Experimental and theoretical studies on the transannular cyclizations of 3,7-dimethylenebicyclo[3.3.1]nonane with polyfluoroalkyl radicals

Journal of Fluorine Chemistry 127 (2006) 842–849 www.elsevier.com/locate/fluor

Experimental and theoretical studies on the transannular cyclizations of 3,7-dimethylenebicyclo[3.3.1]nonane with polyfluoroalkyl radicals Maxim V. Ponomarenko a, Yurii A. Serguchev a,*, Bogdan V. Ponomarenko a, Gerd-Volker Ro¨schenthaler b, Andrey A. Fokin c,* a

Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanskaya Str., 02094 Kiev, Ukraine b Institute of Inorganic & Physical Chemistry, University of Bremen, Leobener Strasse, 28334 Bremen, Germany c National Technical University of Ukraine ‘‘Kiev Polytechnic Institute’’, 37 Pobeda Ave, 03056 Kiev, Ukraine Received 28 December 2005; received in revised form 6 March 2006; accepted 10 March 2006 Available online 28 March 2006

Abstract Radical cyclizations of 3,7-dimethylenebicyclo[3.3.1]nonane with CF3I, n-C3F7I, ICF2COOEt and ICF2PO(OEt)2 selectively led to corresponding 3,7-noradamantanes, which were used for preparation of various polyfluoroalkyl substituted noradamantyl amines and carboxylates. DFT computations revealed that chemoselectivity of the radical cyclizations is realized due to the high electrophilicity of the CF3 radical, as well as due to efficient trapping of intermediate noradamantylmethyl radicals by perfluoroiodoalkane. # 2006 Elsevier B.V. All rights reserved. Keywords: Cyclization; 3,7-Dimethylenebicyclo[3.3.1]nonane; Perfluoroalkyl iodide; Ethyl iododifluoroacetate; Diethyl iododifluorophosphonate; Noradamantane derivatives; Ab initio calculations

1. Introduction Incorporation of fluorine and fluoroalkyl groups into organic molecules increases the lipophilicity and resistance to metabolism causing dramatic changes in biological activities [1–4]. The most important and convenient methods for preparing fluoroalkyl-substituted compounds are based on radical additions of perfluoroalkyl iodides to unsaturated substrates [5–8]. Among the latter the non-conjugated polyenes are of special interest because such transformations lead to various biologically active polycyclic compounds [9,10]. Adamantyl and noradamantyl moieties are often used as the building blocks for new drugs with antiarrhythmic, hypoglycemic, antiviral and other types of physiological activity [11–15]. Convenient and selective preparations of functional derivatives of adamantane and noradamantane are

* Corresponding authors. Tel.: +7 38 044 5590436; fax: +7 38 044 5732643. E-mail addresses: [email protected] (M.V. Ponomarenko), [email protected] (Y.A. Serguchev), [email protected] (A.A. Fokin). 0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2006.03.006

based on transannular cyclizations of bicyclo[3.3.1]nonane dienes with electrophilic or radical agents [16–24]. It has been shown previously, that transannular cyclizations of polyunsaturated bicyclo[3.3.1]nonane derivatives with electrophiles (iodine, bromine, acids, NHlgS (Hlg = Cl, Br, I), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) [16–20] lead to adamantane derivatives. In contrast, noradamantane, and adamantane derivatives, are formed in the reactions with radical agents (CCl4/AIBN, CHCl3/g-irradiation, C6H5SH, CH3PhSO2Hlg (Hlg = Cl, Br)) [21–24]. The ratio of adamantane/noradamantane products depends on the reagent used [21], and this fact still awaits its mechanistic interpretation. The purpose of this work was to examine the radical cyclizations of 3,7-dimethylenebicyclo[3.3.1]nonane with CF3I, n-C3F7I, and with difluoromethylene-substituted iodides ICF2COOEt and ICF2PO(OEt)2, that were used for preparation of potent biologically active molecules [25–30]. To elucidate the factors determining the chemoselectivity of radical cyclizations of 3,7-dimethylenebicyclo[3.3.1]nonane, we performed computational study on the key reaction steps.

