Significant Acceleration of 6π-Azaelectrocyclization Resulting from a

(g) Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org. Chem. 1999 ...... Steven T. Staben , Joshua J. Kennedy-Smith , David Huang , Brit...
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J. Org. Chem. 2001, 66, 3099-3110

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Significant Acceleration of 6π-Azaelectrocyclization Resulting from a Remarkable Substituent Effect and Formal Synthesis of the Ocular Age Pigment A2-E by a New Method for Substituted Pyridine Synthesis Katsunori Tanaka, Hajime Mori, Mako Yamamoto, and Shigeo Katsumura* School of Science, Kwansei Gakuin University, Uegahara, Nishinomiya, Hyogo 662-8501, Japan [email protected] Received December 21, 2000

The remarkable acceleration of 6π-azaelectrocyclization due to the combination of the C4-carbonyl and the C6-alkenyl or phenyl substituents in 1-azatrienes was found. This observation was rationalized by considering the remarkable orbital interaction between the HOMO and LUMO of 1-azatrienes, which were obtained by molecular orbital calculations. The formal synthesis of the unusual retinal metabolite, A2-E, was achieved by two types of the new one-pot synthesis of substituted pyridines by utilizing the obtained facile 6π-azaelectrocyclization, one of which is compatible with the proposed metabolic pathway of A2-E. Introduction The thermal cyclization of 1-azatrienes to 1,2-dihydropyridines1 is analogous to the well-known ring closure of 1,3,5-hexatrienes to 1,3-cyclohexadienes.2-4 This process is considered to involve the classical concerted electrocyclization, which proceeds in a disrotatory mode.5 As an example of the thermal cyclization of 1-azatriene, which is called 6π-azaelectrocyclization, cis-dienone oximes are known to form pyridines at 160 °C in about 25% yield via azaelectrocyclization followed by dehydration of the intermediary 1,2-dihydropyridine derivatives.6 Also, it was reported that O-acyl hydroxamic acid derivatives directly gave N-acyl-1,2-dihydropyridine derivatives through the electrocyclization of N-acylazatrienes, which were produced by heating the hydroxamic acid at 650 °C under flash vacuum pyrolysis.7 Although there are a number of examples of 6π-azaelectrocyclization reactions, the study of the reactivity of 1-azatrienes toward 6πazaelectrocyclization is limited and the application of this reaction to natural product synthesis is also very limited in the literature. This is presumably because the azaelectrocyclization process has been believed to require high temperature, and in addition, the method for * To whom correspondence should be addressed. Phone: 81-079854-6381. Fax: 81-0798-51-0914. (1) Marvell, E. N. Thermal Electrocyclic Reactions; Academic Press: New York, 1980. (2) (a) Marvell, E. N.; Caple, G.; Schatz, B.; Pippin, W. Tetrahedron 1973, 29, 3781. (b) Marvell, E. N.; Caple, G.; Delphey, C.; Platt, J.; Polston, N.; Tashiro, J. Tetrahedron 1973, 29, 3797. (3) Spangler, C. W.; Jondahl, T. P.; Spangler, B. J. Org. Chem. 1973, 38, 2478. (4) (a) Palenzuela, J. A.; Elnagar, H. Y.; Okamura, W. H. J. Am. Chem. Soc. 1989, 111, 1770. (b) Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877. (c) Okamura, W. H.; de Lera, A. R. Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Paquette, L. A., Volume Ed.; Pergamon Press: London, 1991; Vol. 5, Chapter 6.2, pp 699-750. (5) Maynard, D. F.; Okamura, W. H. J. Org. Chem. 1995, 60, 1763. (6) Schiess, P.; Chia, H. L.; Ringele, P. Tetrahedron Lett. 1972, 313. (7) (a) Cheng, Y.-S.; Lupo, A. T., Jr.; Fowler, F. W. J. Am. Chem. Soc. 1983, 105, 7696. (b) Wyle, M. J.; Fowler, F. W. J. Org. Chem. 1984, 49, 4025.

Scheme 1

preparation of 3-cis-1-azatrienes as precursors of the electrocyclization was not well established. Recently, Okamura and co-workers reported that the Schiff base 1, obtained by the reaction of 13-tert-butyl13-cis-retinal with n-butylamine, exceptionally produced the corresponding 1,2-dihydropyridine derivative at 23 °C with a half-life of only 11 min (Scheme 1).8 Their explanation was based on conformational analysis that the smooth azaelectrocyclization of 1 was due to the predominant 12,13-s-cis arrangement, which leads to the smooth 6π-electrocyclization. Then, they prepared various 4-tert-butyl-1-azatriene derivatives and examined how the steric and electronic factors affected the disrotatory 6π-azaelectrocyclization through structure-reactivity studies.5 They found that the introduction of either an electron donor or an acceptor group at the 1-azatriene terminus moderately accelerated the reaction rate of the electrocyclization in comparison with the parent azatriene system. (8) de Lera, A. R.; Reischl, W.; Okamura, W. H. J. Am. Chem. Soc. 1989, 111, 4051.

10.1021/jo005779+ CCC: $20.00 © 2001 American Chemical Society Published on Web 04/12/2001

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During the course of our recent studies on the syntheses of enzyme inhibitors and then on the elucidation of their inhibitory mechanism, we found that the (E)-3carbonyl-2,4,6-trienal compound AO inhibited the hydrolytic ability of phospholipase A2 (PLA2) by the formation of the dihydropyridine derivative resulting from the reaction with particular lysine residue of PLA2 via 6πelectrocyclization of the intermediary Schiff base.9 Moreover, we observed that the reaction of AO with n-propylamine quantitatively yielded the corresponding 1,2-dihydropyridine derivative within 5 min at room temperature; on the other hand, the derivatives BO and CO only gave the corresponding Schiff bases BN and CN within 30 min. Thus, the presence of both the C4-carbonyl group and the C6-alkenyl group in 1-azatriene AN significantly contributed to acceleration of the azaelectrocyclization. Although we found this rapid azaelectrocyclization reaction very attractive, there were some limitations in order to apply this methodology for dihydropyridine formation into a wide range of compounds. One is the general preparation method for the (E)-3-carbonyl-2,4,6-trienal compounds, and another is the generality and understanding of the quite obvious substituent effect. It was necessary to examine whether the previous results obtained could be applicable for more usual linear compounds. Herein, we disclose in detail a new and efficient method for the synthesis of the 3-cis-1-azatriene derivatives and the result of their 6π-azaelectrocyclization reactions. On the basis of the cyclization studies, we concluded that the combination of the C4-carbonyl and the C6-alkenyl or phenyl groups in 1-azatrienes actually contributed to the remarkable acceleration of the azaelectrocyclization based on the orbital interaction between the HOMO of the olefin part and the LUMO of the azadiene part under the reverse-electron-demand mode. This conclusion was supported by the molecular orbital calculation of the azatriene. Moreover, the results obtained here were applied to the formal synthesis of the ocular age pigment A2-E by means of two types of the new and efficient onepot synthesis of substituted pyridines, which involves the smooth 6π-azaelectrocyclization of the Schiff base derived from (E)-3-carbonyl-2,4,6-trienal.10 Results and Discussion Synthesis of 3-cis-1-Azatriene Derivatives and Their Reactivities toward Azaelectrocyclization. In our previous studies of the smooth 6π-azaelectrocyclization, the mainly investigated azatrienes were in a retinoid system containing the 2,6,6-trimethylcyclohexane substituent, which might be a characteristic system because of its steric bulkiness and fairly twisted nature around the C6-C7 single bond of the azatriene AN.11 Therefore, the derivatives DN-GN in Scheme 2 were (9) (a) Tanaka, K.; Kamatani, M.; Mori, H.; Fujii, S.; Ikeda, K.; Hisada, M.; Itagaki, Y.; Katsumura, S. Tetrahedron Lett. 1998, 39, 1185. (b) Tanaka, K.; Kamatani, M.; Mori, H.; Fujii, S.; Ikeda, K.; Hisada, M.; Itagaki, Y.; Katsumura, S. Tetrahedron 1999, 55, 1657. (c) Tanaka, K.; Katsumura, S. J. Synth. Org. Chem. Jpn. 1999, 57, 876. (10) Tanaka, K.; Katsumura, S. Org. Lett. 2000, 2, 373. (11) For example, (a) Wada, A.; Sakai, M.; Kinumi, T.; Tsujimoto, K.; Yamaguchi, M.; Ito, M. J. Org. Chem. 1994, 59, 6922. (b) Doering, W. E.; Leventis, C. S.; Roth, W. R. J. Am. Chem. Soc. 1995, 117, 2747. (c) Lou, J.; Hashimoto, M.; Berova, N.; Nakanishi, K. Org. Lett. 1999, 1, 51. (d) Mori, H.; Ikoma, K.; Isoe, S.; Kitaura, K.; Katsumura, S. J. Org. Chem. 1998, 63, 8704.

Tanaka et al. Scheme 2a

a Conditions: (a) diethylphosphonoacetic acid ethyl ester, NaH, THF; (b) LiAlH4, ether, 89% in two steps; (c) TBDMSCl, Et3N, DMAP, DMF, 86%; (d) n-Bu3SnH, AlBN, 120 °C, 49%; (e) TBDMSCl, Et3N, DMAP, DMF, 97%; (f) CH2Cl2, rt, 99% from 2-butene1,4-diol, Z/E ) 10:1; (g) p-TsOH, MeOH, 83%; (h) Pd(PPh3)4, LiCl, DMF, 75-120 °C, 71-91%; (i) MnO2, CH2Cl2, 59-80%.

selected as another and a more general azatriene system. Although we previously established the highly stereoselective synthesis of (E)-3-alkoxycarbonyl-2,4,6-trienal compounds such as AO by hydrometalation of ethynyl groups as the key step,9,12 we knew that this method was not applicable for a wide range of derivatives. The compounds DO-GO could be stereoselectively synthesized by means of Pd(0)-catalyzed Stille coupling13 between (E)-vinylstannane VS and (Z)-vinyl halide VH as a more general method for the synthesis of such types of compounds. Vinylstannanes 4, 5 and vinyl halides 6, 10 were prepared as shown in Scheme 2. (E)-Vinylstannane 2, which was obtained by the hydrostannylation of propargyl alcohol with tri-n-butyltin hydride14 followed by oxidation with manganese dioxide in 88% yield, was subjected to the Horner-Emmons reaction with the sodium salt of diethyl phosphonoacetic acid ethyl ester (12) Sato, F.; Ishikawa, H.; Watanabe, H.; Miyake, T.; Sato, M. J. Chem. Soc., Chem. Commun. 1981, 718. (13) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic Reactions; Paquette, L. A., Ed.; John Wiley and Sons: New York, 1997; Vol. 50, pp 1-652. (c) Mitchell, T. N. Synthesis 1992, 803. (14) Oddon, G.; Uguen, D. Tetrahedron Lett. 1998, 39, 1153.

