The hfcl4-mediated diels-alder reaction of furan

3.98±3.91 (m, 2 H), 3.60±3.53 (m, 2 H), 3.40±3.35 (m, 2 H), 2.21±2.14 (m, The HfCl4-Mediated Diels±Alder Reaction of 2 H), 1.93±1.57 ppm (m, 6 H); 13C NMR (CDCl3, 100 MHz): d ¼ 155.9, 152.2, 135.3, 133.0, 127.6, 126.1, 125.7, 125.5, 124.8, 122.9, 122.2, 121.9,120.8, 120.0, 118.4, 111.7, 98.8, 66.8, 62.1, 30.9, 30.6, 29.6, 25.4, 19.5 ppm; HRMS (EI) calcd for C24H24O3 224.1201, found 224.1207. 2 i: 1H NMR Shigehiro Nakao, Tae Inoue, and Mitsuru Shoji (CDCl3, 200 MHz): d ¼ 8.49 (s, 1 H), 8.06 (s, 1 H), 7.93±7.87 (m, 1 H), 7.82(s, 1 H), 7.79±7.46 (m, 5 H), 7.36±7.24 (m, 2 H), 2.60 (t, J ¼ 6.8 Hz, 2 H),1.77±1.37 (m, 4 H), 1.00 ppm (t, J ¼ 7.0 Hz, 3 H); 13C NMR (CDCl3, 7-Oxabicyclo[2.2.1]hept-2-ene derivatives are useful inter- 50 MHz): d ¼ 154.5, 154.2, 134.0, 132.4, 132.3, 132.0, 131.3, 128.3, 127.9, mediates for the synthesis of naturalproducts such as 127.2, 127.1, 126.8, 126.8, 125.9, 124.6, 122.8, 121.2, 118.3, 110.9, 105.8, carbohydrates and prostaglandins.[1] One of the most straight- 30.6, 29.7, 19.5, 13.6 ppm; HRMS (EI) calcd for C24H20O 324.1515,found 324.1512.
forward methods for the construction of the 7-oxabicy- 2 j: 1H NMR (CDCl3, 200 MHz): d ¼ 8.50 (s, 1 H), 8.07 (s, 1 H), 7.84 (s, 1 H), 7.80±7.29 (m, 8 H), 2.60 (t, J ¼ 6.8 Hz, 2 H), 1.83± clo[2.2.1]hept-2-ene skeleton is the Diels±Alder reaction 1.22 (m, 6 H), 0.95 (t, J ¼ 6.8 Hz, 3 H); 13C NMR (CDCl3, 50 MHz): d ¼ between furan and appropriate dienophiles. However, the 154.3, 154.1, 134.1, 132.4, 132.3, 132.0, 131.4, 128.3, 127.3, 127.1, 126.9, facile retro-Diels±Alder reaction and the low reactivity of 126.8, 126.5, 125.8, 124.6, 122.8, 121.2, 119.0, 111.0, 105.8, 31.3, 29.6, furan as a diene, as a result of its aromatic character, make the 22.3, 19.8, 14.0 ppm; HRMS (EI) calcd for C25H22O 338.1671, found338.1667. 2 k: 1H NMR (CDCl Diels±Alder reaction of furan one of the most difficult 3, 200 MHz): d ¼ 7.99 (t, J ¼ 1.2 Hz, 1 H), 7.52 (d, J ¼ 1.4 Hz, 2 H), 7.44±7.31 (m, 2 H), 7.11 (dd, J ¼ 6.8, 1.4 Hz, 1 H), cycloadditions.[2] In addition to the use of highly reactive 3.15 (t, J ¼ 7.6 Hz, 2 H), 1.89±1.74 (m, 2 H), 1.65±1.50 (m, 2 H), 1.45 (s, dienophiles in the Diels±Alder reaction,[3] severalmethods 9 H), 1.03 ppm (t, J ¼ 7.6 Hz, 3 H); 13C NMR (CDCl3, 50 MHz): d ¼ have been developed to overcome these difficulties, such as 156.7, 154.2, 145.6, 138.4, 126.6, 124.1, 123.9, 122.9, 122.5, 118.7, 110.7,109.0, 34.7, 33.8, 32.0, 31.8, 22.9, 14.0 ppm; HRMS (EI) calcd for the use of high pressure[4] or Lewis acid mediated reactions.[5] Although several Lewis acids have been reported to promote [8] Treatment of p-tert-butylphenol with bis(pyridium)iodonium(i)tetra- the reaction efficiently, there are problems in terms of fluoroborate (Ipy2BF4) gave 2-iodo-4-tert-butylphenol in 31 % yield.
