Copyright 2009
Volume 28, Number 2, January 26, 2009
American Chemical Society
Communications Selectfluor-Mediated Dialkoxylation of Tungsten η2-Pyridinium Complexes George W. Kosturko,† Daniel P. Harrison,† Michal Sabat,† William H. Myers,‡ and W. Dean Harman*,† Departments of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904 and UniVersity of Richmond, Richmond, Virginia 27173 ReceiVed NoVember 7, 2008 Summary: η2-coordinated pyridinium complexes of {TpW(NO)(PMe3)} undergo a stereoselectiVe dialkoxylation reaction when treated with Selectfluor in an alcohol. The alkoxy groups add to the 5- and 6-positions in a syn fashion (proVen by X-ray diffraction). When the N-acetylpyridinium complex is dialkoxylated, the resulting acyldihydropyridinium system readily undergoes nucleophilic addition with cyanide ion to stereoselectiVely generate a third stereocenter at C2 of the pyridine ring. Treatment with CAN decomplexes the tetrahydropyridine.
moiety through an azide nucleophilic addition5 or Garner aldehyde.6,7 However, Comins et al. showed the potential of utilizing a pyridine as a synthon to oxygenated piperidines with their elegant synthesis of 1-deoxynojirimycin (3) from 4-methoxy-3-(triisopropylsilyl)pyridine.8
A multitude of polyhydroxylated piperidine alkaloids have been isolated from plants and animals, and several show promise as potential therapeutics.1 For example, nojirimycin (1) and mannojirimycin (2) are potential therapeutic agents for diabetes and tumor metastasis,2,3 and derivatives of 1-deoxynojirimycin (3) have been shown to inhibit the development of HIV in vitro.4 Most syntheses of these molecules incorporate the nitrogen
With the advent of the dearomatization agent {TpW(NO)(PMe3)},9 new synthetic opportunities have emerged for arenes and aromatic heterocycles that use this tungsten moiety to activate the aromatic ring through η2 coordination.10 We
* To whom correspondence should be addressed. E-mail:
[email protected]. † University of Virginia. ‡ University of Richmond. (1) Pearson, M. S. M.; Mathe´-Allainmat, M.; Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159–2191. (2) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750–770. (3) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401–404. (4) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645–1680.
(5) Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem. Soc. 1994, 116, 5099–5107. (6) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H.; Kato, A.; Adachi, I. J. Org. Chem. 2003, 68, 3603–3607. (7) Takahata, H.; Banba, Y.; Sasatani, M.; Nemoto, H.; Kato, A.; Adachi, I. Tetrahedron 2004, 60, 8199–8205. (8) Comins, D. L.; Fulp, A. B. Tetrahedron Lett. 2001, 42, 6839–6841. (9) Graham, P. M.; Meiere, S. M.; Sabat, M.; Harman, W. D. Organometallics 2003, 22, 4364. (10) Keane, J. M.; Harman, W. D. Organometallics 2005, 24, 1786– 1798.
10.1021/om801068u CCC: $40.75 2009 American Chemical Society Publication on Web 01/02/2009
388 Organometallics, Vol. 28, No. 2, 2009
Communications Scheme 1. Dimethoxylation of an η2-Pyridinium Complex
Figure 1. ORTEP diagrams of the complexes 7 and 14.