Acceleration of 6π-Azaelectrocyclization

to provide 3. Reduction of 3 without purification and then protection of the resulting primary alcohol with tertbutyldimethylsilyl chloride completed the synthesis of the vinyl stannyl fragment 4 in 77% yield for three steps. The vinylstannane 5 was similarly prepared by the hydrostannylation of 4-pentyn-1-ol with tri-n-butyltin hydride followed by the protection of the alcohol in 48% yield for two steps. Meanwhile, (Z)-vinyl bromide 10 was synthesized by the stereoselective Wittig reaction as the key step. Thus, aldehyde 7 prepared from 2-butene-1,4diol by the protection of the dialcohol as the tetrahydropyranyl ether followed by ozonolysis15 was reacted with the Wittig reagent, triphenylcarboethoxybromomethylenephosphorane 8,16 to provide 9 in nearly quantitative yield from the diol. The ratio of Z to E was 10:1 based on an NMR analysis. After removal of the THP group by treatment with p-toluenesulfonic acid, the Z and E stereoisomers were separated by column chromatography on silica gel to give pure (Z)-vinyl bromide 10 in 83% yield. The THP group was superior for the protection of the primary alcohol to silyl protection groups in the largescale synthesis of 10. Vinyl iodide 6 was synthesized by hydroalumination of 2-butyn-1-ol with lithium aluminum hydride in THF followed by the reaction with iodine in 76% yield.17 The Stille coupling between stannane 4 and bromide 10 proceeded smoothly in the presence of 5 mol % tetrakis(triphenylphosphine)palladium(0) and 2 equiv of lithium chloride in dimethyl formamide at 115 °C to give the corresponding alcohol in 71% yield with the complete retention of their stereochemistry.18,19 The oxidation of the alcohol with manganese dioxide provided DO in 80% yield. Thus, the new stereoselective synthesis of 3-alkoxycarbonyl-2(E),4(E),6(E)-trienal was achieved. This is believed to be a general and practical method for the synthesis of (E)-3-alkoxycarbonyl-conjugated aldehydes. Similarly, the Stille coupling between 4 and 6 and between 5 and 6 produced the corresponding alcohols in 71 and 91% yield, and then the oxidation of the obtained alcohols provided the corresponding aldehydes, FO and GO, in 67 and 59% yield, respectively. The Stille coupling between 5 and 10 produced the corresponding alcohol, which was oxidized to yield an equilibrium mixture of EP and EO. In this mixture, EP was predominant, and a very small amount of EO was detected by its characteristic 1H NMR signal of the aldehyde proton. It is wellknown that the dienal derivatives are in equilibrium with their corresponding R-pyran derivatives via electrocyclization.1 Thus, the syntheses of conjugated aldehydes DO-GO were efficiently achieved from simple building blocks in a few steps. Preparation of 1-azatrienes and subsequent azaelectrocyclization from the synthesized DO, EO (EP), FO, and GO were investigated. Compounds DO-GO were treated with 1.1 equiv of n-propylamine, and each reaction was monitored over time by 1H NMR in benzene-d6 at 23 °C.5,8 The results are shown in Figure 1. As expected, (E)-3carbonyl-2,4,6-trienal DO smoothly produced the corre(15) Francesch, A.; Alvarez, R.; Lopez, S.; de Lera, A. R. J. Org. Chem. 1997, 62, 310. (16) (a) Denney, D. B.; Ross, S. T. J. Org. Chem. 1962, 27, 998. (b) Speziale, A. J.; Ratts, K. W. J. Org. Chem. 1963, 28, 465. (17) Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193. (18) Martin, S. F.; Humphrey, J. M.; Ali, A.; Hillier, M. C. J. Am. Chem. Soc. 1999, 121, 866. (19) Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; La Greca, S.; Tsuri, T.; Yue, E. W.; Yang, Z. Angew Chem. 1994, 106, 2309.

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Figure 1. 6π-Azaelectrocyclization of 1-azatrienes DN-GN.

sponding 1,2-dihydropyridine derivative DDHP within 5 min as well as the case of AO, and the formation of the corresponding azatriene DN was not detected. On the contrary, trienal GO lacking both the C4-carbonyl group and the C6-alkenyl group smoothly produced the corresponding azatriene GN, which was detected by its 1H NMR, and slowly cyclized to the dihydropyridine derivative GDHP. FN was smoothly produced from FO, which has no carbonyl group in the azatriene system, and was almost inactive toward the azaelectrocyclization within 7 h.8 In the case of EO (EP), the equilibrium mixture between EO, EP, and EN gave the corresponding dihydropyridine derivative EDHP over 10 h by reaction with propylamine. Thus, although the electrocyclic process of 1-azatriene EN could not be directly observed, the present results clearly showed that the presence of a carbonyl group at C4 and an alkenyl group at C6 remarkably accelerated the 6π-azaelectrocyclization of 1-azatrienes. Thus, the results previously obtained in the retinoid compounds corresponded well to those in the more usual linear compounds. Next, to understand the obtained results in more detail, further substituent effects at N1, C4, and C6 positions of the retinoid system AN toward the electrocyclization were investigated. The N1-, C4-, and C6modified azatrienes HN-O were selected for this purpose, and their electrocyclization was examined (Scheme 3). Thus, the C6-alkenyl group in AN was exchanged with para-substituted phenyl groups (HN-JN), and the C4ester group in AN was replaced by a carboxylic acid and an amide group (KN and LN), respectively. For the modification of the N-1 alkyl substituent in AN, Nhydroxy derivatives (M-O) were planned. The trienals

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Figure 2. 6π-Azaelectrocyclization of 1-azatrienes HN-LN.

Scheme 3

HO-JO were stereoselectively synthesized by the method previously established. Thus, the (E)-β-styryltributyltin compounds, which were obtained from the corresponding acetylenes by hydrostannylation,20 were reacted with vinyl bromide 10 under Stille coupling conditions followed by oxidation to provide HO-JO. Meanwhile, the aldehydes KO and LO were prepared from 11, which was stereoselectively synthesized by means of the Cp2TiHClcatalyzed hydromagnesiation of ethynyl alcohol.9,12 Thus, aldehyde KO was obtained by oxidation of 11 with manganese dioxide in 53% yield. The reaction of 11 with pivaloyl chloride and then propylamine gave the corresponding amide in 68% yield, which was oxidized with (20) Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983, 48, 4634.

manganese dioxide to provide LO in 94% yield. The azatrienes M and N were easily prepared by treatment of AO with hydroxylamine and methoxylamine hydrochloride in pyridine, respectively, and O was obtained by the reaction of M with acetyl chloride. The reactions between HO-LO and propylamine were examined under the same conditions as before, and the results are shown in Figure 2. All of the derivatives HOJO rapidly produced the corresponding dihydropyridines HDHP-JDHP within 10 min, and no clear effect on the reaction rate of the electrocyclization due to the para substituents of the phenyl group was observed. Thus, C6phenyl substituents in 1-azatrienes were found to similarly accelerate the azaelectrocyclization as well as the C6-double bond in AN. Moreover, the reaction of KO and LO with propylamine smoothly produced the corresponding dihydropyridines KDHP and LDHP within 1 and 3 h, which were very unstable and gradually decomposed to unidentified products, respectively. The preparation of the corresponding intermediary imines KN and LN was only detected by the observation of the characteristic signals in their 1H NMR. Although both the carboxylic acid and amide substituents as the electron-withdrawing groups at C4 of the 1-azatriene similarly contributed to the acceleration of the azaelectrocyclization, the rate of their electrocyclization was apparently slower than the case of AN, which bears an ester group at C4, as shown in Figure 2. Interestingly, no cyclization of azatrienes M and N occurred within 60 min at 23 °C. This phenomenon is different from the case of the N-alkyl-1-azatriene derivative AN. However, azatriene O smoothly produced the corresponding pyridine derivative 12 within 40 min at 23 °C (Scheme 3). The reaction must proceed via the rapid azaelectrocyclization of N-acetoxy-1-azatriene O to give the corresponding dihydropyridine, which smoothly gave the pyridine derivative 12 by the elimination of acetic acid in the presence of pyridine. Schiess and coworkers reported that the cis-dienone oximes and their benzoate derivatives, which could be obtained from pyridine N-oxides, provided the corresponding pyridines by heating at 50-160 °C.6 Since our pyridine 12 is readily obtained in one pot by treatment of (E)-3-carbonyltrienal with hydroxylamine and acetyl chloride at room temperature, this novel reaction is believed to be a useful method for the synthesis of substituted pyridine deriva-

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Figure 3. Pictorial presentation of the MO calculation results of 1-azatrienes AN-CN.

tives. Thus, a new and convenient method for the synthesis of substituted pyridine derivatives was realized. Computational Analysis. We attempted to rationalize the substituent effect on the electrocyclization by molecular orbital calculations. The calculation was performed on the retinoid compounds AN, BN, CN, M, and O. First, the 2,3-s-cis, 4,5-s-cis conformation of 4-methylazatriene BN was optimized with a semiempirical method (PM3) using the software packages SPARTAN version 5.0 (Wavefunction, Inc., Irvine CA). That conformation of BN was required for the electrocyclization to proceed.21 The stable conformations of AN, CN, M, and O were also obtained by the calculation using the same PM3 method similar to the case of BN. Then, the electron densities of the frontier orbitals and the HOMO-LUMO energy gaps of these five azatrienes were calculated at the HF/6-31G* level by SPARTAN. The pictorial presentation of the calculation results is shown in Figure 3. By comparing the calculated results of AN, BN, and CN to each other, the energy gap of AN was evidently found to be the smallest of the three. Furthermore, in the azatriene system of AN, the HOMO electron density was arranged around C5-C6 and the LUMO electron density was arranged around N1-C4, respectively. It is proposed that both the C4 carbonyl group and the C6-alkenyl group would significantly contribute to the strong interaction between the HOMO of the C5-C6 olefin part and the LUMO of the N1-C4 azadiene part in the 1-azatriene system, thus promoting the azaelectrocyclization of AN. This remarkable substituent effect is quite similar to that of the well-known reverse-electron-demand aza-DielsAlder reactions, in which electron-deficient azadienes smoothly react with electron-rich dienophiles.22 The computational analysis also supported the observed result that the aromatic groups at C6 and some electronwithdrawing groups at C4 of 1-azatriene similarly accelerated the azaelectrocyclization. The faster reaction rate of the azaelectrocyclization of AN in comparison with those of the carboxylic acid and amide derivative, KN and LN, is rationalized by considering the stronger electron withdrawing ability of the ester substituent in AN. As described previously, the distinctly different reactivities between M and O toward azaelectrocyclization were noted. The similar calculations of these two compounds, however, showed that the HOMO-LUMO energy gaps and the distributions of their electron densities were almost the same as one another. The low reactivities (21) Rodriguez-Otero, J. J. Org. Chem. 1999, 64, 6842. (22) Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley: New York, 1987.