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2. Results and discussion 2.1. Transannular cyclizations of 3,7dimethylenebicyclo[3.3.1]nonane with polyfluoroalkyl radicals Cyclization of 3,7-dimethylenebicyclo[3.3.1]nonane (1) with RFI {RF = CF3, n-C3F7, CF2COOEt, CF2PO(OEt)2} in dry acetonitrile upon irradiation with a Hg lamp in Pyrex or quartz apparatus or under heating in the presence of activated copper powder (20 mol.%) gave the corresponding noradamantanes 2–5 in quantitative yields (Scheme 1, Table 1). Compounds with the adamantane structure were not detected. The reaction of 1 with a two to three-fold excess of CF3I or n-C3F7I lead to corresponding noradamantane derivatives 2 and 3 after simple removal of the excess perfluoroalkyl iodides and acetonitrile by evaporation. In the reaction of 1 with ethyl iododifluoroacetate and diethyl iododifluorophosphonate equimolecular amounts of reagents were used in order to simplify the workup of the reaction mixtures. After the reaction of 1 with ICF2PO(OEt)2 and copper traces of HCF2PO(OEt)2 were found (<1%, 19F NMR of the reaction mixture (CDCl3): 138.2 ppm, dd, 2 JF,P = 90.0 Hz, 2JF,H = 48.0 Hz). Similar formation of reduced byproducts was reported earlier [31]. An analytical sample of adduct 5 was isolated by column chromatography on silica gel. The 1H NMR spectra of products 2–5 show the characteristic singlet of the CH2I group at 3.2 ppm. In the 1H NMR spectra of 2 and 4, the multiplets of the CH2RF groups (RF = CF3, CF2COOEt) at ca. 2.2 ppm with characteristic coupling constants 3JH,F 11.0 Hz (RF = CF3) and 18.0 Hz (RF = CF2COOEt) are clearly resolved. For compounds 3 and 5

Scheme 1.

RFI

Reaction conditions Initiation

Temperature

Time (h)

CF3I n-C3F7I n-C3F7I ICF2COOEt ICF2COOEt ICF2PO(OEt)2 ICF2PO(OEt)2

hn hn Cua hn Cua hn Cua

r.t. r.t. r.t. r.t. r.t. r.t. Reflux

6 6 12 20 12 16 12

20 mol.% Cu.

the signals of the CH2RF groups {RF = n-C3F7, CF2PO(OEt)2} are masked by the signals of noradamantane protons. The 19F NMR spectra of 2–5 are also consistent with the proposed structure. The formation of radical species in the reactions of 1 with the RFI agents upon UV-irradiation and copper catalysis takes place through different mechanisms (Fig. 1) and was well documented earlier. Photoirradiation leads to homolytic dissociation of the I–CF2 bond with formation of the electrophilic radical RF (Fig. 1, path a) [5,6,32]. In contrast, a single electron transfer mechanism has been proposed in the copper-catalyzed reaction of perfluoroalkyl iodides or iododifluoroacetate and iododifluorophosphonate with alkenes [25,26,29,31]. It was suggested that the initiation step involves an electron transfer from copper to RFI to produce the radical anion RFI , which rapidly decomposes to give the fluoroalkyl radical and the iodide anion (Fig. 1, path b). The fluoroalkyl radicals RF thus formed add to diene 1 with formation of fluoroalkylnoradamantyl radical 6. The latter abstracts iodine from RFI to give the adducts 2–5 and radical RF, propagating the chain process (Fig. 1). The exclusive formation of noradamantane derivatives differs from the previously observed selectivities for the radical cyclization of 3,7-dimethylenebicyclo[3.3.1]nonane [21–24]. For instance, in the reaction of 1 with CCl4 the 3:1 ratio of the respective noradamantane/adamantane products was found; the reaction with CBr4 is more selective (9:1) [21]. 2.2. Computational studies of the radical cyclization of 3,7-dimethylenebicyclo[3.3.1]nonane

Table 1 Reactions of 1 with RFI

a

Fig. 1. Mechanisms for reactions of 3,7-dimethylene[3.3.1]nonane (1) with polyfluoroalkyl iodides.

Product

Isolated yield (%)

2 3 3 4 4 5 5

91 98 95 92 94 98 96

In order to rationalize the reaction mechanistically, quantum-chemical calculations [33] on the cyclization of 3,7-dimethylenebicyclo[3.3.1]nonane with model radicals CF3 and CH3 were performed. The exo-attack of the radicals on one of the double bonds of 1 leads to intermediate minimum MIN1 (Fig. 2). The addition is much more exergonic for CF3 than for the CH3 radical ( 114.2 kJ mol 1 versus 73.6 kJ mol 1, B3LYP/6-31G*); consequently, the barrier for the addition of the CF3 radical is 18.8 kJ mol 1 lower (TS1). The exo-trig [34] transannular cyclization of MIN1 gives