generality. For example, BF3¥OEt2 is a good catalyst for Compound 12 k was treated with tert-butyldimethylsilyl chloride using methyl acrylate but a poor promoter for other dienopliles,[5c] imidazole as a base to give 13k in 91 % yield. Finally, compound 13k ZnI2 is suitable for acrylonitrile but not for a,b-unsaturatedesters,[5a] while methyl vinyl ketone and acrylonitrile are activated by BiCl3.[5l] Some Lewis acids supported on silica gel have also been utilized for the promotion of a particular dienophile with furan.[5e,g,i,j] However, low endo/exo selectivity 12k (31%)
13k ( 91%)
is generally obtained because of the facile retro-Diels±Alderreaction. Herein we report the endo-selective Diels±Alder reaction of furan with a,b-unsaturated esters catalyzed by [Pd(PPh3)4]
First, we looked for an appropriate Lewis acid using the 11k (38%)
employing furan as the solvent (40 equiv). The reaction wasperformed in the presence of an equimolar amount of Lewis was coupled with 7 a using palladium as a catalyst to give 11 k (TBS ¼ acid at room temperature for 15 h. Of the severalLewis acids tert-butyldimethylsilyl) in 38 % yield.
screened,[6] HfCl4 was found to have suitable Lewis acidity topromote the Diels±Alder reaction in moderate yield (60 %).[7]Although most of the reported Lewis acids lose their Lewisacidity by coordination with furan, which acts as a Lewis base,HfCl4 still activates a,b-unsaturated esters efficiently even inthe presence of an excess amount of furan. Next, the use of asolvent was examined, and CH2Cl2 was found to be the bestwith respect to both yield and endo/exo selectivity.[8] Forexample, the Diels±Alder reaction of dimethyl maleate andfuran proceeds in CH2Cl2 at À20 8C within 5 h to afford thecycloadduct in good yield (91 %) and high diastereoselectivity [*] Prof. Dr. Y. Hayashi, M. Nakamura, S. Nakao, T. Inoue, Dr. M. Shoji Department of IndustrialChemistryFaculty of EngineeringTokyo University of ScienceKagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)Fax: (þ 81) 3-5261-4631E-mail: [**] This research was supported by the Asahi Glass Foundation and a Grant-in-Aid for Scientific Research on Priority Areas (A) ™Exploi-tation of Multi-Element Cyclic Molecules∫ from the Ministry ofEducation, Culture, Sports, Science, and Technology, Japan.
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Table 1. The Diels±Alder reaction of furan.[a] [a] Furan/dienophile ¼ 20/1. [b] Yield of isolated product. [c] The ratio (endo/exo) is determined by 1H NMR analysis (400 MHz).
(endo/exo ¼ 93/7; Table 1, entry 2). The effect of temperature high endo/exo selectivity (entry 4). On the other hand, on the yield and diastereoselectivity of the reaction is shown fumarate ester is not a suitable substrate for the present in entries 1±3. As the temperature is lowered, the diastereo- reaction, with the Diels±Alder adducts being formed in low selectivity increases, and very high endo selectivity (98/2) was yield when the amount of HfCl4 was reduced to 20 mol% attained when the reaction was conducted at À50 8C. This is (entry 7). The yield for the catalytic reaction using benzyl only the second highly endo-selective Diels±Alder reaction of acrylate as the dienophile increased with increasing reaction furan with a maleic acid derivative, the first being a reaction time, while the diastereoselectivity decreased (entries 10±12).
performed under high-pressure conditions,[4a] and the present This observation can be attributed to thermodynamic equili- reaction is complimentary to the thermal Diels±Alder reac- bration in the presence of HfCl4 at 0 8C in favor of the tion of maleic anhydride and furan, which affords predom- exo isomer. High endo selectivity in the reaction using an inantly the thermodynamically stable exo isomer.[3c] equimolar amount of HfCl4 at low temperature can be The generality of this HfCl4-mediated Diels±Alder reaction achieved under kinetic control(Table 1, entry 9).