of M and N are presumably due to the unfavorable electrostatic repulsion between the oxygen atom at N1 and C5-C6 π-electrons developing in the transition state, or due to the thermodynamic stability of the oximes relative to the corresponding cyclized products.23 In summary, we achieved significant acceleration of 6π-azaelectrocyclization by the introduction of the substituent pair of the C4-carbonyl and C6-alkenyl or phenol groups; the observed results were in accord with MO calculations. The calculation clearly demonstrated that both functions contribute to the strong HOMO-LUMO interaction between the C5-C6 olefin part and the N1C4 azadiene part in the azatriene. Now, our next interests are to apply the obtained results into natural product synthesis,24-26 and to establish the observed facile 6πazaelectrocyclization as a new synthetic strategy. Formal Synthesis of the Ocular Age Pigment A2E: A New Method for Substituted Pyridine Synthesis via Azaelectrocyclization. Pyridinium bisretinoid “A2-E” was isolated from over 40 aged human eyes as the major orange fluorophore of ocular age pigments called lipofuscin; its structure was determined by Nakanishi and co-workers.27 Lipofuscin accumulates in the human retinal pigment epithelium (RPE) cells28 with age (23) Schiess and co-workers reported that the benzoate derivatives of cis-dienone oximes easily cyclized rather than the corresponding oximes; they tried to explain the obtained results by considering the relative thermodynamic stability between the starting compounds and the products, see ref 6. (24) Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1. (b) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223. (25) For some examples for the recent references concerning the 1,2dihydropyridine as the intermediates of natural product syntheses, see: (a) Krow, G. R.; Carey, J. T.; Cannon, K. C.; Henz, K. J. Tetrahedron Lett. 1982, 23, 2527. (b) Kunng, F.-A.; Gu, J.-M.; Chao, S.; Chen, Y.; Mariano, P. S. J. Org. Chem. 1983, 48, 4262. (c) Raucher, S.; Lawrence, R. F. Tetrahedron Lett. 1983, 24, 2927. (d) Szantay, C.; Keve, T.; Bolcskei, H.; Acs, T. Tetrahedron Lett. 1983, 24, 5539. (e) Ogawa, M.; Kuriya, N.; Natsume, M. Tetrahedron Lett. 1984, 25, 969. (f) Shono, T.; Matsumura, Y.; Onomura, O.; Yamada, Y. Tetrahedron Lett. 1987, 28, 4073. (g) Matsumura, Y.; Nakamura, Y.; Maki, T.; Onomura, O. Tetrahedron Lett. 2000, 41, 7685. (26) (a) Comins, D. L.; Abdullah, A. H.; Smith R. K. Tetrahedron Lett. 1983, 24, 2711. (b) Comins, D. L.; Joseph, S. P. Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; JAI Press: Greenwich, CT, 1996; Vol. 2, pp 251-294. (c) Comins, D. L.; LaMunyon, D. H.; Chen, X. J. Org. Chem. 1997, 62, 8182. (d) Comins, D. L.; Stolze, D. A.; Thakker, P.; McArdle, C. L. Tetrahedron Lett. 1998, 39, 5693. (e) Comins, D. L.; Zhang, Y.; Zheng, X. J. Chem. Soc., Chem. Commun. 1998, 2509. (f) Comins, D. L.; Kuethe, J. T.; Hong, H.; Lakner, F. J. J. Am. Chem. Soc. 1999, 121, 2651. (g) Comins, D. L.; Libby, A. H.; Alawar, R. S.; Foti, C. J. J. Org. Chem. 1999, 64, 2184. (h) Comins, D. L.; Brooks, C. A.; Al-awar, R. S.; Goehring, R. R. Org. Lett. 1999, 1, 229. (i) Comins, D. L.; Zhang, Y.; Joseph, S. P. Org. Lett. 1999, 1, 657. (j) Comins, D. L.; Green, G. M. Tetrahedron Lett. 1999, 40, 217. (k) Comins, D. L. J. Heterocycl. Chem. 1999, 36, 1491. (l) Brooks, C. A.; Comins, D. L. Tetrahedron Lett. 2000, 41, 3551. (27) Sakai, N.; Decatur, J.; Nakanishi, K. J. Am. Chem. Soc. 1996, 118, 1559.

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and is considered as the possible cause of age-related decline of cell functions and related eye diseases, such as age-related macular degeneration (AMD),29 which leads to blindness in elderly people. For this reason, the main component of lipofuscin, “A2-E”, which might be involved in the process of AMD, has been the potential target molecule for remedies of this disease. Nakanishi and co-workers proposed the production pathway of A2-E in the human epithelium cell as shown in Scheme 4.27 Thus, 2 equiv of all-trans-retinal and ethanolamine would give azatriene 13, which would produce A2-E via an 6πazaelectrocyclization reaction followed by autoxidation. Furthermore, they synthesized A2-E by the double-Wittig olefination of bis-aldehyde 15 with the Wittig reagent 16, and the bis-aldehyde 15 was synthesized from 4-methyl2-pyridone 14 via the allylic oxidation of the 4-methyl group and the installation of the unsaturated side chain at the 2 position by Pd(0)-catalyzed Stille coupling.30,31 Herein, we describe the formal synthesis of the substituted pyridine derivative A2-E by the two types of methods utilizing the 6π-azaelectrocyclization. One is the one-pot pyridine synthesis established in Scheme 3, which involves the smooth 6π-azaelectrocyclization of the N-acetoxy-1-azatriene followed by the elimination of acetic acid. Another is based on the azaelectrocyclization followed by oxidation, which is compatible with Nakanishi’s hypothetical metabolic pathway from all-transretinal to A2-E (Scheme 5). In the latter method, we selected the trimethylsilylimine derivative 22 as the attractive synthetic precursor in order to achieve the efficient oxidation of the dihydropyridine to the corresponding pyridine; this silylimine 22 would be synthesized by utilizing the Peterson reaction of 20 with lithium (28) (a) Feeney-Burns, L.; Hilderbrand, E. S.; Eldridge, S. Invest. Ophthalmol. Visual Sci. 1984, 25, 195. (b) Porta, E. A. Arch. Gerontol. Geriatr. 1991, 12, 303. (c) Sarna, T. J. Photochem. Photobiol., B 1992, 12, 215. (29) Tso, M. O. M. Invest. Ophthalmol. Visual Sci. 1989, 30, 2430. (30) Ren, R. X.-F.; Sakai, N.; Nakanishi, K. J. Am. Chem. Soc. 1997, 119, 3619. (31) Nakanishi and co-workers also succeeded in the efficient synthesis of A2-E from 2 equivalents of all-trans-retinal and ethanolamine in 49% yield in one step, and they obtained a sufficient quantity of A2-E for the elucidation of its biological properties in RPE cells: Parish, C. A.; Hashimoto, M.; Nakanishi, K.; Dillon, J.; Sparrow, J. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 14609.

Tanaka et al. Scheme 5

bis(trimethylsilyl)amide.32 The (E)-3-carbonyl-2,4,6-trienal 20, which would be the common intermediate for both pyridine syntheses, could be prepared by the similar procedure used for the preparation of compound DO in Scheme 2. Thus, the Horner-Emmons reaction of 2 with the sodium salt of triethylphosphonoacetate provided 17, which was reduced with lithium aluminum hydride followed by protection of the alcohol with TBDMSCl to give the desired vinylstannane 18 in 78% yield in three steps. The Stille coupling between 18 and 10 in the presence of tertakis(triphenylphosphine)palladium(0) and lithium chloride in DMF produced 19 in 72% yield, which was oxidized with manganese dioxide to yield 20 in 85% yield. As the first trial for the pyridine synthesis, 20 was reacted with hydroxylamine in pyridine for 15 min, and the produced oxime derivative was continuously reacted with acetyl chloride at room temperature for 10 min. In this first method, the corresponding pyridine derivative 21 was successfully obtained in 53% yield. Next, the second method of pyridine synthesis, which is biogenetic type synthesis of A2-E, was examined. Thus, treatment of 20 with excess lithium bis(trimethylsilyl)amide in THF at room temperature cleanly produced the corresponding N-trimethylsilyl-1,2-dihydropyridine derivative within 1 min via the Peterson reaction, followed by the smooth azaelectrocyclization of the resulting intermediary azatriene 22. The reaction mixture of the unstable 1,2dihydropyridine derivative obtained was then continuously treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an oxidant33 to successfully yield the (32) (a) Hart, D. J.; Kanai, K.; Thomas, D. G.; Yang, T.-K. J. Org. Chem. 1983, 48, 289. (b) Cainelli, G.; Giacomini, D.; Panunzio, M.; Martelli, G.; Spunta, G. Tetrahedron Lett. 1987, 28, 5369. (c) Uyehara, T.; Suzuki, I.; Yamamoto, Y. Tetrahedron Lett. 1990, 31, 3753.

Acceleration of 6π-Azaelectrocyclization

desired pyridine derivative 21 in one pot. Reaction of the obtained crude 21 with lithiun aluminum hydride gave 23 in 77% total yield from 20. No Michael adducts of LiN(TMS)2 to the 3-carbonyltrienal system and no other byproducts were detected in the reaction mixture. These two types of efficient one-pot procedures, which utilize the electrocyclization of 1-azatriene derived from (E)-3carbonyltrienal, provide a new entry for the synthesis of the substituted pyridine derivative. Finally, the synthesis of bis-aldehyde 15, mp 91 °C, was successfully realized from 23 by the deprotection of the TBDMS group followed by oxidation with manganese dioxide. The spectral characteristics (1H and 13C NMR) of the synthesized bisaldehyde 15 were in good agreement with those reported by Nakanishi and co-workers.10 Thus, we achieved the formal synthesis of the ocular age pigment A2-E by focusing on the efficient one-pot synthesis of the pyridine derivative by utilizing two methods: (1) one is the smooth azaelectrocyclization of N-acetoxy-1-azatriene, which was readily obtained from the (E)-3-carbonyl-2,4,6-trienal 20, hydroxylamine, and acetyl chloride, followed by elimination of acetic acid; (2) the other involves the Peterson reaction of 20 with lithium bis(trimethylsilyl)amide, the facile 6π-azaelectrocyclization of the corresponding 1-azatriene derivative, and then oxidation. The latter sequence of the 6πazaelectrocyclization followed by oxidation is compatible with Nakanishi’s hypothetical metabolic pathway of A2-E. Summary Herein, we established the new stereoselective synthesis of 3-cis-1-azatriene derivatives and examined their reactivities toward azaelectrocyclization. It was elucidated that the presence of a combination of C4-ester and C6-alkenyl or phenyl substituents in 1-azatriene significantly accelerated the 6π-azaelectrocyclization. Then, it was concluded that these functions contributed to the strong HOMO-LUMO interaction between the C5-C6 olefin part and the N1-C4 azadiene part of 1-azatrienes under the reverse-electron-demand mode, based on the MO calculation. This activation was also observed in the electrocyclization of azatrienes HN-LN, which possessed phenyl groups at C6 and some electron-withdrawing groups at C4, and of azatriene O, which contained acetoxy group at N1 of 1-azatriene. Moreover, the two types of the novel one-pot synthesis of the substituted pyridine derivatives were developed, and the methods were successfully applied to the formal synthesis of the A2-E. Thus, the observed smooth azaelectrocyclization can be regarded as one of the new synthetic strategies. We believe that the results mentioned in this paper are valuable enough not only for understanding the further reactivity of pericyclic 6π-azaelectrocyclization but also for the elucidation of the plausible action of azaelectrocyclization in a biofunctional process. For example, some enzyme can be inactivated resulting from the irreversible modification of its particular lysine residue via azaelectrocyclization9 or some biologically important aldehydes may produce the undesired metabolites of age-related decline of cell functions such as a (33) (a) Omote, Y.; Komatsu, T.; Kobayashi, R.; Sugiyama, N. Tetrahedron Lett. 1972, 93. (b) Dommisse, R.; Desseyn, H. O.; Alderweireldt, F. C. Spectrochim. Acta 1973, 29, 107.

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retinal metabolite, A2-E, by reaction with a naturally occurring amine via azaelectrocyclization.