questioned whether common pyridines could be elaborated into oxygenated piperidines through such a strategy.11 The complex TpW(NO)(PMe3)(η2-benzene) (4) serves as a convenient precursor to η2 complexes of many aromatic molecules. In the case of pyridines, nitrogen coordination is suppressed by utilizing a π-donor group at the 2-position of the heterocycle.11 Hence, our studies commenced with the 2-methoxypyridine complex 5, prepared from 4 in 79% yield.11 While this species is isolated as a 2:1 ratio of coordination diastereomers, they are easily separated by selective precipitation from methanol. An earlier exploration of 2H-phenol complexes of tungsten revealed that electrophilic heteroatoms could be added to the uncoordinated π system without oxidation of the metal.12 Unfortunately, treatment of 5 with mCPBA resulted in an intractable mixture of products, presumably a result of oxidative degradation of the complex. Earlier studies have shown that the reduction potential for the W(I/0) couple dramatically increases when 5 is protonated (Ep,a ) +0.74 V for 5 · HOTf; cf. -0.06 V for 5), indicating that the conjugate acid 5 · HOTf is substantially more difficult to oxidize. Unfortunately, the reaction of 5 · HOTf with mCPBA or with NMO/OsO4 (Upjohn process) also resulted in decomposition. However, when the oxidant Selectfluor (6; Aldrich)13 was combined with 5 · HOTf in the presence of methanol,14,15 a ligand-based reaction product was isolated (7; 74%). A 31P-181W coupling constant of 266 Hz and nitrosyl stretching frequency of 1570 cm-1 suggested a neutral, nonaromatic π complex.11 A positive shift in the anodic peak potential from Ep,a ) -0.06 V (5) to +0.84 V (7) (NHE) indicated the presence of electron-withdrawing groups on the pyridine framework. 1H NMR data did not reveal any H-F coupling, but singlets between 3 and 4 ppm signified the incorporation of two methoxy groups. Ultimately, an X-ray diffraction study (Figure 1) confirmed that 7 was a trimethoxydihydropyridine complex, the product of a syn-dimethoxylation reaction at C5 and C6 of the pyridine ring (Scheme 1). Selectfluor has previously been used in the electrophilic addition of a primary alkoxide and fluoride across a CC double bond, sometimes en route to R-keto ethers.16,17 However, the (11) Delafuente, D. A.; Kosturko, G. W.; Graham, P. M.; Harman, W. H.; Myers, W. H.; Surendranath, Y.; Klet, R. C.; Welch, K. D.; Trindle, C. O.; Sabat, M.; Harman, W. D. J. Am. Chem. Soc. 2007, 129, 406–416. (12) Todd, M. A.; Sabat, M.; Myers, W. H.; Smith, T. M.; Harman, W. D. J. Am. Chem. Soc. 2008, 130, 6906–6907. (13) Syvret, R. G.; Butt, K. M.; Nguyen, T. P.; Bulleck, V. L.; Rieth, R. D. J. Org. Chem. 2002, 67, 4487–4493. (14) While Selectfluor is a common source of an electrophilic fluorine atom, it also has the ability to chemically modify heteroatomic nucleophiles to potential electrophiles. (15) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; ChiHuey, W. Angew. Chem., Int. Ed. 2004, 44, 192–212. (16) Stavber, S.; Sotler, T.; Zupan, M. Tetrahedron Lett. 1994, 35, 1105– 1108. (17) Manandhar, S.; Singh, R. P.; Eggers, G. V.; Shreeve, J. M. J. Org. Chem. 2002, 67, 6415–6420.
dialkoxylation of alkenes using this fluorinating reagent appears to be previously undocumented. The dialkoxylation of the pyridinium complex 5 · HOTf was successful with other primary alcohols, including ethanol (8; 68%), allylic alcohol (9; 52%), 4-methoxybenzyl alcohol (PMB) (10; 59%), and ethylene glycol (11; 66%). Secondary or tertiary alcohols failed to react in this manner. Both 31P NMR and cyclic voltammetric data indicated that the dialkoxylation of the pyridine ring occurred within seconds at ambient temperature. These four products (8-11) show electrochemical and spectroscopic features similar to those of 7. Further, proton-proton coupling data for H4-H5 (∼2 Hz) and H5-H6 (∼3 Hz) of 8-10 suggest that these products have the same configurations at C5 and C6 as does 7. A single diastereomer resulted (dr > 10:1) in all cases but for compound 9 (dr ) 3:1).18 The dialkoxylation reaction is potentially a valuable new synthetic tool for pyridines, and its optimization and mechanism are currently under investigation. The tungsten apparently stabilizes the purported allyl cation intermediate (see Scheme 1) resulting from addition of either E+ ) “MeO+” or “F+”.12 Rozen and Kol