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Fig. 2. The B3LYP/6-31G* relative energies (DG298, kJ mol 1) for the reaction of 3,7-dimethylenebilyclo[3.3.1]nonane (1) with the CH3- (first line, X = H) and ˚ ). CF3- (second line, X = F) radicals (selected bond distances in A

the noradamantane structure (MIN2 via TS3), whereas endotrig path lead to the adamantane derivative MIN3 via TS2. The exo-trig cyclization is favored kinetically, because the barrier for the endo-trig cyclization is ca. 17 kJ mol 1 higher. The formation of adamantane products through MIN3, which are more stable thermodynamically than MIN2 are precluded by much higher barriers via TS2. It is important to note, that the potential energy surface for the transannular cyclization step (after MIN1) is virtually identical for CH3 and CF3, i.e., is independent of the nature of the attack involved. The adamantane derivatives may form only via the rearrangement of MIN2. The transition structure for the transformation of MIN2 to MIN3 (not shown) is located 48.6 kJ mol 1 (for X = F) above MIN2. Hence, because the MIN3 is separated from MIN2 by relatively high barrier, formation of adamantane derivatives in the reaction of 1 with radical is possible in low-homolyzable solvents, where the lifetime of MIN2 is relatively high. This agrees nicely with the experimental data, where the ratio of noradamantane versus adamantane derivative is larger (9:1) in CBr4 than in less homolizabylity CCl4 (3:1) [21]. Radical additions studied herein experimentally in presence of RFI, which serves as an effective radical trap for MIN2, lead to noradamantane

derivatives exclusively. Thus, our computations revealed, that the selectivity of the cyclization depend on the homolizabylity of the reagent, rather than on the nature of the attacking radical. This, in combination with low-barrier radical addition of electrophilic RF radical (36.8 kJ mol 1 computed for CF3) allows us to propose an efficient way to various fluorinecontaining 3,7-noradamantane derivatives trough radical additions of RFI to 1 avoiding formation of undesired adamantane derivatives. 2.3. Preparation of fluoroalkyl noradamantanes via derivatization of the CH2I group Iodine in CH2I groups may be substituted by nucleophiles readily to give a large number of useful products. In order to demonstrate the synthetic potential of iodomethyl-containing noradamantanes, we have used well-known methods [35,36] for preparation of same products with key pharmacophoric groups, e.g., hydrochlorides of amines 9, 10 and derivatives of carboxylic acids 11, 14, 15 from noradamantanes 3 and 4. Substitution of iodine atom in 3, 4 by azide in dry dimethyl sulfoxide gave corresponding azides 7, 8 in good yields

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Scheme 2.

Scheme 3.

ing amino alcohol in overall 82% yield; the latter also characterized as hydrochloride 10 (Scheme 3). The unexpected result was observed when Raney Ni was used as a reducing agent for azide 8, the product of cyclization (lactam 11) was obtained (Scheme 3). All attempts to obtain a carboxylic acid from noradamantane derivative 3 through a subsequent treatment of n-BuLi or Mg and CO2 failed. Instead, dimerization product 12 was observed as a sole product (Scheme 4). Amide 14 was obtained in the reaction of noradamantane derivative 3 with KCN in dry dimethyl sulfoxide (Scheme 5), followed by the hydrolysis of nitrile 13 with 50% aqueous sulphuric acid at room temperature. Hydrolysis of 13 at higher temperatures in an aqueous-alcoholic solution of NaOH leads to acid 15 in 80% yield (Scheme 5). 3. Conclusion

Scheme 4.

(Scheme 2). The reduction of 7 with LiAlH4 in dry THF gave the amine, which was characterized and isolated as hydrochloride 9 in 90% yield (Scheme 2). The use of NaBH4 as the reducing agent requires a more prolonged reaction time (7 days under reflux in i-PrOH). The use of NaBH4 for the reduction of azide 8 led to reduction of both ester and azide groups, forming correspond-

We have demonstrated that radical cyclizations of 3, 7-dimethylenebicyclo[3.3.1]nonane with perfluoroalkyl iodides as well as with difluoromethylene-substituted iodides upon UV-irradiation or copper catalysis produce corresponding noradamantane derivatives selectively. Further derivatization of these noradamantane derivatives via the CH2I moiety leads to various polyfluoroalkyl-containing noradamantanes (9–11, 14, and 15) with various pharmacophoric groups in good preparative yields. DFT computations show, that the exclusive formation of noradamantane derivatives in this reaction is observed due to high electrophilicity of CF3 radical, and, more importantly, due to efficient trapping of intermediate noradamantylmethyl radicals by perfluoroiodoalkane. 4. Experimental

Scheme 5.

