Intramolecular Ionic Diels-Alder Reactions of r-Acetylenic Acetals
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Seung-Bo Shim, Yoon-Joo Ko, Byeong-Wook Yoo, Chang-Keun Lim, and Jung-Hyu Shin* School of Chemistry, Seoul National University, Seoul 151-742, Korea
[email protected] Received July 5, 2004
Abstract: The intramolecular ionic Diels-Alder reaction of R-acetylenic acetals as a precursor of the propargyl cation has been investigated in the presence of Lewis acids and in protic acids. The reaction of diene-tethered R-acetylenic acetals (1-2) with formic acid yielded the regioselective intramolecular ionic Diels-Alder reaction products, bicyclodienal (9) and bicyclodienone (11) derivatives, in good yields.
The intramolecular Diels-Alder reaction1 is one of the most powerful methods for the synthesis of many polycyclic compounds, including natural products. However, it is prerequisite that activating groups have to be built into dienophiles to achieve the desired reactivity.2 Gassman et al. demonstrated that both the inter- and intramolecular ionic Diels-Alder reactions of allylic alcohols and allylic ethers using protic acid proceed under mild conditions give cycloadducts in high yields.3 For example, the intermolecular ionic Diels-Alder reaction of olefinic acetals is an excellent method for the synthesis of corresponding cycloadducts bearing a protected carbonyl group without acrolein polymerization.4 Gassman also reported that the protic acid-catalyzed intermolecular Diels-Alder reaction of cyclic acetals gives better yields than that of acyclic acetals.4 Recently, Sammakia reported that the chiral olefinic acetals derived from 2,4pentanediol undergo a Lewis acid promoted Diels-Alder reaction, giving the corresponding cycloadducts in good diastereoselectivity.5 On the basis of these reports, we envisioned that acetylenic acetals seemed to be powerful dienophiles provided that they were activated into propargyl cations. Although there are known examples of the intermolecular Diels-Alder reaction of propargyl cations generated from propargyl halides,6 1,1-diphenyl-2-propyn-l-ol,7 and triethyl orthopropiolate8 as dienophiles, to the best of our knowledge, the intramolecular ionic Diels-Alder reaction
of R-acetylenic acetals as dienophiles has not previously been reported. We report herein the intramolecular Diels-Alder reaction of R-acetylenic acetals 1 and 2 under (1) Lewis and (2) protic acid catalysts. The synthesis of diene-tethered R-acetylenic acetal 1 and 2 was accomplished from the coupling reaction of 7 or 8 with dienyl iodide 6,9 using the method reported by Chong.10 The dienyl iodide 6 was prepared from aldehyde 311 through a sequence of propenyl additions, followed by acetylation (4), elimination (5), and conversion of the acetate to iodide 6 as depicted in Scheme 1. When acetal 1 (Scheme 1) was treated with 0.1-1.0 equiv of alternative Lewis acids (BF3(OEt)2, AlCl3, SnCl4, and TiCl4) in methylene chloride at -78 °C, only polymerized products were obtained. At the beginning, we expected that the reaction might involve a Lewis acid complex of oxonium ion (14, Scheme 2) from 1 as in the case of olefinic acetal.5 Attempted use of Ti(O-iPr)4 in methylene chloride at room temperature failed to promote any cycloaddition. Acetal 1 was recovered in 90% yield. However, treatment of 1 with 1.0 equiv of TiCl2(Oi Pr)212 in methylene chloride at -78 °C yielded a novel 6-methyl-4-indancarbaldehyde 10 in 25% yield (entry 1). Reaction of 2 containing a cyclic acetal moiety with TiCl2(O-iPr)2 at room temperature over 2 h gave 10 in a lower yield of 10% (entry 2). Gassman established that catalysis by a strong protic acid, such as trifluoromethanesulfonic acid (TfOH), is generally preferred in the intermolecular ionic DielsAlder reaction of acrolein acetals and substituted propargyl alcohol.4,7 Treatment of acetal 1 with 0.1 equiv of
(1) For reviews on the intramolecular Diels-Alder reaction, see: (a) Roush, W. R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon: Oxford, UK, 1991; Vol. 5, Chapter 4.4, pp 513-550. (b) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464. (2) (a) House, H. O.; Cronin, T. H. J. Org. Chem. 1965, 30, 1061. (b) Roush, W. R. J. Am. Chem. Soc. 1978, 100, 3599. (c) Roush, W. R.; Peseckis, S. M. J. Am. Chem. Soc. 1981, 103, 6696. (d) Shea, K. J.; Gilman, J. W. Tetrahedron Lett. 1983, 24, 657. (3) (a) Gassman, P. G.; Singleton, D. A. J. Am. Chem. Soc. 1984, 106, 7993. (b) Gassman, P. G.; Singleton, D. A. J. Org. Chem. 1986, 51, 3075. (4) Gassman, P. G.; Singleton, D. A.; Wilwerding, J. J.; Chavan, S. P. J. Am. Chem. Soc. 1987, 109, 2182. (5) Sammakia, T.; Berliner, M. A. J. Org. Chem. 1994, 59, 6890.
