Preparation and Regioselective SN2′ Reaction of Novel gem-Difluorinated Vinyloxiranes with RLi Hisanori Ueki, Takashi Chiba, Takashi Yamazaki,*,† and Tomoya Kitazume Graduated School of Bioscience and Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8510, Japan
[email protected] Received June 10, 2004
A series of hitherto unknown 3,4-epoxy-1,1-difluorobutenes were prepared from the readily accessible R,β-epoxy ketones and these compounds were found to undergo regioselective SN2′ reactions with hard RLi nucleophiles occurring at the highly positively charged terminal fluorine-possessing sp2 carbon atom in quite sharp contrast to the cases of the corresponding nonfluorinated vinyloxiranes which only attained a low level of regioselectivity. Addition of HMPA substantially improved the products’ olefinic stereoselectivity. Theoretical calculations were used to qualitatively explore the nature of selectivity in these reactions. Introduction Introduction of fluorine into organic compounds sometimes brings about a quite significant change toward their chemical and physical properties due to the unique effect of this atom,1 which is why fluorine-containing compounds have drawn profound interest in fine chemical and pharmaceutical fields. Despite such characteristics, utilization of fluorinated organic materials is not always easy because they are rare in nature2 and such remarkable changes in properties enormously affect their reactivity, which does not often allow application of various synthetic methods developed for nonfluorinated prototypes. For instance, fluorinated carbon atoms in gemdifluorinated olefins have appeared to possess extraordinarily high electrophilicity due to the strong electronic repulsion between lone pairs around fluorine atoms and π-electrons while the corresponding nonfluorinated counterparts usually show nucleophilicity.3 Therefore, independent synthetic pathways should be developed, and accordingly, various methods as well as building units with fluorine have been synthesized and reported thus far.1b,4 Recently, we have established the preparation of compounds 1,5 the terminally fluorine-substituted analogues of vinyloxiranes, from easily obtained R,β-epoxy ketones by way of the difluoro Wittig reaction,4b,6 which, † Present address: Department of Applied Chemistry, Tokyo University of Agriculture and Technology, 2-24-16, Nakamachi, Koganei 184-8588, Japan. (1) (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3. (b) Kitazume T.; Yamazaki T. Experimental Methods in Organic Fluorine Chemistry; Kodansya: Tokyo, Japan, 1998. (c) Schlosser, M. Angew. Chem., Int. Ed. 1998, 110, 1496. (d) O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645. (e) Howard, J. A. K.; Hoy, V. J.; O’Hagan, D.; Smith, G. T. Tetrahedron 1996, 52, 12613. (f) Schlosser, M.; Michel, D. Tetrahedron 1996, 52, 99. (g) Banks, R. E.; Tatlow, J. C. J. Fluorine Chem. 1986, 33, 227. (2) (a) O’Hagan, D.; Harper, D. B. J. Fluorine Chem. 1999, 100, 127. (b) Harper, D. B.; O’Hagan, D. Nat. Prod. Rep. 1994, 11, 4. (3) Borisov, Y. A. J. Struct. Chem. 2002, 43, 734.
as far as we know, have not been reported thus far except for perfluorinated 3,4-epoxybutene (Chart 1).7 Moreover, considering the synthetic utility of vinyloxiranes as intermediates8 for a wide variety of molecules, compounds 1 are regarded as highly potent and versatile building blocks possessing a CF2dC moiety, which, by reaction with appropriate nucleophiles, could be readily converted to the sp3-hybridized CF2 groups known to be isosteric and isopolar to an oxygen atom9 especially in (4) (a) Percy, J. M. Top. Curr. Chem. 1997, 193, 131. (b) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619. (c) Burton, D. J.; Yang, Z.-Y.; Morken, P. A. Tetrahedron 1994, 50, 2993. (d) Be´gue´, J.-P.; Bonnet-Delpon, D. Tetrahedron 1991, 47, 3207. (e) Tsuchiya, T. Adv. Carbohydr. Chem. Biochem. 1990, 1, 661. (f) Welch, J. T. Tetrahedron 1987, 43, 3123. For chiral building blocks see: (g) Iseki, K.Tetrahedron 1998, 54, 13887. (h) Kitazume, T.; Yamazaki, T. Top. Curr. Chem. 1997, 193, 91. (i) Resnati, G. Tetrahedron 1993, 49, 9385. (j) Bravo, P.; Resnati, G. Tetrahedron: Asymmetry 1990, 1, 661. (5) Yamazaki, T.; Ueki, H.; Kitazume, T. Chem. Commun. 