The 1H (299.9 MHz), 13C (75.4 MHz) and 19F (282.2 MHz) NMR spectra were recorded on a Varian VXR-300 spectrometer using CDCl3 and DMSO-d6 as solvent and TMS or CCl3F as internal standards. Mass spectra (EI) were obtained on an MX-1321 instrument at 70 eV. 3,7-Dimethylenebicyclo[3.3.1]nonane (1) was prepared by the known procedure [37]. Ethyl iododifluoroacetate [25] and diethyl iododifluoromethylphosphonate [38,39] were prepared by literature procedures. Copper powder was activated before use [40]. The UV-irradiation with Hg lamp (PRK-4, 950 W) was carried out in quartz or Pyrex reactors. All reactions of 1 were carried out under the inert atmosphere (argon, nitrogen) and monitored by TLC and 19F NMR spectroscopy.

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4.1. Reaction 1 with CF3I A solution of diene 1 (2 mmol) in anhydrous acetonitrile (1 mL) was placed in a Pyrex tube and cooled to 0 8C. Trifluoroiodomethane (5–6 mmol) was introduced by bubbling through the solution (weight control). The mixture was irradiated with Hg lamp for 6 h at room temperature. The solvent was removed by evaporation to give 3-iodomethyl-7(2,2,2-trifluoroethyl)tricyclo[3.3.1.03,7]nonane (2, 91%). White crystals: mp 40–41 8C (pentane); 1H NMR (CDCl3): d 1.50–2.30 (m, 12H, norAd), 2.20 (q, 2H, 3JH,F = 11.0 Hz, CH2CF3), 3.24 (s, 2H, CH2I); 13C NMR (CDCl3): d 17.4 (s, CH2I), 33.6 (s, C-9), 35.3 (s, C-1,5), 40.4 (q, 2JC,F = 26.7 Hz, CH2RF), 46.3 (s, C-3 or C-7), 49.9 (s, C-6,8), 50.8 (s, C-2,4), 51.9 (s, C-3 or C-7), 126.7 (q, 1JC,F = 280.3 Hz, CF3); 19F NMR (CDCl3): d 60.8 (t, 3JF,H = 11.0 Hz, CF3). Anal. Calcd. for C12H16F3I: C, 41.9; H, 4.7; I, 36.9. Found: C, 41.9; H, 4.7; I, 36.7. 4.2. Reaction 1 with RFI (RF = n-C3F7, CF2COOEt, CF2PO(OEt)2). General procedure A mixture of diene 1 (2 mmol) and RFI {n-C3F7I (4 mmol), ICF2COOEt (2 mmol), ICF2PO(OEt)2 (2 mmol)} in anhydrous acetonitrile (1 mL) was irradiated with Hg lamp or stirred with copper powder (20 mol.%) (Table 1). The solvent was removed by evaporation. In the case of reaction catalyzed by copper, hexane (2 mL) was added to the residue and solids were filtered off and washed with hexane. The filtrate was concentrated in vacuum to leave 3–5. The reaction products, if necessary, were purified by column chromatography on silica gel using hexane or hexane–ethyl acetate (5:1) as the eluent. 4.2.1. 3-(2,2,3,3,4,4,4-Heptafluorobutyl)-7iodomethyltricyclo[3.3.1.03,7]nonane (3, 95–98%) Colorless oil; 1H NMR (CDCl3): d 1.50–2.30 (m, 14H, norAd, and CH2RF), 3.27 (s, 2H, CH2I); 13C NMR (CDCl3): d 17.0 (s, CH2I), 33.2 (s, C-9), 35.0 (s, C-1,5), 35.5 (t, 2 JC,F = 20.0 Hz, CH2RF), 46.4 (s, C-3 or C-7), 49.9 (t, 4 JC,F = 2.4 Hz, C-2,4), 50.3 (s, C-6,8), 52.1 (s, C-3 or C-7), 102–128 (m, RF); 19F NMR (CDCl3): d 128.9 (m, 2F, CH2CF2), 114.2 (m, 2F, CF2CF3), 81.4 (m, 3F, CF3); EIMS 70 eV, m/z (%): 317 [M I]+ (100), 275 [M RF]+ (13), 261 [M CH2RF]+ (19). Anal. Calcd. for C14H16F7I: C, 37.9; H, 3.6; I, 28.6. Found: C, 37.8; H, 3.5; I, 28.4. 4.2.2. Ethyl 2,2-difluoro-3-(7-iodomethyl-3tricyclo[3.3.1.03,7]nonyl)propanoate (4, 92–94%) White crystals: mp 33–33.5 8C (pentane); 1H NMR (CDCl3): d 1.34 (t, 3H, 3JH,H = 7.2 Hz, CH3), 1.50–2.25 (m, 12H, norAd), 2.21 (t, 2H, 3JH,F = 18.0 Hz, CH2RF), 3.26 (s, 2H, CH2I), 4.30 (q, 2H, 3JH,H = 7.2 Hz, OCH2); 13C NMR (CDCl3): d 14.3 (s, CH3), 18.0 (s, CH2I), 33.5 (s, C-9), 35.3 (s, C-1,5), 40.8 (t, 2JC,F = 21.6 Hz, CH2RF), 46.7 (s, C-3 or C-7), 49.7 (s, C-2,4), 50.7 (s, C-6,8), 52.2 (s, C-3 or C-7), 63.2 (s, OCH2), 117.0 (t, 1JC,F = 252.1 Hz, CF2), 165.0 (t, 2JC,F = 32.4 Hz, CO); 19 F NMR (CDCl3): d 102.8 (t, 3JF,H = 18.0 Hz). Anal. Calcd.