Experimental Section All commercially available reagents were used without further purification. All solvents were used after distillation. Tetrahydrofuran and diethyl ether were refluxed over and distilled from sodium. Dichloromethane was refluxed over and distilled from CaH2. Dimethylformamide (DMF) was distilled from CaH2 under reduced pressure. Preparative separation was usually performed by column chromatography on silica gel (FUJI silysia LTD, BW-200 and BW-300). 1H NMR and 13C NMR spectra were recorded on a JEOL R-400 spectrometer and chemical shifts were represented as δ-values relative to the internal standard TMS. IR spectra were recorded on a JASCO FT/IR-8000 Fourier transform infrared spectrometer. High-resolution mass spectra (HRMS) were measured on a Hitachi M-4100 tandem mass spectrometer. Melting points were uncorrected. Ethyl (2E,4E)-5-(Tri-n-butylstannyl)pentadienoate (3). To a THF (260 mL) solution of sodium hydride (2.96 g, 77.4 mmol) was added dropwise diethylphosphonoacetic acid ethyl ester (15.4 mL, 77.4 mmol) at -15 °C over 30 min. The reaction mixture was stirred at -15 °C for 30 min, and a THF (50 mL) solution of (E)-3-tri-n-butylstannylpropenal 2 (20.5 g, 59.5 mmol) was added at this temperature. After the mixture was warmed to room temperature and stirred for an additional 1 h, H2O was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (5% ethyl acetate in hexane) gave ester 3 as a colorless oil that was reduced without further purification: IR (neat, cm-1) 1717, 1626, 1462, 1294, 1273, 1211, 1152; 1H NMR (400 MHz, CDCl3) δ 0.87-0.96 (m, 15H) including 0.89 (t, 9H, J ) 7.3 Hz), 1.24-1.35 (m, 9H) including 1.29 (t, 3H, J ) 7.1 Hz), 1.46-1.54 (m, 6H), 4.21 (q, 2H, J ) 7.1 Hz), 5.80 (d, 1H, J ) 15.4 Hz), 6.65 (ddd, 1H, J ) 18.8, 10.2, 0.5 Hz), 6.81 (d, 1H, J ) 18.8 Hz), 7.19 (dd, 1H, J ) 15.4, 10.3 Hz); 13C NMR (100 MHz, CDCl3) δ 9.6, 13.7, 14.3, 27.2, 29.0, 60.3, 119.9, 144.2, 146.3, 147.2, 167.4; FAB HRMS m/z calcd for C19H37O2118Sn (M + H)+ 415.1809, found 415.1783. (1E,3E)-1-(Tri-n-butylstannyl)-5-tert-butyldimethylsiloxypentadiene (4). To an ether (250 mL) solution of lithium aluminum hydride was added dropwise an ether (60 mL) solution of the ester 3 obtained above at 0 °C over 30 min. After the mixture was warmed to room temperature and stirred for an additional 40 min, H2O was carefully added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with H2O, saturated NH4Cl solution, 1 N HCl solution, and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (gradually from 5% to 20% ethyl acetate in hexane) gave the corresponding alcohol (19.7 g, 89% from the aldehyde 2) as a colorless oil: IR (neat, cm-1) 3314, 2957, 2926, 2872, 2853, 1462, 1084, 999; 1H NMR (400 MHz, CDCl3) δ 0.82-0.99 (m, 15H) including 0.89 (t, 9H, J ) 7.3 Hz), 1.26-1.35 (m, 6H), 1.42-1.58 (m, 6H), 4.20 (t, 2H, J ) 5.9 Hz), 5.79 (dt, 1H, J ) 15.9, 5.9 Hz), 6.24 (ddm, 1H, J ) 15.4, 9.8 Hz), 6.26 (d, 1H, J ) 18.8 Hz), 6.54 (dd, 1H, J ) 18.8, 9.8 Hz); 13C NMR (100 MHz, CDCl3) δ 9.5, 13.7, 27.2, 29.1, 63.3, 130.7, 134.6, 135.1, 145.9. To a DMF (200 mL) solution of the alcohol obtained above (19.7 g, 52.9 mmol) were added 4-(dimethylamino)pyridine (DMAP) (3.23 g, 26.4 mmol), triethylamine (11.0 mL, 79.3 mmol), and tert-butyldimethylchlorosilane (TBDMSCl) (7.97 g, 52.9 mmol) at room temperature. After the reaction mixture was stirred at room temperature for 1 h, H2O was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (from 2% to 3% ethyl

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acetate in hexane) gave 4 (22.1 g, 86%) as a colorless oil: IR (neat, cm-1) 1462, 1377, 1254, 1105, 1057, 1001; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.87-0.96 (m, 24H) including 0.89 (t, 9H, J ) 7.1 Hz) and 0.92 (s, 9H), 1.26-1.35 (m, 6H), 1.421.58 (m, 6H), 4.23 (dd, 2H, J ) 5.1, 1.2 Hz), 5.71 (dt, 1H, J ) 15.1, 4.9 Hz), 6.19 (d, 1H, J ) 18.5 Hz), 6.21 (ddm, 1H, J ) 15.1, 10.5 Hz), 6.53 (dd, 1H, J ) 18.8, 9.8 Hz); 13C NMR (100 MHz, CDCl3) δ -5.2, 9.5, 13.7, 18.3, 26.0, 27.3, 29.1, 63.4, 131.5, 133.1, 133.4, 146.3; EI HRMS m/e calcd for C19H39OSi118Sn (M - Bu)+ 429.1784, found 429.1758. (E)-1-(Tri-n-butylstannyl)-5-tert-butyldimethylsiloxypentene (5). To a solution of 4-pentyn-1-ol (2.21 mL, 23.8 mmol) and tri-n-butyltin hydride (8.31 mL, 30.9 mmol) was added 2,2′-azobisisobutyronitrile (AIBN) (156 mg, 0.951 mmol) at room temperature. After the mixture was stirred at 120 °C for 5 h, the crude products were purified by column chromatography on silica gel (gradually from 1% to 25% ethyl acetate in hexane) to afford the corresponding (E)-vinylstannyl alcohol (4.39 g, 49%) as a colorless oil: IR (neat, cm-1) 3314, 2957, 2926, 2872, 2853, 1462, 1071, 990; 1H NMR (400 MHz, CDCl3) δ 0.84-0.91 (m, 15H), including 0.89 (t, 9H, J ) 7.3 Hz), 1.261.35 (m, 6H), 1.45-1.55 (m, 6H), 1.69 (tt, 2H, J ) 6.6, 6.6 Hz), 2.23 (dt, 2H, J ) 4.6, 7.1 Hz), 3.64-3.69 (m, 2H), 5.86-6.04 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 9.4, 13.7, 27.3, 29.1, 31.8, 34.1, 62.6, 128.2, 148.6. To a DMF (30 mL) solution of the alcohol obtained above (2.00 g, 5.33 mmol) were added 4-(dimethylamino)pyridine (DMAP) (326 mg, 2.67 mmol), triethylamine (1.11 mL, 8.00 mmol), and tert-butyldimethylchlorosilane (TBDMSCl) (884 mg, 5.86 mmol) at room temperature. After the reaction mixture was stirred at room temperature for 25 min, H2O was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (from 2% to 3% ethyl acetate in hexane) gave 5 (2.54 g, 97%) as a colorless oil: IR (neat, cm-1) 2957, 2928, 2857, 1464, 1254, 1103, 837, 775; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6H), 0.83-0.90 (m, 24H) including 0.89 (t, 9H, J ) 7.3 Hz) and 0.90 (s, 9H), 1.25-1.35 (m, 6H), 1.45-1.55 (m, 6H), 1.63 (tt, 2H, J ) 6.8, 6.8 Hz), 2.18 (td, 2H, J ) 7.3, 5.6 Hz), 3.61 (t, 2H, J ) 6.6 Hz), 5.81-6.03 (m, 2H); 13C NMR (100 MHz, CDCl3) δ -5.3, 9.4, 13.7, 18.3, 26.0, 27.3, 29.1, 32.0, 34.0, 62.6, 127.5, 149.0; EI HRMS m/e calcd for C19H41OSi118Sn (M - Bu)+ 431.1941, found 431.1934. Ethyl (Z)-2-Bromo-4-hydroxy-2-butenoate (10). To a dichloromethane (100 mL) solution of 2-butene-1,4-diol (5.0 g, 56.7 mmol) were added 3,4-dihydro-2H-pyran (15.5 mL, 170 mmol) and pyridinium p-toluenesulfonate (713 mg, 2.84 mmol) at room temperature. After the reaction mixture was stirred at room temperature for 28 h, saturated aqueous NaHCO3 solution was added, and the resulting mixture was extracted with chloroform. The organic layers were combined, washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (from 9% to 25% ethyl acetate in hexane) gave the corresponding bis-tetrahydropyranyl (THP) ether as a colorless oil which was subjected to ozonolysis without further purification. A solution of the THP ether derivative obtained above in dichloromethane (125 mL) and methanol (125 mL) was treated with O3 (2 mL/min) at -78 °C, and the reaction was monitored by TLC. After the starting material was consumed (5 h), a solution of triphenylphosphine (24.2 g, 92.3 mmol) in dichloromethane (50 mL) was added at -78 °C over 30 min. After the resulting mixture was warmed to room temperature and stirred for an additional 30 min, the solvents were removed in vacuo and the residue was roughly purified by column chromatography on silica gel (from 25% to 50% ethyl acetate in hexane) to give the crude aldehyde 7 as a colorless oil that was reacted with the Wittig reagent 8 without further purification. To a dichloromethane (300 mL) solution of the aldehyde obtained above was added ylide 8 (38.4 g, 89.9 mmol) at room temperature. After the reaction mixture was stirred at room

Tanaka et al. temperature for 14 h, the bulk of dichloromethane was removed in vacuo, H2O was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (17% ethyl acetate in hexane) gave the inseparable 10:1 mixture of 9 and its (E)-stereoisomer (16.5 g, 99% in 3 steps) as a colorless oil, which was used for the next step without further purification:1H NMR (400 MHz, CDCl3) δ 7.40 (vinyl proton for (Z)-stereoisomer 9, t, 1H, J ) 5.2 Hz), 6.83 (vinyl proton for its (E)-stereoisomer, t, 1H, J ) 5.2 Hz). To a methanol (100 mL) solution of a mixture of 9 and its (E)-stereoisomer obtained above (9.34 g, 31.8 mmol) was added p-toluenesulfonic acid monohydrate (606 mg, 3.18 mmol) at room temperature. After the mixture was stirred at room temperature for 3.8 h, saturated aqueous NaHCO3 solution was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (gradually 9% to 25% ethyl acetate in hexane) gave pure (Z)vinyl bromide 10 (5.55 g, 83%) as a colorless oil: IR (neat, cm-1) 3434, 1730, 1630, 1447, 1370, 1262, 1067, 1028; 1H NMR (400 MHz, CDCl3) δ 1.34 (t, 3H, J ) 7.1 Hz), 4.29 (q, 2H, J ) 7.1 Hz), 4.44 (d, 2H, J ) 5.1 Hz), 7.45 (t, 1H, J ) 5.1 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 62.7, 62.8, 115.1, 144.7, 161.8; FAB HRMS m/z calcd for C6H10O379Br (M + H)+ 208.9813, found 208.9844. Ethyl (E,E,E)-4-Oxo-2-(5-tert-butyldimethylsiloxy-1,3pentadienyl)but-2-enoate (DO). To a solution of the previously prepared vinylstannane 4 (10.8 g, 22.1 mmol) and vinyl bromide 10 (5.54 g, 26.5 mmol) in DMF (200 mL) were added tetrakis(triphenylphosphine)palladium(0) (1.28 g, 1.10 mmol) and lithium chloride (1.88 g, 44.2 mmol) at room temperature. After the reaction mixture was stirred at 115 °C for 3.5 h, 10% aqueous NH3 solution was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (gradually 9% to 33% ethyl acetate in hexane) gave the corresponding alcohol (5.15 g, 71%) as a colorless oil: IR (neat, cm-1) 3436, 1719, 1464, 1258, 1105, 1063, 1030, 992; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.92 (s, 9H), 1.32 (t, 3H, J ) 7.1 Hz), 4.25 (q, 2H, J ) 7.1 Hz), 4.26 (brd, 2H, J ) 2.4 Hz), 4.49 (brd, 2H, J ) 5.1 Hz), 5.88 (dt, 1H, J ) 15.1, 4.9 Hz), 6.28 (d, 1H, J ) 15.6 Hz), 6.32 (ddt, 1H, J ) 15.1, 10.5, 1.7 Hz), 6.52 (dd, 1H, J ) 15.6, 10.5 Hz), 6.73 (t, 1H, J ) 6.1 Hz); 13C NMR (100 MHz, CDCl3) δ -5.3, 14.2, 18.4, 25.9, 59.8, 61.0, 63.3, 123.5, 129.7, 130.6, 135.0, 135.2, 140.1, 166.7. To a solution of the alcohol obtained above (5.15 g, 15.8 mmol) in dichloromethane (150 mL) was added manganese dioxide (100 g) at room temperature, and the mixture was stirred for 30 min. The reaction mixture was filtered and concentrated in vacuo to give the crude products, which were purified by column chromatography on silica gel (from 11% to 25% ethyl acetate in hexane) to afford DO (4.07 g, 80%) as a yellow oil: IR (neat, cm-1) 1726, 1674, 1597, 1464, 1375, 1252, 1128; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.92 (s, 9H), 1.34 (t, 3H, J ) 7.1 Hz), 4.29 (brd, 2H, J ) 3.4 Hz), 4.31 (q, 2H, J ) 7.1 Hz), 6.07 (dt, 1H, J ) 15.1, 4.6 Hz), 6.41-6.48 (m, 1H), 6.53 (d, 1H, J ) 7.3 Hz), 6.75-6.85 (m, 2H), 10.09 (dd, 1H, J ) 7.3, 0.7 Hz); 13C NMR (100 MHz, CDCl3) δ -5.4, 14.1, 18.4, 25.9, 61.9, 63.0, 121.7, 128.4, 130.5, 140.0, 141.5, 146.0, 166.3, 191.2; EI HRMS m/e calcd for C17H28O4Si (M+) 324.1755, found 324.1765. [4-Ethoxycarbonyl-2-(3-tert-butyldimethylsiloxypropyl)]-r-pyran (EP). To a solution of the previously prepared vinylstannane 5 (50 mg, 0.102 mmol) and vinyl bromide 10 (32 mg, 0.153 mmol) in DMF (1.0 mL) were added tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.00511 mmol) and lithium chloride (9 mg, 0.204 mmol) at room temperature. After the reaction mixture was stirred at 75 °C for 4.5 h, 10% aqueous NH3 solution was added, and the resulting mixture