2002, 2670. (6) (a) Burton, D. J.; Yang, Z.; Qiu, W. Chem. Rev. 1996, 96, 1641. (b) Motherwell, W. B.; Tozer, M. J.; Ross, B. C. J. Chem. Soc., Chem. Commun. 1989, 1437. (c) Fried, J.; Kittisopikul, S.; Hallinan, E. A. Tetrahedron Lett. 1984, 25, 4329. (d) Vinson, W. A.; Prickett, K. S.; Spahic, B.; Oritz de Montellano, P. R. J. Org. Chem. 1983, 48, 4661. (e) Hayashi, S.; Nakai, T.; Ishikawa, N.; Burton, D. J.; Naae, D. G.; Kesling, H. S. Chem. Lett. 1979, 983. (f) Burton, D. J.; Naae, D. G. Synth. Commun. 1973, 3, 197. (g) Burton, D. J.; Naae, D. G. J. Fluorine. Chem. 1971, 1, 123. (7) (a) Kaneko, I.; Nakamura, H.; Oharu, K. Jpn. Kokai Tokkyo Koho JP 02,040,373, Feb. 9, 1990. (b) Stockburger, L., III; Heicklen, J. J. Am. Chem. Soc. 1971, 93, 3331. (c) Sianesi, D.; Bernardi, G. C.; Pasetti, A. French Patent 1,499,094, October 20, 1967. (8) (a) Lautens, M.; Ouellet, S. G.; Raeppel, S. Angew. Chem., Int. Ed. 2000, 39, 890. (b) Olofsson, B.; Khamrai, U.; Somfai, P. Org. Lett. 2000, 2, 4087. (c) Trost, B. M.; Tang, W.; Schult, J. L. Org. Lett. 2000, 25, 4013. (d) Koizumi, T.; Ando, T.; Kojima, T.; Endo, T. Macromolecules 1998, 31, 9096. (e) Shim, J.-G.; Yamamoto, Y. J. Org. Chem. 1998, 63, 3067. (f) Harada, S.; Kowase, N.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1997, 38, 1957. (g) Aurrecoechea, J. M.; Izutueta, E. Tetrahedron Lett. 1995, 36, 7129. (h) Bideau, F. L.; Aubert, C.; Malacria, M. Tetrahedron: Asymmetry 1995, 6, 697. (i) Hedhli, A.; Blaklouti, A. J. Org. Chem. 1994, 59, 5277. (j) Feldman, K. S.; Fisher, T. E. Tetrahedron 1989, 45, 2969. (9) (a) Stremler, K. E.; Poulter, C. D. J. Am. Chem. Soc. 1987, 109, 5542. (b) Motherwell, W. B.; Tozer, M. J.; Ross, B. C. J. Chem. Soc., Chem. Commun. 1989, 1437. 10.1021/jo049025x CCC: $27.50 © 2004 American Chemical Society
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J. Org. Chem. 2004, 69, 7616-7627
Published on Web 09/24/2004
Regioselective SN2′ Reaction of F2-Vinyloxiranes CHART 1. gem-Difluorinated Vinyloxiranes Prepared in the Present Work
FIGURE 1. Ab initio calculation of gem-difluorinated vinyloxirane 1a and its prototype 2a.
nonfluorinated species was known to attain only a low level of regioselectivity to yield a mixture of products.12 In this article, we would like to describe the full details of the preparation of hitherto not synthesized gemdifluorinated vinyloxiranes and their reactions with RLi which will be discussed from the standpoint of semiempirical or ab initio computation. Results and Discussion
the field of medicinal chemistry and thus utilized as enzyme inhibitors.4f,10 On the basis of the ab initio calculation11 of 1a and the corresponding nonfluorinated counterpart 2a (Figure 1), introduction of fluorine atoms has unambiguously demonstrated that the charge on the fluorine-possessing carbon atom was unusually altered from -0.425 to +0.805 (NBO (natural bond orbital) charges). This result led to the expectation that hard nucleophiles such as RLi would realize the smooth addition to 1 at this specific site in a highly regioselective manner. This was actually the case, and we have already reported in the previous communication5 that the regioselective SN2′ reactions of RLi toward 1 in THF afforded a wide range of difluorinated allylic alcohols, while the (10) (a) Schirlin, D.; Baltzer, S.; Altenburger, J. M.; Tarnus, C.; Remy, J. M. Tetrahedron 1996, 52, 305. (b) Nieschalk, J.; O’Hagan, D. J. Chem. Soc., Chem. Commun. 1995, 719. (c) Burke, T. R., Jr.; Smyth, M. S.; Otaka, A.; Nomizu, M.; Roller, P. P.; Wolf, G.; Case, R.; Shoelson, S. E. Biochemistry 1994, 33, 6490. (d) Blackburn, G. M.; Jakeman, D. L.; Ivory, A. J.; Williamson, M. P. Bioorg. Med. Chem. Lett. 1994, 4, 2573. (e) Thatcher, G. R. J.; Campbell, A. S. J. Org. Chem. 1993, 58, 2272. (f) Gelb, M. H. J. Am. Chem. Soc. 1986, 108, 3146. (g) Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985, 24, 1813. (h) Blackburn, G. M.; Kent, D. E.; Kolkmann, F. J. Chem. Soc., Perkin Trans. 1 1984, 1119. (11) Computation was carried out by Gaussian W03 version 6.0 at the B3LYP/6-31+G* level of theory. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian W03, version 6.0; Gaussian, Inc., Pittsburgh, PA, 2003.