for C15H21F2IO2: C, 45.2; H, 5.3; I, 31.9. Found: C, 45.2; H, 5.3; I, 31.7. 4.2.3. Diethyl 1,1-difluoro-2-(7-iodomethyl-3tricyclo[3.3.1.03,7]nonyl)phosphonate (5, 96–98%) Colorless oil; 1H NMR (CDCl3): d 1.39 (t, 6H, 3 JH,H = 7.3 Hz, 2CH3), 1.50–2.35 (m, 14H, norAd and CH2RF), 3.29 (s, 2H, CH2I), 4.28 (m, 4H, 2OCH2); 13C NMR (CDCl3): d 16.9 (d, 3JC,P = 4.4 Hz, 2CH3), 18.6 (s, CH2I), 33.7 (s, C-9), 35.5 (s, C-1,5), 38.8 (td, 2JC,F = 19.8 Hz, 2JC,P = 14.1 Hz, CH2RF), 47.6 (d, 3JC,P = 9.9 Hz, C-3), 50.7 (t, 4JC,F = 2.0 Hz, C-2,4), 50.8 (s, C-6,8), 52.4 (s, C-7), 64.9 (d, 2JC,P = 7.1 Hz, 2OCH2), 122.4 (td, 1JC,F = 262.8 Hz, 1JC,P = 214.7 Hz, CF2); 19 F NMR (CDCl3): d 112.7 (dt, 2JF,P = 106.9 Hz, 3 31 JF,H = 22.4 Hz); P NMR (CDCl3): d 8.6 (tm, 2 JP,F = 106.9 Hz); EIMS 70 eV, m/z (%): 335 [M I]+ (10), 207 (68), 150 (100). Anal. Calcd. for C16H26F2IO3P: C, 41.6; H, 5.7; I, 27.4; P, 6.7. Found: C, 41.5; H, 5.6; I, 27.2; P, 6.6. 4.3. Reactions of 3 and 4 with NaN3. General procedure A mixtures of 3 or 4 (0.5 mmol) and NaN3 (1 mmol) in anhydrous Me2SO (3 mL) were heated at 100 8C with stirring for 4 h. The reaction mixtures were poured into water (50 mL) and extracted with CH2Cl2 (15 mL  5 mL). The combined extracts were washed with water (10 mL  5 mL), dried (Na2SO4) and concentrated by evaporation to leave 7 (91%) or 8 (75%), respectively. 4.3.1. 3-Azidomethyl-7-(2,2,3,3,4,4,4heptafluorobutyl)tricyclo[3.3.1.03,7]nonane (7) Colourless oil; 1H NMR (CDCl3): d 1.50–1.75 (m, 8H, norAd), 1.93 (m, 2H, norAd), 2.18 (t, 2H, 3JH,F = 21.0 Hz, CH2RF), 2.26 (m, 2H, norAd), 3.37 (s, 2H, CH2N3); 13C NMR (CDCl3): d 33.8 (s, C-9), 35.0 (t, 2JC,F = 20.1 Hz, CH2RF), 35.6 (s, C-1,5), 46.0 (s, C-3 or C-7), 46.7 (s, C-2,4), 49.5 (t, 4 JC,F = 2.6 Hz, C-6,8), 52.3 (s, C-3 or C-7), 57.0 (s, CH2N3), 104–124 (m, RF); F19 NMR (CDCl3): d 129.0 (m, 2F, CH2CF2), 114.1 (m, 2F, CF2CF3), 81.4 (m, 3F, CF3). Anal. Calcd. for C14H16F7N3: C, 46.8; H, 4.5; N, 11.7. Found: C, 46.7; H, 4.5; N, 11.6. 4.3.2. Ethyl 3-(7-azidomethyl-3-tricyclo[3.3.1.03,7]nonyl)2,2-difluoropropanoate (8) Colourless oil; IR (CH2Cl2, n (cm 1)): 2070 (N3), 1720 (C O); 1H NMR (CDCl3): 1.35 (t, 3H, 3JH,H = 7.2 Hz, CH3), 1.49–1.54 (m, 8H, norAd), 1.81 (m, 2H, norAd), 2.22 (m, 2H, norAd), 2.23 (t, 2H, 3JH,F = 18.3 Hz, CH2CF2), 3.35 (s, 2H, CH2N3), 4.30 (q, 2H, 3JH,H = 7.2 Hz, OCH2); 13C NMR (CDCl3): d 13.9 (s, CH3), 33.9 (s, C-9), 35.7 (s, C-1,5), 40.1 (t, 2 JC,F = 21.6 Hz, CH2CF2), 46.0 (s, C-3 or C-7), 46.9 (s, C-6,8), 48.9 (s, C-2,4), 52.2 (s, C-3 or C-7), 57.4 (s, CH2N3), 62.8 (s, OCH2), 116.9 (t, 1JC,F = 251.3 Hz, CF2), 164.8 (t, 2 JC,F = 34.2 Hz, CO); 19F NMR (CDCl3): d 102.9 (t, 3 JF,H = 18.5 Hz); EIMS 70 eV, m/z (%): 285 [M N2]+ (5), 271 [M N3]+ (8), 162 [M N2-CF2COOEt]+ (23), 83 (100).

