a-f can also be obtained in a “one pot” reaction from phosphonates 2 (Table 2). Finally, primary enamines 1 were used as starting materials for the preparation of vinylogous trifluoromethyl β-amino nitriles 9. Reaction of primary enamines 1a,d (R1 ) H, CH3, RF ) CF3) with butyllithium, followed by the addition of aldehydes and subsequent addition of metalated acetonitrile gave only the E-isomer of vinylogous trifluoromethyl β-amino nitriles 9a,b (Scheme 3) (57-60%).22 Formation of compounds 9 can be explained by an olefination reaction (22) General procedure for the preparation of vinylogous trifluoromethyl β-amino nitriles 9: Butyllithium (1.6 M in hexanes) (3.12 mL, 5 mmol) was added to a solution of fluorinated enaminophosphonate 1a (1.23 g, 5 mmol) in THF (15 mL) at 0 °C under an N2 atmosphere. The mixture was stirred for 1 h at the same temperature. Then, a solution of p-methylbenzaldehyde (600 mg, 5 mmol) in THF (15 mL) was added and the reaction was stirred at room temperature until TLC showed the disappearance of 1a. In another flask, butyllithium (1.6 M in hexanes) (3.12 mL, 5 mmol) was added to a solution of acetonitrile (0.26 mL, 5 mmol) in THF (15 mL) at -78 °C. The mixture was stirred for 1 h at -78 °C and then was added via cannula into the solution of the previously prepared unsaturated imine 7 cooled at -78 °C. The reaction was stirred at -78 °C until TLC indicated the disappearance of 7. Then, 0.1 N HCl was poured into the reaction, and the organic layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over anhydrous MgSO4 and filtered, and the solvent was evaporated under vacuum. The crude product was purified by chromatography using silica gel (hexane/ethyl acetate) to give pure 9a (762 mg, 3 mmol).
772
of enamines 1, followed by subsequent selective addition of metalated acetonitrile to the imine carbon-nitrogen double bond of R,β-unsaturated imine 7. Fluorine-containing amino acid derivatives or their precursors are important compounds in organic synthesis and in medicinal chemistry.8 In conclusion, the synthesis of primary fluoroalkyl enamino phosphonates 1 from fluoronitriles and alkyl phosphonates under mild reaction conditions is described. These primary enamines are versatile intermediates for the preparation of fluorinated R,β-unsaturated imines and ketones as well as of fluorinated allylamines and vinylogous β-amino nitriles. Simple fluorinated building blocks are useful compounds not only for their application in organic synthesis7,8 but also for their biological activities.7 Further studies of the use of the enamines 1 as starting materials for the preparation of acyclic compounds and heterocycles are in progress in our laboratory. Acknowledgment. The present work has been supported by the Direccio´n General de Investigacio´n del Ministerio de Ciencia y Tecnologı´a (MCYT, Madrid DGI, BQU2000-0217) and by the Universidad del Paı´s Vasco (UPV, G11/99). S.P. thanks the U.P.V. for a predoctoral fellowship. Supporting Information Available: General procedures and characterization data of compounds 1a-e, 6a-f, 8a-f, and 9a,b. This material is available free of charge via Internet at http://pubs.acs.org. OL017254P
Org. Lett., Vol. 4, No. 5, 2002