Taking relatively high reactivity of a terminally difluorinated olefin part reported into account, difluoromethylenation was planned to be carried out at the last step of the preparation of 1, which led to the formation of various types of starting materials 1 from a wide variety of R,β-epoxy ketones easily obtained by many protocols including their enantioselective pathways. For the clarification of the scope and limitation of 1 as building blocks, R,β-epoxy ketones 3b-i were prepared from the corresponding ketones basically by such a routine method as NaOH-mediated H2O2 epoxidation, while 3j and 3k were obtained from epoxy alcohols by way of oxidation with Jones reagent and pyridinium dichromate (PDC), respectively, and trans-2,3-epoxy-1,3diphenyl-1-propanone 3l was purchased from a commercial supplier. At the final stage, their carbonyl moieties were difluoromethylenated with CF2Br2-hexamethylphosphorus triamide (HMPT)4b,6 in the presence of MS 4A due to moisture sensitivity of the reaction intermediates.13 All epoxy ketones 3b-l were smoothly converted into the corresponding gem-difluoro vinyloxiranes 1b-l in excellent yields (Table 1), and a slightly decreased yield of 1e might stem from its inherent volatility. On standing at ambient temperature after chromatographic purification, 1b was found to be partially decomposed within a few days and, from the residual mixture, acid fluoride 4b and CF3-containing allylic alcohol 5b were isolated as the sole isomeric product in both cases whose stereochemistry was not clarified yet (Scheme 1). 1b probably reacted with air moisture in an SN2′ fashion under concentrated conditions and the subsequent HF elimination14 produced 4b, and moreover, HF thus generated was added to 1b to form 5b. Because of this inherent (12) (a) Rose, C. B.; Taylor, S. K. J. Org. Chem. 1974, 39, 578. (b) Johnson, C. R.; Wilbur Herr, R. J. Am. Chem. Soc. 1970, 92, 4979. (13) Hooz, J.; Gilani, S. S. H. Can. J. Chem. 1968, 46, 86. (14) (a) Tellier, F.; Sauveˆtre, R. Tetrahedron Lett. 1993, 34, 5433. (b) Elsheimer, S.; Michael, M.; Landavazo, A.; Slattery, D. K.; Weeks, J. J. Org. Chem. 1988, 53, 6151.
J. Org. Chem, Vol. 69, No. 22, 2004 7617
Ueki et al. TABLE 1. Preparation of gem-difluorinated
TABLE 2. Solvent Effect for the SN2′ Reaction of 1b
Vinyloxiranes 1a
with n-BuLi
entry 1 2 3 4 5 6 7 8 9 10 11 a
product 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l
time (h)
yield of 1 (%)
1 6 1 1 1 1 2 2 1 1 1
94 (85) 88 75 (>99) 94 >99 93 96 99 91 97
Yields in parentheses were determined by
19F
NMR.