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Anal. Calcd. for C15H21F2N3O2: C, 57.5; H, 6.7; N, 13.41. Found: C, 57.6; H, 6.8; N, 13.3. 4.4. 3-Aminomethyl-7-(2,2,3,3,4,4,4heptafluorobutyl)tricyclo[3.3.1.03,7]nonane hydrochloride (9) A solution of azide 7 (0.5 mmol) in THF (2 mL) was added dropwise with stirring to mixture LiAlH4 (0.6 mmol) in anhydrous THF (1 mL). The reaction mixture was refluxed for 4 h. THF was removed by evaporation, then anhydrous diethyl ether (5 mL) was added to the residue. A rest of LiAlH4 was decomposed by water, solids was filtered off and washed with diethyl ether. HCl gas was passed through the diethyl ether solution. The precipitate was filtered off and washed with diethyl ether, then dried in vacuum to give 9 (90%). White crystals: mp > 270 8C; 1H NMR (DMSO-d6): d 1.40– 1.90 (m, 10H, norAd), 2.22 (m, 2H, norAd), 2.37 (t, 2H, 3 JH,F = 22.8 Hz, CH2RF), 2.95 (m, 2H, CH2NH3), 8.13 (bs, 3H, NH3); 13C NMR (DMSO-d6): d 33.0 (s, C-9), 33.3 (t, 2 JC,F = 20.0 Hz, CH2RF), 35.4 (s, C-1,5), 44.4 (s, C-3 or C7), 45.8 (s, C-2,4), 46.7 (s, C-3 or C-7), 48.3 (s, C-6,8), 50.2 (s, CH2NH3), 108–128 (m, RF); 19F NMR (DMSO-d6): d 126.3 (m, 2F, CH2CF2), 111.1 (m, 2F, CF2CF3), 79.0 (m, 3F, CF3); EIMS 70 eV, m/z (%): 333 [M HCl]+ (24), 316 [M NH4Cl]+ (57), 276 (37), 108 (52), 93 (100). Anal. Calcd. for C14H19ClF7N: C, 45.5; H, 5.2; Cl, 9.6; N, 3.8. Found: C, 45.4; H, 5.2; Cl, 9.5; N, 3.7. 4.5. 3-(7-Aminomethyl-3-tricyclo[3.3.1.03,7]nonyl)-2,2difluoro-1-propanol hydrochloride (10) A mixture of azide 8 (0.5 mmol) with NaBH4 (1.5 mmol) in i-C3H7OH (3 mL) was refluxed for 90 h. i-C3H7OH was removed by evaporation and water (3 mL) was added. The mixture was extracted with CH2Cl2 (3 mL  3 mL). The combined extracts were dried (Na2SO4), concentrated by evaporation, and dissolved in 10 mL diethyl ether. The solution was worked up as in Section 4.4 to give 10 (82%). White crystals: mp 188–189 8C; 1H NMR (DMSO-d6): d 1.48–1.55 (m, 8H, norAd), 1.81 (m, 2H, norAd), 1.99 (t, 2H, 3 JH,F = 19.5 Hz, CH2CF2), 2.19 (m, 2H, norAd), 2.82 (m, 2H, CH2NH3) 3.52 (t, 2H, 3JH,F = 13.2 Hz, CH2OH), 5.54 (bs, 1H, OH), 8.03 (bs, 3H, NH3); 13C NMR (DMSO-d6): d 33.1 (s, C-9), 35.2 (s, C-1,5), 37.3 (t, 2JC,F = 22.3 Hz, CH2CF2), 45.1 (s, C-3 or C-7), 45.9 (s, C-6,8), 46.9 (s, C-3,7), 48.8 (s, C-2,4), 49.5 (s, CH2NH3), 63.7 (t, 2JC,F = 31.4 Hz, CH2OH), 124.9 (t, 1 JC,F = 243.8 Hz, CF2); 19F NMR (DMSO-d6): d 103.7 (m); EIMS 70 eV, m/z (%): 245 [M HCl]+ (8), 228 [M NH4Cl]+ (38), 92 (100). Anal. Calcd. for C13H22ClF2NO: C, 55.4; H, 7.9; Cl, 12.6; N, 5.0. Found: C, 55.4; H, 7.9; Cl, 12.5; N, 4.9. 4.6. 5,5-Difluoro-3azatetracyclo[7.3.1.17,11.01,7]tetradecan-4-one (11) Raney Ni was obtained from 0.5 g of Ni/Al alloy [35] was washed with i-C3H7OH and added to a solution azide 8