of furan with respect to dienophiles was investigated Next, substituted furans were employed in the Diels±Alder (Table 1). The reaction of diethyl fumarate proceeds smoothly reaction (Table 2). Not only furan, but substituted furans also at À20 8C to afford the Diels±Alder product in good react efficiently with several dienophiles in the presence of yield (entry 5). The ester group has a large effect both on both equimolar and catalytic amounts of HfCl4. The higher the yield and selectivity in the reaction of acrylate derivatives; HOMO levels of 2-methylfuran and 2,5-dimethylfuran rela- the reaction of the benzylester is faster (8 h) and tive to those of the parent furan means the reactions proceed more selective (endo/exo ¼ 78/22, entry 9) than that of the much faster. Although a long reaction time (66 h) is necessary tert-butylester (25 h, endo/exo ¼ 69/31, entry 8). Methyl for the reaction of dimethylmaleate and furan at À50 8C in the methacrylate is not a reactive dienophile, and its Diels±Alder presence of an equimolar amount of HfCl4 (Table 1, entry 3), cycloadduct is formed in very low yield (8 %), even the reaction of the same dienophile with 2-methylfuran and under high-pressure conditions (15 kbar).[4a] HfCl4, however, with 2,5-dimethylfuran proceeds within 5 h at the same accelerates the Diels±Alder reaction of benzyl methacrylate temperature with the same loading of the catalyst (Table 2, and furan to afford the cycloadduct in 34 % yield, with entries 1, 3). High endo selectivity was attained in these the exo isomer predominating (entry 13). Though there is reactions of dimethyl maleate (Table 2, entries 1±4). Diethyl room for improvement of the yield, this is the first example of fumarate also reacts with 2,5-dimethylfuran to give the a Diels±Alder reaction of furan with a methacrylate deriva- cycloadduct in 81 % yield (Table 2, entry 5). Benzyl acrylate also reacts with substituted furans to give the Diels±Alder We found that HfCl4 behaves as a true catalyst of this products in good yield with moderate endo selectivity. Higher reaction. That is, when the reaction of furan and diethyl endo/exo selectivity was obtained in this reaction when a maleate was performed in the presence of only a catalytic catalytic amount of HfCl4 was employed, compared with that amount (20 mol%) of HfCl4, the reaction proceeded at 0 8C to of the reaction using an equimolar amount of Lewis acid afford the Diels±Alder adducts in good yield (88 %), and with ¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Table 2. The Diels±Alder reaction of substituted furan.[a] [a] Furan/dienophile ¼ 20/1. [b] Yield of isolated product. [c] The ratio (endo/exo) is determined by 1H NMR analysis (400 MHz).
The regio- and stereochemistries of the Diels±Alder high diastereomeric excess (endo/exo ¼ 68/32, endo ¼ 87 % de, adducts of 2-methylfuran and benzyl acrylate (Table 2, exo ¼ 91 % de). The absolute stereochemistry of the en- entries 6, 7) were determined from NOESY spectra, and byconversion of the major isomer into the correspondingiodolactone.
Methylvinylketone, however, did not afford the Diels± Alder product under the same reaction conditions, but insteadgave 4-furyl-2-butanone as a major product. As this wasreasoned to be generated by over-reaction of the initiallyformed Diels±Alder product, the reaction conditions were do isomer was determined by comparison of its optical screened to reduce the Lewis acidity of HfCl4. It was found rotation with the literature value after conversion into the that the Diels±Alder product was obtained in 65 % yield with corresponding iodolactone.[12] This highly diastereoselective moderate endo/exo selectivity (67/33) when a catalytic Diels±Alder reaction is synthetically useful and practical, as amount of HfCl4 was employed at low temperature (À78 8C) demonstrated by our recent totalsynthesis of epoxyquinols A and B from the endo isomer in high opticalpurity.[13] In summary the Diels±Alder reaction of furan is efficiently promoted by a catalytic amount of HfCl4 to give cycloadductsin good yield with high endo selectivity. As HfCl4 is an activeLewis acid catalyst, even in the presence of an excess amountof furan, the reaction proceeds at low temperature andprevents the usual endo/exo isomerization and gives high endo selectivity. This is a unique feature of HfCl applied to the diastereoselective reaction of a chiral dieno- with the other Lewis acids,[5] the Lewis acidity of which are phile, since the chiral 7-oxabicyclo[2.2.1]hept-5-ene deriva- reduced by the coordination with furan to give low yields and tives obtained are important chiral building blocks for natural low endo selectivity. A wide range of reactive a,b-unsaturated product synthesis.[9] There are few successfulexamples of this esters and methyl vinyl ketone can be successfully employed kind of reaction, however, because of the easy reversibility of as dienophiles in the HfCl4-mediated reactions, and not only the reaction. For example, (1R,2S,5R)-8-phenylmenthyl acry- furan but substituted furans can also be employed as dienes, late,[10] which is a widely used chiral dienophile in the carbo- again with high endo selectivity, this not having been achieved Diels±Alder reaction, reacts at 25 8C over 24 h with furan in by previous methods mediated by Lewis acids. The highly diastereoselective Diels±Alder reaction of a chiral acrylate afford the cycloadduct in 79 % yield with low to moderate reaction to the (À)-(1R,2R)-2-(naphthalene-2-sulfonyl)cyclo- Typical procedure (Table 1, entry 4): Dimethyl maleate (80 mL, 0.64 mmol) hexyl acrylate developed by Sarakinos and Corey[11] expecting and freshly distilled furan (0.93 mL, 12.8 mmol) were added successively at to achieve a high diastereomeric excess because the high 0 8C to a suspension of HfCl4 (40.8 mg, 0.13 mmol) in CH2Cl2 (0.5 mL).