Acceleration of 6π-Azaelectrocyclization was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (20% ethyl acetate in hexane) gave the corresponding alcohol (26 mg, 77%) as a colorless oil: IR (neat, cm-1) 3434, 1719, 1472, 1389, 1366, 1256, 1103, 1032, 970; 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 6H), 0.86 (s, 9H), 1.28 (t, 3H, J ) 7.1 Hz), 1.62 (tt, 2H, J ) 6.4, 6.4 Hz), 2.19 (td, 2H, J ) 8.3, 8.3 Hz), 3.60 (t, 2H, J ) 6.3 Hz), 4.19 (q, 2H, J ) 7.1 Hz), 4.41 (d, 2H, J ) 6.1 Hz), 5.81 (dt, 1H, J ) 15.9, 6.8 Hz), 6.10 (d, 1H, J ) 15.9 Hz), 6.67 (t, 1H, J ) 6.1 Hz); 13C NMR (100 MHz, CDCl3) δ -5.3, 14.2, 18.3, 25.9, 29.8, 32.2, 59.9, 60.8, 62.4, 122.3, 131.2, 137.7, 139.1, 167.0. To a solution of the alcohol obtained above (97 mg, 0.295 mmol) in dichloromethane (3.0 mL) was added manganese dioxide (2.91 g) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude products which were purified by column chromatography on silica gel (from 1% to 2% ethyl acetate in hexane) to afford EP (62 mg, 64%) as a colorless oil: IR (neat, cm-1) 1721, 1258, 1098, 1067, 835; 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.30 (t, 3H, J ) 7.1 Hz), 1.59-1.79 (m, 3H), 1.84-1.94 (m, 1H), 3.65 (t, 2H, J ) 6.1 Hz), 4.22 (q, 2H, J ) 7.1 Hz), 4.77-4.82 (m, 1H), 5.63 (dd, 1H, J ) 5.9, 1.7 Hz), 6.22-6.24 (m, 1H), 6.43 (dd, 1H, J ) 5.6, 1.2 Hz); 13C NMR (100 MHz, CDCl3) δ -5.3, 14.2, 18.3, 25.9, 28.1, 30.2, 60.8, 62.7, 74.7, 99.7, 126.5, 127.0, 145.5, 164.5; EI HRMS m/e calcd for C17H30O4Si (M+) 326.1912, found 326.1902. (2Z,4E,6E)-8-tert-Butyldimethylsiloxy-3-methyloctatrienal (FO). To a solution of the previously prepared vinylstannane 4 (2.26 g, 4.63 mmol) and vinyl iodide 617 (1.10 g, 5.56 mmol) in DMF (25 mL) was added tetrakis(triphenylphosphine)palladium(0) (268 mg, 0.231 mmol) and lithium chloride (394 mg, 9.26 mmol) at room temperature. After the reaction mixture was stirred at 120 °C for 1.5 h, 10% aqueous NH3 solution was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (gradually 9% to 25% ethyl acetate in hexane) gave the corresponding alcohol (878 mg, 71%) as a colorless oil: IR (neat, cm-1) 3364, 1462, 1379, 1256, 1107, 1059; 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 6H), 0.87 (s, 9H), 1.83 (d, 3H, J ) 1.0 Hz), 4.20 (d, 2H, J ) 4.4 Hz), 4.24 (d, 2H, J ) 7.1 Hz), 5.51 (brt, 1H, J ) 7.1 Hz), 5.76-5.83 (m, 1H), 6.22-6.30 (m, 2H), 6.47-6.54 (m, 1H); 13C NMR (100 MHz, CDCl3) δ -5.2, 18.4, 20.3, 25.9, 58.3, 63.5, 128.2, 128.5, 130.1, 130.2, 133.8, 135.3. To a solution of the alcohol obtained above (63 mg, 0.235 mmol) in dichloromethane (2.0 mL) was added manganese dioxide (1.89 g) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude products which were purified by column chromatography on silica gel (from 2% to 3% ethyl acetate in hexane) to afford FO (42 mg, 67%) as a colorless oil: IR (neat, cm-1) 1669, 1607, 1379, 1256, 1111, 1059; 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 6H), 0.88 (s, 9H), 2.04 (d, 3H, J ) 1.0 Hz), 4.25 (dd, 2H, J ) 4.6, 1.5 Hz), 5.80 (d, 1H, J ) 7.8 Hz), 6.00 (dt, 1H, J ) 15.1, 4.6 Hz), 6.38 (ddt, 1H, J ) 15.1, 10,7, 2.0 Hz), 6.61 (dd, 1H, J ) 15.4, 11.0 Hz), 7.16 (d, 1H, J ) 15.1 Hz), 10.14 (d, 1H, J ) 8.1 Hz); 13C NMR (100 MHz, CDCl3) δ -5.3, 18.4, 21.1, 25.9, 63.1, 126.3, 128.2, 128.8, 136.6, 138.7, 154.3, 189.9; EI HRMS m/e calcd for C15H26O2Si (M+) 266.1701, found 266.1694. (2Z,4E)-8-tert-Butyldimethylsiloxy-3-methyloctadienal (GO). To a solution of the previously prepared vinylstannane 5 (432 mg, 0.883 mmol) and vinyl iodide 617 (210 mg, 1.06 mmol) in DMF (5.0 mL) were added tetrakis(triphenylphosphine)palladium(0) (51 mg, 0.0441 mmol) and lithium chloride (75 mg, 1.77 mmol) at room temperature. After the reaction mixture was stirred at 75 °C for 3.0 h, 10% aqueous NH3 solution was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chroma-

J. Org. Chem., Vol. 66, No. 9, 2001 3107 tography on silica gel (gradually 3% to 9% ethyl acetate in hexane) gave the corresponding alcohol (217 mg, 91%) as a colorless oil: IR (neat, cm-1) 3349, 1472, 1439, 1387, 1254, 1100, 1007, 963; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6H), 0.90 (s, 9H), 1.63 (tt, 2H, J ) 6.6, 6.6 Hz), 1.84 (d, 3H, J ) 0.7 Hz), 2.20 (dt, 2H, J ) 6.8, 6.8 Hz), 3.62 (t, 2H, J ) 6.6 Hz), 4.27 (d, 2H, J ) 7.1 Hz), 5.47 (brt, 1H, J ) 6.6 Hz), 5.78 (dt, 1H, J ) 15.1, 6.8 Hz), 6.42 (dd, 1H, J ) 15.4, 0.7 Hz); 13C NMR (100 MHz, CDCl3) δ -5.3, 18.3, 20.6, 25.9, 29.5, 32.4, 58.4, 62.5, 126.3, 126.6, 132.5, 135.6. To a solution of the alcohol obtained above (217 mg, 0.802 mmol) in dichloromethane (8.0 mL) was added manganese dioxide (4.30 g) at room temperature, and the mixture was stirred for 4.3 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude products which were purified by column chromatography on silica gel (from 3% to 5% ethyl acetate in hexane) to afford GO (127 mg, 59%) as a colorless oil: IR (neat, cm-1) 1671, 1636, 1254, 1103, 837; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6H), 0.89 (s, 9H), 1.68 (tt, 2H, J ) 6.4, 6.4 Hz), 2.06 (s, 3H), 2.31 (dt, 2H, J ) 7.2, 7.2 Hz), 3.64 (td, 2H, J ) 6.4, 1.2 Hz), 5.81 (d, 1H, J ) 8.0 Hz), 6.21 (dt, 1H, J ) 14.8, 6.8 Hz), 7.09 (d, 1H, J ) 15.2 Hz), 10.17 (dd, 1H, J ) 8.0, 0.8 Hz); 13C NMR (100 MHz, CDCl3) δ -5.3, 18.3, 21.4, 25.9, 29.9, 31.9, 62.3, 125.6, 127.4, 140.3, 155.0, 190.2; EI HRMS m/e calcd for C15H28O2Si (M+) 268.1857, found 268.1848. Ethyl (E,E)-4-Oxo-2-styrylbut-2-enoate (HO). To a solution of (E)-β-styryltributyltin (430 mg, 1.09 mmol) and the previously prepared vinyl bromide 10 (274 mg, 1.31 mmol) in DMF (7.0 mL) was added tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.0547 mmol) and lithium chloride (93 mg, 2.19 mmol) at room temperature. After the reaction mixture was stirred at 115 °C for 1 h, 10% aqueous NH3 solution was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude products. Rough purification by column chromatography on silica gel (25% to 33% ethyl acetate in hexane) gave the corresponding alcohol (143 mg, 56%) as a colorless oil which was oxidized without further purification. To a solution of the crude alcohol obtained above (100 mg, 0.431 mmol) in dichloromethane (4.0 mL) was added manganese dioxide (805 mg) at room temperature, and the mixture was stirred for 30 min. The reaction mixture was filtered and concentrated in vacuo to give the crude products which were purified by column chromatography on silica gel (gradually from 1% to 5% ethyl acetate in hexane) to afford HO (59 mg, 60%) as a yellow oil: IR (neat, cm-1) 1723, 1672, 1615, 1578, 1451, 1372, 1244, 1140; 1H NMR (400 MHz, CDCl3) δ 1.37 (t, 3H, J ) 7.1 Hz), 4.35 (q, 2H, J ) 7.1 Hz), 6.69 (d, 1H, J ) 7.1 Hz), 7.09 (d, 1H, J ) 15.9 Hz), 7.35-7.41 (m, 4H), 7.51-7.53 (m, 2H), 10.15 (d, 1H, J ) 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 62.0, 119.2, 127.5, 128.9, 129.7, 131.5, 135.6, 141.6, 146.0, 166.3, 191.3; EI HRMS m/e calcd for C14H14O3 (M+) 230.0942, found 230.0941. Ethyl (E,E)-4-Oxo-2-(p-methoxystyryl)but-2-enoate (IO). To a solution of (E)-β-(p-methoxystyryl)tributyltin (370 mg, 0.874 mmol) and the previously prepared vinyl bromide 10 (183 mg, 0.874 mmol) in DMF (8.0 mL) were added tetrakis(triphenylphosphine)palladium(0) (51 mg, 0.0437 mmol) and lithium chloride (74 mg, 1.75 mmol) at room temperature. After the reaction mixture was stirred at 120 °C for 30 min, 10% aqueous NH3 solution was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Rough purification by column chromatography on silica gel (25% to 50% ethyl acetate in hexane) gave the corresponding alcohol (96 mg, 42%) as a colorless oil which was oxidized without further purification. To a solution of the crude alcohol obtained above (90 mg, 0.343 mmol) in dichloromethane (3.0 mL) was added manganese dioxide (500 mg) at room temperature, and the mixture was stirred for 40 min. The reaction mixture was filtered and concentrated in vacuo to give the crude products which were