(6) Mayr, H.; Halberstadt, I. K. Angew. Chem., Int. Ed. Engl. 1980, 19, 814. (7) Gassman, P. G.; Singleton, D. A. Tetrahedron Lett. 1987, 28, 5969. (8) Gassman, P. G.; Chavan, S. P. Tetrahedron Lett. 1988, 29, 3407. (9) Cramer, C. J.; Harmata, M.; Rashatasakhon, P. J. Org. Chem. 2001, 66, 5641. (10) Chong, J. M.; Wong, S. Tetrahedron Lett. 1986, 27, 5445. (11) Stowell, J. C. J. Org. Chem. 1970, 35, 244. (12) (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 3949. (b) Kumareswaran, R.; Vankar, P. S.; Reddy, M. V. R.; Pitre, S. V.; Roy, R.; Vankar, Y. D. Tetrahedron 1999, 55, 1099. (c) Aso, M.; Ojida, A.; Yang, G.; Cha, O.-J.; Osawa, E.; Kanematsu, K. J. Org. Chem. 1993, 58, 3960. 10.1021/jo048867t CCC: $27.50 © 2004 American Chemical Society
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Published on Web 10/14/2004
TABLE 1. Intramolecular Diels-Alder Reactions of Acetals 1 and 2
a
entry
acetal
acid and solvent
temp (°C)
1 2 3 4 5 6 7 8
1 2 1 1 1 2 1 2
1.0 equiv of TiCl2(O-iPr)2 in CH2Cl2 1.0 equiv of TiCl2(O-iPr)2 in CH2Cl2 0.5 equiv of TfOH in CH2Cl2 0.1% v/v HCOOH in CHCl3 10% v/v HCOOH in CHCl3 10% v/v HCOOH in CHCl3 10% v/v HCOOH in pentane 10% v/v HCOOH in pentane
-78 -78 to rt -78 to rt 50 rt rt rt rt
time (h) 0.5 2 0.5 48 24 46 0.5 0.5
9
tb 21 23
yielda (%) 10 25 10 tb 95 47 33
11
tb 17 27 86 82
Isolated yields. b Trace amount.
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TfOH, however, gave only trace amounts of Diels-Alder cycloadducts (entry 3). In contrast, when the reaction was subjected to acetic acid, acetal 1 remained unreacted. After screening a variety of protic acids, formic acid was our choice for cyclization of acetals 1 and 2. Reaction of acetal 1 with 0.1% v/v formic acid in chloroform at 50 °C for 48 h afforded 10 in 95% yield as the sole product (entry 4). Similar treatment of acetal 1 with 10% v/v formic acid in chloroform at room temperature for 24 h gave a mixture of 9 (21%), 10 (41%), and 11 (17%) (entry 5). Treatment of acetal 2 with 10% v/v formic acid in chloroform gave similar results to acetal 1 (entry 6). Interestingly, the use of 10% v/v formic acid in pentane (i.e., two-phase system) rapidly gave 11 in good yields (entries 7 and 8). The structure of each of the novel compounds 9, 10, and 11 was assigned on the basis of extensive spectral studies.13 Furthermore, the structure of 11 was confirmed by oxidation to the known 6-methyl1-tetralone 12 (Scheme 2). The 1H and 13C NMR spectra (13) The coupling pattern of the 1H signal in the 1, 4-cyclohexadiene moiety of 11 was investigated by decoupling experiments. Irradiation of the H-4 and H-10 resulted in a long-range coupling between H-4 and H-1. In addition, the analysis of the HMBC correlation confirmed the unambiguous structure of 11. The IR spectrum showed the presence of a carbonyl carbon with a strong CdO stretch at 1693 cm-1.