After stirring the reaction mixture for 20 h at the same temperature, temperature under kinetic control. As expected, the Diels± 3 was added. After filtration of the inorganic materials, the organic materials were extracted with CHCl3 (î 3) and the combined Alder reaction [Eq. (4)] proceeds at low temperature organic phase was dried over anhydrous MgSO4, filtered, and concentrated (À45 8C) to afford the cycloadduct in good yield (83 %) with in vacuo. Purification by flash column chromatography on silica gel (ethyl ¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim acetate/hexane ¼ 1/10±1/1) gave 105.6 mg (78 %) of the endo isomer and K. A. Jorgensen), Wiley-VCH, Weinheim, 2001, p. 5; for a catalytic asymmetric reaction by the use of a chiralLewis acid, see b) E. J.
Corey, T. P. Loh, Tetrahedron Lett. 1993, 34, 3979; c) I. Yamamoto, K.
Narasaka, Chem. Lett. 1995, 1129; d) D. A. Evans, D. M. Barnes, Tetrahedron Lett. 1997, 38, 57; for a diastereoselective reaction by theuse of a chiraldienophile, see e) H. Takayama, A. Iyobe, T. Koizumi, J.
Chem. Soc. Chem. Commun. 1986, 771; f) J. M. Fraile, J. I. Garcia, D.
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[2] Review of the Diels±Alder reaction of furan; C. O. Kappe, S. S.
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[6] The yields obtained with other representative Lewis acids are as follows: ZrCl4 50 %, ZnI2 46 %, LiClO4 24 %, AlCl3 18 %, CuCl11 %,and NiCl2 10 %.
[7] Recently HfCl4 and Hf(OTf)4 have been employed as unique Lewis acid catalysts in the following reactions: a) direct condensationreaction of carboxylic acids with alcohols: K. Ishihara, S. Ohara, H.
Yamamoto, Science 2000, 290, 1140; b) Friedel±Crafts acylation: I.
Hachiya, M. Morikawa, S. Kobayashi, Bull. Chem. Soc. Jpn. 1995, 68,2053; c) Fries rearrangement: S. Kobayashi, M. Morikawa, I. Hachiya,Bull. Chem. Soc. Jpn. 1997, 70, 267; d) intramolecular aryl silylation:N. Asao, T. Shimada, T. Shimada, Y. Yamamoto, J. Am. Chem. Soc.
2001, 123, 10 899; e) asymmetric Michaeladdition of thiol Kobayashi, C. Ogawa, M. Kawamura, M. Sugiura, Synlett 2001, 983;f) 1,3-cycloaddition of N-tert-butylarylmethylideneamine N-oxides: [*] Prof. P. v. R. Schleyer, Dr. Z.-X. Wang P. J. Dunn, A. B. Graham, R. Grigg, P. Higginson, V. Sridharan, M.
Thornton-Pett, Chem. Commun. 2001, 1968.
[8] The yield and endo/exo selectivity obtained in other solvents when the reaction was carried out in the presence of HfCl4 at À20 8C for 5 h are as follows: CH3CN: 49 %, endo/exo ¼ 73/27; toluene: 53 %, endo/ exo ¼ 87/13; Et2O: 71 %, endo/exo ¼ 92/8.
[9] For a recent review of asymmetric Diels±Alder reactions, see [**] This work was supported by the University of Georgia.
a) ™Catalytic Asymmetric Diels±Alder Reactions∫: Y. Hayashi in Supporting information for this article is available on the WWW under Cycloaddition Reactions in Organic Synthesis (Eds.: S. Kobayashi, or from the author.
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim


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