have described the ability of MeO+ (via methyl hypofluorite) to act on alkenes to form fluoroalkoxides.19,20 However, those reactions were carried out in acetonitrile; utilizing an alcohol as the solvent either pre-empts fluoride addition, or the F is replaced by the alkoxide in a subsequent substitution reaction. Possibly relevant is a report by Shreeve et al. describing the formation of 6-alkoxylated bipyridyls from primary alcohols and the potent fluorinating agent MeC-31.17 Finally, it is noteworthy that while Selectfluor often participates in single-electron-transfer (SET) processes,15 the tungsten is not oxidized in the conversion of 5 · HOTf to 7. The intact W(0) center of 5 · HOTf not only activates the pyridinium ligand but also protects the bound azadiene products from further oxidation. With the oxygenated dihydropyridine complexes in hand, we hoped to hydrolyze the imidate functionality in order to prevent the rearomatization of the pyridine ring upon decomplexation. Hence, treatment of 7 with 1 M HCl for 16 h yields the lactam 12 in 67% yield (eq 1). Unfortunately, the other dialkoxylated products (8-11) failed to yield the corresponding lactam products with 1 M HCl (20-55 °C, 5 days) and attempts to hasten this reaction by heating (>55 °C) resulted in decomposition. Furthermore, attempts to oxidatively decomplex 12 proved to be futile, as treatment of this lactam complex with CAN, (18) For 9, a minor impurity was detected that we believe could be the other coordination diastereomer. (19) Rozen, S.; Mishani, E.; Kol, M. J. Am. Chem. Soc. 1992, 114, 7643– 7645. (20) Kol, M.; Rozen, S.; Appelman, E. J. Am. Chem. Soc. 1991, 113, 2648–2651.
Communications
mCPBA, CuBr2, Fe(Cp)2+, or NBS under neutral or basic conditions yielded only intractable mixtures.
An attractive alternative to the 2-methoxypyridine synthon (5) was the recently reported N-acylpyridinium complex 13.21 This air-stable complex derived from pyridine-borane was also expected to be resistant to oxidation at the metal and offered an additional position (C2) for eventual elaboration of the pyridine ring. Treatment of 13 (available as a 10:1 mixture of coordination diastereomers)21 with 1.05 equiv of Selectfluor and methanol resulted in the dialkoxylation product 14, in a coordination diastereomer ratio of 8:1. Conveniently, we found that the major isomer could be isolated in pure form (55% yield) by precipitating it from a THF solution (Scheme 2). Significant back-bonding by the tungsten greatly stabilizes the acyliminium group in 14, and it resists reaction, even in the presence of water. However, C2 is still sufficiently electrophilic to smoothly react with NaBH4 and NaCN to form the dihydropyridine complexes 15 and 16, respectively (Scheme 2). Oxidative demetalation of 15 and 16 is accomplished using CAN in CDCl3 solution to generate 17 (40%) and 18, respectively (62%). H NMR spectra indicate that 17 and 18, as well as their precursors, are present as two-component mixtures; NOESY, HSQC, and COSY data confirm that, in all cases, the two NMR-resolved species are conformational isomers resulting from the hindered rotation of the amide C-N bond. (21) Harrison, D. P.; Welch, K. D.; Nichols-Nielander, A. C.; Sabat, M.; Myers, W. H.; Harman, W. D. J. Am. Chem. Soc. 2008, 130, 16844.
Organometallics, Vol. 28, No. 2, 2009 389 Scheme 2.
Bis-Alkoxylation of the N-Acetylpyridinium Complex and Elaboration
In conclusion, this work demonstrates that a transition-metal complex may be used to stereoselectively elaborate a pyridine into a highly functionalized piperidine. Specifically, a new approach to the preparation of polyoxygenated piperidines has been described that utilizes Selectfluor, a primary alcohol, and a η2-pyridinium complex. Dihapto coordination of the heterocycle allows for predictable stereocontrol of all electrophilic and nucleophilic addition reactions, and decomplexation unmasks the remaining alkene carbons.
Acknowledgment. Acknowledgement is made to the donors of the American Chemical Society Petroleum Research Fund (Grant No. 47306-AC1) and to the NSF (Grant No. CHE-0116492 (UR)). Supporting Information Available: CIF files giving crystallographic data for 7 and 14 and text and figures giving details of the syntheses, characterization data, and 1H and 13C NMR spectra of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. OM801068U