SCHEME 1
instability, compounds 1 are highly recommended to be kept as a hexane solution under an argon atmosphere in a refrigerator for a couple of days, except for 1h and 1i which are stable enough even at ambient temperature. 1b was selected as the representative substrate for finding out suitable reaction conditions with n-BuLi. At first, an excess amount of n-BuLi (5 equiv) was employed for treatment of 1b in several solvents at 0 °C. In hexanes, the anticipated SN2′ product 6b was obtained only in 38% yield as an inseparable E/Z mixture along with 23% recovery of the starting material 1b, which did not compete at all with the possible SN2 type direct epoxide opening pathway (Table 2, entry 1). Acceleration of this process and increase of the chemical yields were observed for such ethereal solvents as Et2O, THF, and 1,4-dioxane. The reaction in 1,4-dioxane recorded the best yield among solvents employed, but this solvent brought about no olefinic stereoselectivity and rate retardation (entry 4). THF and Et2O gave comparable yields, but the former attained the better product E/Z ratio (entries 2 and 3), which was improved by lowering the temperature but with longer reaction time necessary for completion (entry 5). Then, we fixed THF as a solvent, and tried to decrease the amount of n-BuLi (entries 6∼8). Usage of 2 equiv was eventually found to be effective for suppression of unfavorable defluorination with an increase in the chemical yields at the same E/Z ratio, but 1 equiv of n-BuLi led to the partial recovery of 1b. This defluori7618 J. Org. Chem., Vol. 69, No. 22, 2004
entry
X (equiv)
solvent
time (h)
yielda (%)
E/Z ratioa
recoverya (%)
1 2 3 4 5b 6 7 8
5.0 5.0 5.0 5.0 5.0 3.0 2.0 1.0
n-hexane Et2O THF 1,4-dioxane THF THF THF THF
24 2 2 24 24 2 2 2
38 52 52 66 42 59 63 36
66/34 60/40 72/28 53/47 81/19 73/27 73/27 74/26
23 1 0 15 10 0 0 41
a
Determined by 19F NMR. b The reaction was conducted at -78
°C.
nation is considered to be the major reason we could not obtain good material balance in all experiments examined. It is well-known that reactivities of RLi and selectivities of the products change in the presence of hexamethylphosphoric triamide (HMPA) possessing the strongly chelating ability to metals.15,16 In our instance, the E/Z ratio of the product was proved to be dramatically improved to 95/5 by the addition of an excess amount of HMPA (Table 3, entry 5). Further study clarified that only 0.5 equiv of HMPA was suffice to achieve the same level of E/Z ratio, while still 2.0 equiv of RLi was required for complete consumption of 1b (entries 2-5). When the reaction was conducted at -78 °C, the stereoisomeric ratio was further increased (entries 3 and 9) with thorough consumption of 1b, which was in quite sharp contrast to the fact that only low conversion was realized in the absence of HMPA (see Table 2, entry 5). Addition of n-BuLi to a mixed solution of 1b and HMPA turned out to be the method of choice, one reason being that HMPA itself can react with RLi.17 Next, we checked the effect of additives. Safe substitutes for HMPA like tetramethylethylenediamine (TMEDA), 12-crown-4, 1,3dimethyl-2-imidazolidinone (DMI), and 1,3-dimethyl3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) attained only slight to moderate improvement on the chemical yields as well as the E/Z ratio of the products (entries 6-10).18 Since the difluoro Wittig reagent from CF2Br2 and HMPT furnishes HMPA as a byproduct, we tried to make (15) (a) Yuan, S. Y. L.; Huang, Z.-Z.; Tang, Y.; Dai, L.-X. J. Org. Chem. 2000, 65, 6257. (b) Ando, K.; Takemasa, Y.; Tomioka, K.; Koga, K. Tetrahedron 1993, 49, 1579. (c) Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.; Vonwiller, S. C. J. Org. Chem. 1989, 54, 1960. (d) Wolf, G.; Wu¨rthwein, E.-U. Tetrahedron Lett. 1988, 29, 3647. (e) Ager, D. J.; East, M. B. J. Org. Chem. 1986, 51, 3983. (f) Hosomi, A.; Araki, Y.; Sakurai, H. J. Am. Chem. Soc. 1982, 104, 2081. (g) Hirama, M. Tetrahedron Lett. 1981, 22, 1905. (h) Wartski, L.; El Bouz, M.; Seyden-Penne, J. Tetrahedron Lett. 1979, 1543. (i) Brown, C. A.; Yamaichi, A. J. Chem. Soc., Chem. Commun. 1979, 100. (j) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868. (k) Panek, E. J.; Rodger, T. J. J. Am. Chem. Soc. 1974, 96, 6921. (16) 300 times stronger interaction with Li was observed for HMPA than THF. See: Reich, H. J.; Kulicke, K. J. J. Am. Chem. Soc. 1996, 118, 273. (17) Kaiser, E. M.; Petty, J. D.; Solter, L. E. J. Organomet. Chem. 1973, 61, C1.
Regioselective SN2′ Reaction of F2-Vinyloxiranes TABLE 3. Effect of HMPA toward the Stereoselectivity
TABLE 4. Reaction of 1 with Various RLia
of the Products
entry 1 2 3b 4 5 6 7 8 9b 10 a
additive HMPA
TMEDA 12-crown-4 DMI DMPU
X (equiv)
yielda (%)
E/Z ratioa
recovery (%)
0 0.5 0.5 1.0 2.0 0.5 0.5 0.5 0.5 0.5
63 76 78 66 62 62 52 66 49 44
73/27 95/5 >99/99/99/99/99/99/99/99/99/