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(0.35 mmol) in i-C3H7OH (1 mL). The reaction mixture was stirred at r.t. for 30 min, then at 70 8C for 30 min. The solids was filtered off and washed with i-C3H7OH. The filtrate was concentrated under reduced pressure, the residue was recrystallized from pentane to give white crystals of 11 (72%). White crystals: mp 161–162 8C; IR (KBr, n (cm 1)): 3200 (NH), 1650 (C O); 1H NMR (CDCl3): d 1.55 (m, 2H, norAd), 1.66 (m, 6H, norAd), 1.76 (m, 2H, norAd), 2.25 (m, 2H, norAd), 2.36 (m, 2H, 3JH,F = 17.4 Hz, CH2CF2), 3.27 (d, 2H, 3 JH,H = 6.0 Hz, CH2N), 6.67 (m, 1H, NH); 13C NMR (CDCl3): d 34.9 (s, C-10), 35.5 (s, C-9,11), 41.1 (t, 2JC,F = 22.9 Hz, CH2CF2), 45.0 (t, 3JC,F = 5.0 Hz, C-7), 46.1 (s, CH2NH), 46.2 (s, C-12,13), 49.5 (s, C-8,14), 50.3 (s, C-1), 114.8 (t, 1 JC,F = 243.3 Hz, CF2), 166.3 (t, 2JC,F = 32.0 Hz, CO); 19F NMR (CDCl3): d 84.5 (m); EIMS 70 eV, m/z (%): 241 [M]+ (58), 186 (83), 92 (100). Anal. Calcd. for C13H17F2NO: C, 64.7; H, 7.1; N, 5.8. Found: C, 64.6; H, 7.1; N, 5.7. 4.7. 1,2-Di[7-(2,2,3,3,4,4,4-heptafluorobutyl)-3tricyclo[3.3.1.03,7]nonyl]ethane (12) About 0.18 mL of n-C4H9Li 2.5N solution in hexane was added to a solution of 3 (0.45 mmol) in anhydrous THF (3 mL) at (55 to 60) 8C. The reaction mixture was stirred at (55 to 60) 8C for 1 h, warmed to 0–5 8C, and 1 mL of water was added dropwise to the solution. THF was removed by evaporation, CH2Cl2 (20 mL) was added to the residue. A usual work up gave 12 (85%). White crystals: mp 149–149.5 8C; 1H NMR (CDCl3): d 1.22 (s, 4H, 2CH2), 1.39 (m, 4H, norAd), 1.55 (m, 4H, norAd), 1.67 (m, 8H, norAd), 1.94 (m, 4H, norAd), 2.03 (t, 4H, 3 JH,F = 21.3 Hz, 2CH2RF), 2.22 (m, 4H, norAd); 13C NMR (CDCl3): d 33.9 (s), 34.0 (s), 36.1 (t, 2JC,F = 20.0 Hz, 2CH2RF), 36.1 (s, C-1,5), 46.6 (s), 48.5 (s), 49.6 (s), 51.8 (s), 104–124 (m, RF); F19 NMR (CDCl3): d 134.5 (m, 2F, CH2CF2), 119.4 (m, 2F, CF2CF3), 87.0 (m, 3F, CF3); EIMS 70 eV, m/z (%): 634 [M]+ (100), 317 [M/2]+ (55), 275 [M/2 RF]+ (10), 261 [M/ 2 CH2RF]+ (26). Anal. Calcd. for C28H32F14: C, 53.0; H, 5.1. Found: C, 53.0; H, 5.1. 4.8. 2-[7-(2,2,3,3,4,4,4-Heptafluorobutyl)-3tricyclo[3.3.1.03,7]nonyl]acetonitrile (13) A mixture of 3 (0.45 mmol) and KCN (0.54 mmol) in anhydrous Me2SO (2 mL) was heated at 100 8C for 3 h. The reaction mixture was worked up as in Section 4.3 to give 13 (89%). Colourless oil; 1H NMR (CDCl3): d 1.60 (m, 2H, norAd), 1.64–1.82 (m, 6H, norAd), 1.97 (m, 2H, norAd), 2.16 (tm, 2H, 3 JH,F = 21.3 Hz, CH2RF), 2.30 (m, 2H, norAd), 2.40 (s, 2H, CH2CN); 13C NMR (CDCl3): d 24.8 (s, CH2CN), 33.1 (s, C-9), 35.2 (t, 2JC,F = 20.4 Hz, CH2CF2), 35.5 (s, C-1,5), 46.0 (s, C-3 or C-7), 48.5 (s, C-2,4), 49.2 (s, C-3 or C-7), 49.4 (t, 4 JC,F = 2.5 Hz, C-6,8), 118.3 (s, CN), 104–124 (m, RF); 19F NMR (CDCl3): d 128.3 (m, 2F, CH2CF2), 113.4 (m, 2F, CF2CF3), 80.9 (m, 3F, CF3); EIMS 70 eV, m/z (%): 343 [M]+ (34), 323 [M HF]+ (14), 316 [M HCN]+ (14), 160