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purified by column chromatography on silica gel (gradually from 2% to 17% ethyl acetate in hexane) to afford IO (47 mg, 53%) as a yellow oil: IR (neat, cm-1) 1723, 1671, 1601, 1574, 1512, 1248, 1177, 1142, 1030; 1H NMR (400 MHz, CDCl3) δ 1.37 (t, 3H, J ) 7.1 Hz), 3.84 (s, 3H), 4.35 (q, 2H, J ) 7.3 Hz), 6.62 (d, 1H, J ) 7.3 Hz), 6.91 (dm, 2H, J ) 8.8 Hz), 7.05 (d, 1H, J ) 16.1 Hz), 7.28 (d, 1H, J ) 15.9 Hz), 7.47 (dm, 2H, J ) 8.5 Hz), 10.14 (d, 1H, J ) 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 55.4, 61.9, 114.3, 117.0, 128.4, 129.2, 130.3, 141.4, 146.4, 161.0, 166.6, 191.3; EI HRMS m/e calcd for C15H16O4 (M+) 260.1048, found 260.1041. Ethyl (E,E)-4-Oxo-2-(p-methoxycarbonylstyryl)but-2enoate (JO). To a solution of (E)-β-(p-methoxycarbonylstyryl)tributyltin (529 mg, 1.17 mmol) and the previously prepared vinyl bromide 10 (350 mg, 1.67 mmol) in DMF (10 mL) were added tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.0837 mmol) and lithium chloride (142 mg, 3.35 mmol) at room temperature. After the reaction mixture was stirred at 115 °C for 40 min, 10% aqueous NH3 solution was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO 4, filtered, and concentrated in vacuo to give the crude products. Rough purification by column chromatography on silica gel (25% to 50% ethyl acetate in hexane) gave the corresponding alcohol (112 mg, 33%) as a colorless oil which was oxidized without further purification. To a solution of the crude alcohol obtained above (80 mg, 0.276 mmol) in dichloromethane (2.0 mL) was added manganese dioxide (300 mg) at room temperature, and the mixture was stirred for 10 min. The reaction mixture was filtered and concentrated in vacuo to give the crude products which were purified by column chromatography on silica gel (gradually from 2% to 25% ethyl acetate in hexane) to afford JO (20 mg, 25%) as a white solid (yellow colored when dissolved in CHCl3): IR (KBr disk, cm-1) 1730, 1719, 1667, 1290, 1252, 1148, 1113; 1H NMR (400 MHz, CDCl3) δ 1.39 (t, 3H, J ) 7.1 Hz), 3.94 (s, 3H), 4.37 (q, 2H, J ) 7.1 Hz), 6.75 (d, 1H, J ) 7.1 Hz), 7.14 (d, 1H, J ) 16.1 Hz), 7.48 (d, 1H, J ) 16.1 Hz), 7.58 (d, 2H, J ) 8.5 Hz), 8.06 (d, 2H, J ) 8.3 Hz), 10.18 (d, 1H, J ) 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 52.2, 62.2, 121.5, 127.4, 130.1, 130.8, 132.3, 139.8, 140.2, 145.2, 166.0, 166.5, 191.1; EI HRMS m/e calcd for C16H16O5 (M+) 288.0997, found 288.1010. (E,E)-4-Oxo-2-[(2,6,6-trimethylcyclohex-1-enyl)vinyl]but-2-enoic Acid (KO). To a solution of (E,E)-4-hydroxy-2[(2,6,6-trimethylcyclohex-1-enyl)vinyl]but-2-enoic acid 119b (140 mg, 0.559 mmol) in dichloromethane (8.0 mL) was added manganese dioxide (4.0 g) at room temperature, and the mixture was stirred for 30 min. The reaction mixture was filtered and concentrated in vacuo to give the crude products which were purified by column chromatography on silica gel (gradually from 9% to 50% ethyl acetate in hexane) to afford KO (73 mg, 53%) as a yellow oil: IR (neat, cm-1) 3476, 1736, 1676, 1603, 1460, 1375, 1242; 1H NMR (400 MHz, CDCl3) δ 1.07 (s, 6H), 1.48-1.51 (m, 2H), 1.58-1.68 (m, 2H), 1.79 (s, 3H), 2.06-2.09 (m, 2H), 6.61 (d, 1H, J ) 15.9 Hz), 6.68 (d, 1H, J ) 16.1 Hz), 6.76 (d, 1H, J ) 7.3 Hz), 10.05 (d, 1H, J ) 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 18.9, 21.9, 28.9, 33.3, 34.1, 39.5, 123.1, 132.2, 134.6, 137.3, 142.2, 146.2, 171.0, 191.6; EI HRMS m/e calcd for C15H20O3 (M+) 248.1412, found 248.1413. N-n-Propyl (E,E)-4-Oxo-2-[(2,6,6-trimethylcyclohex-1enyl)vinyl]but-2-enamide (LO). To a THF (6.0 mL) solution of (E,E)-4-hydroxy-2-[(2,6,6-trimethylcyclohex-1-enyl)vinyl]but2-enoic acid 119b (150 mg, 0.599 mmol) were added triethylamine (0.100 mL, 0.719 mmol) and pivaroyl chloride (0.109 mL, 0.899 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, and n-propylamine (0.0984 mL, 1.20 mmol) was added at this temperature. After the mixture was warmed to room temperature and stirred for an additional 10 min, H2O was added, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (from

Tanaka et al. 33% to 67% ethyl acetate in hexane) gave the corresponding amide alcohol (118 mg, 68%) as a colorless oil: IR (neat, cm-1) 3306, 1649, 1620, 1537, 1458, 1026; 1H NMR (400 MHz, CDCl3) δ 0.91 (t, 3H, J ) 7.6 Hz), 0.98 (s, 6H), 1.41-1.44 (m, 2H), 1.48-1.61 (m, 4H), 1.69 (s, 3H), 1.97-2.01 (m, 2H), 3.27 (td, 2H, J ) 6.8, 6.8 Hz), 4.34 (d, 2H, J ) 6.3 Hz), 5.92 (brs, 1H), 6.04 (d, 1H, J ) 16.3 Hz), 6.24 (d, 1H, J ) 15.9 Hz), 6.26 (t, 1H, J ) 6.3 Hz); 13C NMR (100 MHz, CDCl3) δ 11.4, 19.1, 21.7, 22.8, 28.9, 32.9, 34.1, 39.3, 41.5, 59.3, 125.0, 130.6, 133.4, 134.9, 136.2, 137.2, 168.3. To a solution of the amide alcohol obtained above (100 mg, 0.343 mmol) in dichloromethane (3.0 mL) was added manganese dioxide (2.0 g) at room temperature, and the mixture was stirred for 30 min. The reaction mixture was filtered and concentrated in vacuo to afford LO (93 mg, 94%) as a yellow oil: IR (neat, cm-1) 3289, 1738, 1671, 1599, 1543, 1460, 1177; 1H NMR (400 MHz, CDCl ) δ 0.97 (t, 3H, J ) 7.6 Hz), 1.07 (s, 3 6H), 1.47-1.50 (m, 2H), 1.58-1.66 (m, 4H), 1.79 (s, 3H), 2.062.09 (m, 2H), 3.36 (td, 2H, J ) 6.8, 6.8 Hz), 5.92 (brs, 1H), 6.16 (d, 1H, J ) 7.3 Hz), 6.75 (d, 1H, J ) 16.1 Hz), 6.84 (d, 1H, J ) 16.1 Hz), 10.10 (d, 1H, J ) 7.3 Hz); 13C NMR (100 MHz, CDCl3) (mixture of amide rotamers) δ 11.3, 11.5, 18.9, 21.8, 21.9, 22.8, 22.9, 28.9, 33.4, 33.6, 34.2, 39.6, 39.6, 41.6, 122.8, 125.9, 126.7, 129.0, 134.9, 137.0, 140.0, 141.7, 152.4, 167.2, 190.8, 191.4; EI HRMS m/e calcd for C18H27NO2 (M+) 289.2040, found 289.2047. Representative Procedure of 1-Azatrienes (XN) and 1,2-Dihydropyridine Derivatives (XDHP) from Aldehydes (XO). To a benzene-d6 (0.5 mL) solution of the compound DO (8.7 mg, 0.0267 mmol) was added n-propylamine (2.4 µL, 0.0293 mmol) at 23.5 °C. The reaction was monitored by NMR and mass spectra. The 1,2-dihydropyridine derivative was quantitatively produced within 5 min. After the completion of the reaction, the mixture was concentrated in vacuo at 0 °C, and the IR spectrum was measured. [N-n-Propyl-2-[3-tert-butyldimethylsiloxy-(1E)-propenyl]-4-ethoxycarbonyl]-1,2-dihydropyridine (DDHP): a yellow oil; IR (neat, cm-1) 1719, 1562, 1464, 1379, 1256, 1088; 1H NMR (400 MHz, C D ) δ 0.02 (s, 6H), 0.66 (t, 3H, J ) 7.3 6 6 Hz), 0.95 (s, 9H), 0.95 (t, 3H, J ) 7.1 Hz), 1.15-1.25 (m, 2H), 2.35-2.43 (m, 1H), 2.71 (dt, 1H, J ) 13.9, 6.3 Hz), 3.98 (dm, 2H, J ) 4.6 Hz), 4.02 (qd, 2H, J ) 7.1, 2.0 Hz), 4.27 (brdd, 1H, J ) 6.6, 6.6 Hz), 5.48 (dtd, 1H, J ) 15.4, 4.9, 1.0 Hz), 5.55 (dd, 1H, J ) 7.3, 2.0 Hz), 5.79 (brd, 1H, J ) 7.3 Hz), 5.85 (ddt, 1H, J ) 15.4, 7.3, 1.7 Hz), 6.11 (ddd, 1H, J ) 5.9, 2.0, 0.7 Hz); 13C NMR (100 MHz, C6D6) δ -5.1, 11.1, 14.2, 18.5, 22.1, 26.1, 54.4, 59.0, 60.3, 63.3, 92.1, 118.8, 126.9, 129.1, 130.0, 137.5, 165.7; EI HRMS m/e calcd for C20H35NO3Si (M+) 365.2385, found 365.2376. [N-n-Propyl-2-(3-tert-butyldimethylsiloxypropyl)-4ethoxycarbonyl]-1,2-dihydropyridine (EDHP): a yellow oil; IR (neat, cm-1) 1719, 1562, 1466, 1387, 1366, 1256, 1098; 1H NMR (400 MHz, C6D6) δ 0.03 (s, 6H), 0.66 (t, 3H, J ) 7.3 Hz), 0.96 (s, 9H), 0.98 (t, 3H, J ) 7.3 Hz), 1.20 (qdd, 2H, J ) 7.3, 7.3, 7.3 Hz), 1.34-1.42 (m, 1H), 1.49-1.61 (m, 2H), 1.65-1.74 (m, 1H), 2.44 (dt, 1H, J ) 14.2, 7.3 Hz), 2.64 (dt, 1H, J ) 13.9, 6.6 Hz), 3.45 (t, 2H, J ) 6.1 Hz), 3.84 (brdt, 1H, J ) 6.1, 6.1 Hz), 4.05 (qm, 2H, J ) 7.1 Hz), 5.59 (dd, 1H, J ) 7.1, 1.7 Hz), 5.81 (d, 1H, J ) 7.3 Hz), 6.16 (dm, 1H, J ) 6.1 Hz); 13C NMR (100 MHz, C6D6) δ -5.2, 11.1, 14.3, 18.5, 22.9, 26.2, 27.6, 29.4, 55.0, 56.9, 60.3, 63.3, 92.6, 119.2, 129.5, 137.1, 165.9; EI HRMS m/e calcd for C20H37NO3Si (M+) 367.2540, found 367.2536. (3Z,5E,7E)-1-Aza-N-(n-propyl)-9-tert-butyldimethylsiloxy-4-methyl-1,3,5,7-nonatetraene (FN): a yellow oil; IR (neat, cm-1) 1620, 1462, 1379, 1254, 1107, 1061; 1H NMR (400 MHz, C6D6) δ 0.07 (s, 6H), 0.91 (t, 3H, J ) 7.3 Hz), 0.98 (s, 9H), 1.65 (qt, 2H, J ) 7.1, 7.1 Hz), 1.71 (s, 3H), 3.34 (t, 2H, J ) 6.8 Hz), 4.12 (brd, 2H, J ) 4.9 Hz), 5.74 (dt, 1H, J ) 14.9, 4.9 Hz), 6.31 (dd, 1H, J ) 14.9, 10.5 Hz), 6.33 (d, 1H, J ) 10.5 Hz), 6.44 (ddt, 1H, J ) 14.9, 10.7, 2.0 Hz), 6.94 (d, 1H, J ) 14.9 Hz), 8.31 (d, 1H, J ) 9.3 Hz); 13C NMR (100 MHz, C6D6) δ -5.1, 12.1, 18.4, 20.6, 24.7, 26.1, 63.5, 64.0, 128.4, 129.6, 129.9, 132.0, 135.5, 141.8, 157.3; EI HRMS m/e calcd for C18H33NOSi (M+) 307.2330, found 307.2334.