of 12 obtained were in good agreement with those previously reported.14 The mechanistic steps involved in these intramolecular ionic Diels-Alder reactions are of particular interest to us. We anticipated that protonation of acetal 1 by a Lewis acid or protic acid would give reactive intermediates, such as Lewis acid complexes of oxonium ion 14, propargyl cation 15, and allenyl cation 16,6,15 which might readily undergo cyclization into cycloadducts (Scheme 2). The cyclization of the C8-C9 with the C1-C4 portion of 15 to bicyclodienal 9 followed by slow aromatization16 will give 10. Alternatively, the cyclicization of C9-C10 with the diene moiety of 16 will afford bicyclodienenone 11. However, the ratios of adduct 9 to adduct 11 resulting from treatment of acetals 1 and 2 with formic acid were strongly dependent on the reaction conditions as shown in Table 1. To establish the detailed mechanistic pathways involved in the formation of 9, 10, and 11 outlined in Scheme 2, we performed NMR studies. Treatment of acetal 1 with formic acid in CDCl3 (1:10 v/v) at 25 °C for 10 min provided a 71:21 mixture of compounds 1 and 1317 (Scheme 2) when determined by 1H NMR analysis.18 After a reaction of 2 h, 1 was converted into a mixture of 13 (23%), 9 (43%), 10 (1%), and 11 (10%) with a 77% combined yield (1H NMR analysis). Furthermore, when the reaction mixture was allowed to stand for 5 h, most of acetal 1 and propargyl aldehyde 13 were consumed. After a reaction of 111 h, the slow aromatization of 9 was completed to give indancarbaldehyde 10 quantitatively. We presume that this intramolecular ionic Diels-Alder reaction proceeds via Pathway A or Pathway B to give cycloadducts 9 and 11 (Scheme 2). The above results strongly suggest that one of the key steps in the protic acid-promoted Diels-Alder reaction of acetal 1 is the formation of the propargyl aldehyde 13, which is cyclized (14) Das, J.; Valenta, Z.; Ngooi, T. K. Can. J. Chem. 1991, 6, 474. (15) Mayr, H.; Baeuml, E. Tetrahedron. Lett. 1983, 24, 357. (16) (a) Vanderzande, D. J.; Kiekens, E. G.; Martens, H. J.; Hoornaert, G. J. J. Org. Chem. 1986, 51, 1019. (b) Shakespeare, W. C.; Johnson, R. P. J. Am. Chem. Soc. 1990, 112, 8578. (17) Compound 13 was readily separated by column chromatography and characterized by NMR analysis. See the Supporting Information. (18) See the Supporting Information for the quantification of cyclized products during the course of acetal 1 reaction in 1:10 (v/v) HCOOH/ CDCl3 at 25 °C.
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into bicyclodienal 9 and bicyclodienone 11 via cation species 14-16 (Scheme 2). We also propose the mechanism for the formation of 11 depicted in Scheme 3 to explain our experimental results. Vinyl cation 17 is generated from the cyclization of propargyl cation 15 or allenyl cation 16 (Scheme 2). Rearrangement of vinyl cation 17 through two different mechanistic pathways might lead to the formation of 11 (Scheme 3). One mechanism involves an enol intermediate 18, which undergoes tautomerization to give β-hydroxy ketone 19, the dehydration of which produces 11, while the other involves oxete intermediate19 20 affording 11. When the reaction of acetal 1 with formic acid-d2 in D2O (2:1 v/v) at 25 °C was monitored by 1H NMR, 1 was (19) This oxete mechanism is similar to that postulated by Harding for acid-catalyzed intramolecular cyclization of 5-cyclodecynone. See: (a) Harding, C. E.; Stanford, G. R. J. Org. Chem. 1989, 54, 3054. (b) Harding, C. E.; King, S. L. J. Org. Chem. 1992, 57, 883.
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completely consumed within 3 min and bicyclodienenone 11 was observed as a major product (65% yield) with concomitant formation of several unknown products. The acid-catalyzed dehydration20 of β-hydroxy ketones generally needs a stronger acid, a higher reaction temperature, and a longer time. However, we failed to observe the expected β-hydroxy ketone 19 in our reaction conditions. On the basis of this NMR study, the mechanism involving an oxete intermediate seems to be more suited to explain our results. In conclusion, we have demonstrated that dienetethered R-acetylenic acetals 1 and 2 undergo Lewis acidcatalyzed cyclization, giving indancarbaldehyde 10. In addition, the intramolecular Diels-Alder reactions of 1 and 2 in the presence of formic acid gave bicyclodienal 9, indancarbaldehyde 10, and bicyclodienone 11 in good yields, respectively. The yields and distribution of products in the cyclization reaction were strongly dependent upon the reaction conditions.
Acknowledgment. Support of this work by the Brain Korea 21 project is greatly appreciated. Supporting Information Available: Detailed experimental procedures and compound characterization data. This material is available free of charge via the Internet at http://pubs.acs.org. JO048867T (20) (a) Noyce, D. S.; Reed, W. L. J. Am. Chem. Soc. 1958, 80, 5539. (b) Boyer, F.-D.; Descoins, C. L.; Thanh, G. V.; Descoins, C.; Prange´, T.; Ducrot. P.-H. Eur. J. Org. Chem. 2003, 1172. (c) Kozikowski, A. P.; Li, C.-S. J. Org. Chem. 1987, 52, 3541. (d) Meyer. W. L.; Brannon, M. J.; Merritt, A.; Seebach, D. Tetrahedron. Lett. 1986, 27, 1449.