Acceleration of 6π-Azaelectrocyclization (3Z,5E)-1-Aza-N-(n-propyl)-9-tert-butyldimethylsiloxy4-methyl-1,3,5-nonatriene (GN): 1H NMR (400 MHz, C6D6) δ 0.05 (s, 6H), 0.92 (t, 3H, J ) 7.3 Hz), 0.97 (s, 9H), 1.54 (tt, 2H, J ) 6.3, 6.3 Hz), 1.67 (qt, 2H, J ) 6.8, 6.8 Hz), 1.73 (s, 3H), 2.17 (brdt, 2H, J ) 7.1, 7.1 Hz), 3.39 (t, 2H, J ) 6.8 Hz), 3.50 (t, 2H, J ) 6.1 Hz), 5.70 (dt, 1H, J ) 14.8, 6.8 Hz), 6.32 (d, 1H, J ) 9.6 Hz), 6.85 (d, 1H, J ) 15.2 Hz), 8.43 (dd, 1H, J ) 9.6, 1.2 Hz). [N-n-Propyl-2-(3-tert-butyldimethylsiloxypropyl)-4methyl]-1,2-dihydropyridine (GDHP): yellow oil; IR (neat, cm-1) 1576, 1464, 1254, 1101, 837; 1H NMR (400 MHz, C6D6) δ 0.06 (s, 6H), 0.72 (t, 3H, J ) 7.3 Hz), 0.98 (s, 9H), 1.31 (qdd, 2H, J ) 7.3, 7.3, 7.3 Hz), 1.36-1.46 (m, 1H), 1.62-1.80 (m, 3H), 1.76 (s, 3H), 2.52 (dt, 1H, J ) 14.1, 7.3 Hz), 2.77 (dt, 1H, J ) 13.7, 7.1 Hz), 3.56 (t, 2H, J ) 6.4 Hz), 3.87 (brtd, 1H, J ) 5.4, 5.4 Hz), 4.67 (dd, 1H, J ) 7.1, 2.0 Hz), 4.76 (brd, 1H, J ) 5.4 Hz), 5.84 (d, 1H, J ) 7.3 Hz); 13C NMR (100 MHz, C6D6) δ -5.1, 11.3, 18.5, 21.0, 22.8, 26.2, 27.8, 30.5, 55.0, 57.1, 63.7, 97.0, 108.7, 132.3, 136.5; EI HRMS m/e calcd for C18H35NOSi (M+) 309.2486, found 309.2478. (N-n-Propyl-4-ethoxycarbonyl-2-phenyl)-1,2-dihydropyridine (HDHP): yellow oil; IR (neat, cm-1) 1715, 1572, 1453, 1383, 1368, 1258, 1182, 1088; 1H NMR (400 MHz, C6D6) δ 0.58 (t, 3H, J ) 7.3 Hz), 0.91 (t, 3H, J ) 7.3 Hz), 1.08-1.17 (m, 2H), 2.28 (dt, 1H, J ) 13.9, 7.3 Hz), 2.56 (dt, 1H, J ) 13.7, 7.1 Hz), 3.99 (qm, 2H, J ) 7.1 Hz), 4.98 (d, 1H, J ) 5.4 Hz), 5.50 (dd, 1H, J ) 7.3, 2.0 Hz), 5.87 (dd, 1H, J ) 7.3, 0.7 Hz), 6.25 (dm, 1H, J ) 5.6 Hz), 7.02-7.15 (m, 3H), 7.28-7.30 (m, 2H); 13C NMR (100 MHz, C D ) δ 11.0, 14.2, 21.2, 54.5, 60.3, 62.0, 6 6 90.2, 121.8, 126.9, 128.1, 128.9, 138.0, 143.9, 165.8; EI HRMS m/e calcd for C17H21NO2 (M+) 271.1571, found 271.1583. [N-n-Propyl-4-ethoxycarbonyl-2-(p-methoxyphenyl)]1,2-dihydropyridine (IDHP): a yellow oil; IR (neat, cm-1) 1715, 1609, 1572, 1510, 1464, 1252, 1173, 1086; 1H NMR (400 MHz, C6D6) δ 0.61 (t, 3H, J ) 7.3 Hz), 0.94 (t, 3H, J ) 7.3 Hz), 1.11-1.21 (m, 2H), 2.31 (dt, 1H, J ) 13.9, 7.6 Hz), 2.64 (dt, 1H, J ) 13.4, 6.3 Hz), 3.27 (s, 3H), 4.02 (qm, 2H, J ) 7.1 Hz), 4.97 (d, 1H, J ) 5.4 Hz), 5.52 (dd, 1H, J ) 7.3, 1.7 Hz), 5.89 (d, 1H, J ) 7.3 Hz), 6.28 (dd, 1H, J ) 5.6, 1.5 Hz), 6.73 (dm, 2H, J ) 8.8 Hz), 7.23 (dm, 2H, J ) 8.5 Hz); 13C NMR (100 MHz, C6D6) δ 11.1, 14.2, 21.2, 54.4, 54.7, 60.3, 61.5, 90.0, 114.3, 122.2, 128.3, 136.3, 137.8, 160.0, 165.9; EI HRMS m/e calcd for C18H23NO3 (M+) 301.1677, found 301.1661. [N-n-Propyl-4-ethoxycarbonyl-2-(p-methoxycarbonylphenyl)]-1,2-dihydropyridine (JDHP): yellow oil; IR (neat, cm-1) 1719, 1568, 1464, 1437, 1281, 1103, 1086; 1H NMR (400 MHz, C6D6) δ 0.57 (t, 3H, J ) 7.3 Hz), 0.92 (t, 3H, J ) 7.3 Hz), 1.08 (qdd, 2H, J ) 7.3, 7.3, 7.3 Hz), 2.26 (dt, 1H, J ) 13.9, 7.3 Hz), 2.46 (dt, 1H, J ) 13.7, 6.6 Hz), 3.47 (s, 3H), 4.00 (qm, 2H, J ) 7.1 Hz), 4.91 (d, 1H, J ) 5.6 Hz), 5.48 (dd, 1H, J ) 7.3, 2.0 Hz), 5.83 (dm, 1H, J ) 7.6 Hz), 6.17 (ddd, 1H, J ) 5.9, 2.0, 1.0 Hz), 7.21 (dm, 2H, J ) 8.3 Hz), 8.09 (dm, 2H, J ) 8.3 Hz); 13C NMR (100 MHz, C6D6) δ 11.0, 14.2, 21.4, 51.6, 54.8, 60.4, 61.7, 90.7, 120.7, 126.6, 130.4, 130.5, 137.9, 148.3, 165.6, 166.5; EI HRMS m/e calcd for C19H23NO4 (M+) 329.1626, found 329.1641. (E,E)-5-Aza-N-(n-propyl)-2-[(2,6,6-trimethylcyclohex-1enyl)vinyl]-2,4-pentadienoic acid (KN): 1H NMR (400 MHz, C6D6) (characteristic signals of the imine) δ 3.31 (t, 2H, J ) 6.8 Hz), 6.88 (d, 1H, J ) 16.1 Hz), 6.96 (d, 1H, J ) 16.6 Hz), 7.25 (d, 1H, J ) 9.5 Hz), 8.46 (d, 1H, J ) 9.3 Hz). [N-n-Propyl-4-carboxy-2-(2,6,6-trimethylcyclohex-1enyl)]-1,2-dihydropyridine (KDHP): IR (neat, cm-1) 3422, 1753, 1638, 1561, 1460, 1379; 1H NMR (400 MHz, C6D6) (characteristic signals of the dihydropyridine) δ 0.71 (t, 3H, J ) 7.3 Hz), 1.99 (s, 3H), 2.29-2.36 (m, 1H), 2.64-2.72 (m, 1H), 5.31 (brd, 1H, J ) 3.4 Hz), 5.43 (dd, 1H, J ) 7.6, 1.7 Hz), 5.77 (d, 1H, J ) 7.6 Hz), 6.10 (brd, 1H, J ) 3.4 Hz); 13C NMR (100 MHz, C6D6) (characteristic signals of the dihydropyridine) δ 53.5, 57.6, 90.2, 121.4, 136.5; EI HRMS m/e calcd for C18H27NO2 (M+) 289.2040, found 289.2047. N-n-Propyl (E,E)-5-aza-N-(n-propyl)-2-[(2,6,6-trimethylcyclohex-1-enyl)vinyl]-2,4-pentadienamide (LN): 1H NMR (400 MHz, C6D6) (characteristic signals of the imine) δ 6.677

J. Org. Chem., Vol. 66, No. 9, 2001 3109 (d, 1H, J ) 16.1 Hz), 6.679 (d, 1H, J ) 9.6 Hz), 6.91 (d, 1H, J ) 15.6 Hz), 8.34 (d, 1H, J ) 9.0 Hz). [N-(n-Propyl)-4-(N-n-propylcarbamoyl)-2-(2,6,6-trimethylcyclohex-1-enyl)]-1,2-dihydropyridine (LDHP): IR (neat, cm-1) 3328, 1653, 1622, 1578, 1537; 1H NMR (400 MHz, C6D6) (characteristic signals of the dihydropyridine) δ 2.24 (ddd, 1H, J ) 14.0, 8.8, 7.2 Hz), 2.62 (ddd, 1H, J ) 14.0, 8.8, 4.8 Hz), 4.74 (ddd, 1H, J ) 7.3, 1.7, 0.7 Hz), 5.16 (d, 1H, J ) 3.7 Hz), 5.43 (brs, 1H), 5.67 (d, 1H, J ) 7.6 Hz), 5.75-5.76 (m, 1H); EI HRMS m/e calcd for C21H34N2O (M+) 330.2669, found 330.2677. Methyl (E,E)-5-Aza-N-hydroxy-2-[(2,6,6-trimethylcyclohex-1-enyl)vinyl]-2,4-pentadienoate (M). The compound M existed as 2:1 oxime isomers, and the integration of the aldehyde peak for the predominant isomer was selected as a standard (one proton): IR (pyridine, cm-1) 3246, 2924, 1717, 1468, 1173, 1105; 1H NMR (400 MHz, pyridine-d5) δ 1.03 (s, 3H), 1.05 (s, 6H), 1.37-1.41 (m, 3H), 1.48-1.56 (m, 3H), 1.73 (s, 3H), 1.73 (s, 1.5 H), 1.92-1.95 (m, 3H), 3.72 (s, 3H), 3.73 (s, 1.5H), 6.57 (d, 1H, J ) 16.4 Hz), 6.62 (d, 0.5H, J ) 16.3 Hz), 6.85 (d, 1H, J ) 16.1 Hz), 6.85 (d, 0.5H, J ) 16.1 Hz), 7.55 (d, 1H, J ) 10.0 Hz), 8.14 (d, 0.5H, J ) 10.2 Hz), 8.20 (d, 0.5H, J ) 10.0 Hz), 8.84 (d, 1H, J ) 10.2 Hz); 13C NMR (100 MHz, pyridine-d5) δ 7.26, 7.31, 9.7, 16.8, 20.9, 21.0, 22.2, 27.4, 39.9, 40.0, 110.6, 113.3, 113.6, 118.6, 119.2, 119.6, 121.1, 122.5, 124.9, 125.8, 125.9, 131.9, 135.4, 155.3, 155.8; EI HRMS m/e calcd for C16H23NO3 (M+) 277.1677, found 277.1674. Methyl (E,E)-5-Aza-N-methoxy-2-[(2,6,6-trimethylcyclohex-1-enyl)vinyl]-2,4-pentadienoate (N). The compound N existed as 2:1 oxime isomers, and the integration of the aldehyde peak for the predominant isomer was selected as a standard (one proton): IR (pyridine, cm-1) 2899, 1719, 1468, 1171, 1109; 1H NMR (400 MHz, pyridine-d5) δ 1.02 (s, 3H), 1.04 (s, 6H), 1.37-1.41 (m, 3H), 1.50-1.56 (m, 3H), 1.71 (s, 3H), 1.71 (s, 1.5H), 1.92-1.95 (m, 3H), 3.725 (s, 3H), 3.733 (s, 1.5H), 3.93 (s, 3H), 3.97 (s, 1.5H), 6.51 (d, 1H, J ) 16.4 Hz), 6.56 (d, 0.5H, J ) 16.3 Hz), 6.79 (d, 1H, J ) 16.1 Hz), 6.79 (d, 0.5H, J ) 16.1 Hz), 7.27 (d, 1H, J ) 10.7 Hz), 7.69 (d, 0.5H, J ) 10.0 Hz), 7.91 (d, 0.5H, J ) 10.0 Hz), 8.52 (d, 1H, J ) 10.7 Hz); 13C NMR (100 MHz, pyridine-d5) δ 7.3, 7.4, 9.7, 16.9, 21.0, 21.1, 22.3, 27.5, 40.1, 40.2, 50.4, 51.5, 109.7, 113.0, 113.3, 117.4, 119.1, 119.8, 124.4, 125.8, 132.0, 135.2, 155.1; EI HRMS m/e calcd for C17H25NO3 (M+) 291.1833, found 291.1843. 4-Methoxycarbonyl-2-(2,6,6-trimethylcyclohex-1-enyl)pyridine (12): a colorless oil; IR (neat, cm-1) 1734, 1557, 1460, 1437, 1395, 1308, 1289, 1263, 1221, 1113; 1H NMR (400 MHz, pyridine-d5) δ 0.99 (s, 6H), 1.25 (s, 3H), 1.47-1.49 (m, 2H), 1.60-1.66 (m, 2H), 1.93-1.96 (m, 2H), 3.84 (s, 3H), 7.71-7.75 (m, 2H), 8.86 (dm, 1H, J ) 4.9 Hz); 1H NMR (400 MHz, CDCl3) δ 0.98 (s, 6H), 1.30 (s, 3H), 1.58-1.61 (m, 2H), 1.74-1.80 (m, 2H), 2.07-2.10 (m, 2H), 3.96 (s, 3H), 7.62-7.63 (m, 1H), 7.70 (dd, 1H, J ) 5.1, 1.5 Hz), 8.77 (dd, 1H, J ) 5.1, 1.0 Hz); 13C NMR (100 MHz, CDCl3) δ 19.2, 20.9, 28.6, 31.9, 34.4, 39.2, 52.6, 120.0, 124.2, 131.4, 136.8, 139.8, 149.7, 162.0, 166.0; EI HRMS m/e calcd for C16H21NO2 (M+) 259.1571, found 259.1581. Ethyl (E,E,E)-4-Oxo-2-(5-tert-butyldimethylsiloxy-4methyl-1,3-pentadienyl)but-2-enoate (20). To a solution of (1E,3E)-1-(tri-n-butylstannyl)-5-tert-butyldimethylsiloxy-4methylpentadiene 1834 (451 mg, 0.899 mmol) and vinyl bromide 10 (332 mg, 1.59 mmol) in DMF (20 mL) were added tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.0794 mmol) and lithium chloride (135 mg, 3.18 mmol) at room temperature. After the reaction mixture was stirred at 85 °C for 1.8 h, 10% aqueous NH3 solution was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude products. Column chromatography on silica gel (gradually 9% to 40% ethyl acetate in hexane) gave the corresponding alcohol 19 (220 mg, 72%) as a colorless oil which was oxidized without further purification. To a solution of the alcohol 19 obtained above (300 mg, 0.881 mmol) in dichloromethane (8.0 mL) was added manganese (34) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434.

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J. Org. Chem., Vol. 66, No. 9, 2001

dioxide (8.0 g) at room temperature, and the mixture was stirred for 60 min. The reaction mixture was filtered and concentrated in vacuo to give the crude products which were purified by column chromatography on silica gel (from 5% to 17% ethyl acetate in hexane) to afford 20 (252 mg, 85%) as a yellow oil: IR (neat, cm-1); 1726, 1672, 1248, 841; 1H NMR (400 MHz, CDCl3) δ 0.09 (s, 6H), 0.93 (s, 9H), 1.36 (t, 3H, J ) 7.1 Hz), 1.79 (s, 3H), 4.14 (s, 2H), 4.32 (q, 2H, J ) 7.1 Hz), 6.32 (d, 1H, J ) 11.2 Hz), 6.52 (d, 1H, J ) 7.3 Hz), 6.83 (d, 1H, J ) 15.4 Hz), 7.09 (dd, 1H, J ) 15.1, 11.2 Hz), 10.11 (d, 1H, J ) 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ -5.4, 14.1, 14.5, 18.4, 25.9, 61.9, 67.4, 121.3, 122.7, 130.0, 137.9, 145.8, 146.5, 166.6, 191.3; EI HRMS m/e calcd for C18H30O4Si (M+) 338.1913, found 338.1912. 4-Ethoxycarbonyl-2-[3-tert-butyldimethylsiloxy-2-methyl-(1E)-propenyl]pyridine (21). To a solution of aldehyde 20 (157 mg, 0.464 mmol) in pyridine (2.5 mL) was added hydroxylamine hydrochloride (35 mg, 0.510 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 min, and acetyl chloride (0.165 mL, 2.32 mmol) was added at 0 °C. After the mixture was gradually warmed to room temperature and stirred for an additional 10 min, H2O was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude products. Column chromatography on silica gel (gradually from 2% to 17% ethyl acetate in hexane) to give the corresponding pyridine derivative 21 (82 mg, 53%) as a colorless oil: IR (neat, cm-1) 1732, 1472, 1408, 1375, 1290, 1254, 1215, 1111; 1H NMR (400 MHz, CDCl3) δ 0.12 (s, 6H), 0.95 (s, 9H), 1.40 (t, 3H, J ) 7.1 Hz), 2.051-2.054 (m, 3H), 4.21 (d, 2H, J ) 0.7 Hz), 4.40 (q, 2H, J ) 7.3 Hz), 6.66 (q, 1H, J ) 1.5 Hz), 7.61 (dd, 1H, J ) 5.1, 1.7 Hz), 7.76 (brs, 1H), 8.72 (dd, 1H, J ) 5.1, 0.7 Hz); 13C NMR (100 MHz, CDCl3) δ -5.4, 14.2, 15.3, 18.4, 25.9, 61.6, 68.0, 119.6, 121.9, 123.2, 137.6, 143.7, 149.8, 158.2, 165.5. 2-[3-tert-Butyldimethylsiloxy-2-methyl-(1E)-propenyl]4-hydroxymethylpyridine (23). To a THF (7.0 mL) solution of 20 (250 mg, 0.739 mmol) was rapidly added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 1.48 mL, 1.48 mmol) at room remperature. The reaction mixture was stirred at room temperature for 5 min, and 2,3-dichloro-5,6-dicyano1,4-benzoquinone (DDQ) (335 mg, 1.48 mmol) was added at this temperature. After the mixture was stirred for an additional 5 min, H2O was added, and the resulting mixture was extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the corresponding pyridine ester 21 whose spectral data were in good agreement with those obtained by the previous method. The crude product was reduced without further purification. To a solution of the crude ester 21 in ether (5.0 mL) was slowly added lithium aluminum hydride (34 mg, 0.886 mmol)

Tanaka et al. at 0 °C. After the mixture was warmed to room temperature and stirred for an additional 10 min, H2O was carefully added over 30 min. The resulting mixture was filtered and concentrated in vacuo to give the crude products, which were purified by column chromatography on silica gel (from 33% to 50% ethyl acetate in hexane) to afford the corresponding alcohol 23 (167 mg, 77%) as a colorless oil: IR (neat, cm-1); 3385, 3218, 2955, 2930, 2895, 2857, 1603, 1472, 1254, 1111, 1078, 839, 777; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.92 (s, 9H), 1.97 (s, 3H), 4.15 (brs, 2H), 4.68 (s, 2H), 6.56 (brd, 1H, J ) 1.2 Hz), 7.04 (brd, 1H, J ) 3.7 Hz), 7.17 (s, 1H), 8.46 (d, 1H, J ) 5.1 Hz); 13C NMR (100 MHz, CDCl3) δ -5.3, 15.3, 18.4, 25.9, 63.5, 68.1, 118.4, 121.3, 122.6, 142.5, 149.0, 150.1, 157.1; EI HRMS m/e calcd for C16H27NO2Si (M+) 293.1811, found 293.1804. 4-Formyl-2-[3-oxo-2-methyl-(1E)-propenyl]pyridine (15). To a THF (5.0 mL) solution of 23 (160 mg, 0.545 mmol) was added tetrabutylammonium fluoride (TBAF) (171 mg, 0.654 mmol) at room temperature. After being stirred at room temperature for 75 min, the reaction mixture was concentrated in vacuo to give the crude products. Column chromatography on silica gel (from 9% to 13% methanol in chloroform) gave the corresponding diol (100 mg, 100%) as a white solid that was oxidized without further purification: 1H NMR (400 MHz, CDCl3) δ 2.01 (s, 3H), 4.17 (s, 2H), 4.71 (s, 2H), 6.57 (s, 1H), 7.10 (d, 1H, J ) 4.9 Hz), 7.23 (s, 1H), 8.48 (d, 1H, J ) 5.1 Hz); 13C NMR (100 MHz, CDCl ) δ 15.5, 63.3, 68.1, 118.7, 121.5, 3 123.2, 143.0, 148.7, 150.6, 156.7. To a solution of the diol obtained above (20 mg, 0.112 mmol) in dichloromethane (3.5 mL) was added manganese dioxide (600 mg) at room temperature, and the mixture was stirred for 15 min. The reaction mixture was filtered and concentrated in vacuo to give the crude products which were purified by column chromatography on silica gel (from 33% to 50% ethyl acetate in hexane) to afford bis-aldehyde 15 (20 mg, 100%) as a white solid: mp 91 °C (lit. 110 °C);30 IR (KBr disk, cm-1); 2361, 1709, 1684, 1372, 1150, 831; 1H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 7.35 (s, 1H), 7.69 (d, 1H, J ) 4.9 Hz), 7.90 (s, 1H), 9.01 (d, 1H, J ) 4.9 Hz), 9.69 (s, 1H), 10.14 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 11.1, 121.7, 123.9, 142.0, 142.7, 145.7, 151.3, 156.1, 191.0, 195.4; EI HRMS m/e calcd for C10H9NO2 (M+) 175.0633, found 175.0624.

Acknowledgment. This work was supported by a Grant-in-Aid for Scientific Research 09480145 from the Ministry of Education, Science and Culture of Japan. Supporting Information Available: 400 MHz 1H NMR and 13C NMR spectra of selected XO, XN, XDHP, and the synthetic intermediates. This material is available free of charge via the Internet at http://pubs.acs.org. JO005779+