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[M CH2RF]+ (12), 91 (65), 79 (100). Anal. Calcd. for C15H16F7N: C, 52.5; H, 4.7; N, 4.1. Found: C, 52.4; H, 4.7; N, 4.0. 4.9. 2-[7-(2,2,3,3,4,4,4-Heptafluorobutyl)-3tricyclo[3.3.1.03,7]nonyl]acetamide (14) A mixture of nitrile 9 (0.5 mmol) with 2 mL of aqueous 50% H2SO4 was stirred at room temperature for 4 h. After an extraction with CH2Cl2 (3 mL  5 mL), then a usual work up and purification by column chromatography on silica gel (eluent: diethyl ether) the product 14 (70%) was obtained. White crystals: mp 109–110 8C; IR (KBr, n (cm 1)): 3380 (NH), 1650 (C O); 1H NMR (CDCl3): d 1.55 (m, 2H, norAd), 1.60–1.82 (m, 6H, norAd), 1.94 (m, 2H, norAd), 2.07(tm, 2H, 3 JH,F = 21.9 Hz, CH2RF), 2.26 (m, 4H, norAd, CH2CO), 6.26 (bs, 2H, NH2); 13C NMR (CDCl3): d 33.4 (s, C-9), 35.9 (s, 2 JC,F = 20.2 Hz, CH2RF), 35.9 (s, C-1,5), 43.5 (bs, CH2CO), 46.8 (s, C-3 or C-7), 48.6 (s, C-2,4), 49.2 (s, C-6,8), 49.9 (s, C-3 or C-7), 104–125 (m, RF), 174.4 (s, CO); 19F NMR (CDCl3): d 128.9 (m, 2F, CH2CF2), 114.0 (m, 2F, CF2CF3), 81.4 (m, 3F, CF3); EIMS 70 eV, m/z (%): 361 [M]+ (32), 136 [C10H16]+ (19), 59 [CH3C(O)NH2]+ (100). Anal. Calcd. for C15H18F7NO: C, 49.9; H, 5.0; N, 3.9. Found: C, 49.8; H, 5.0; N, 3.8. 4.10. 2-[7-(2,2,3,3,4,4,4-Heptafluorobutyl)-3tricyclo[3.3.1.03,7]nonyl]acetic acid (15) A mixture of nitrile 9 (0.5 mmol) with 2 mL of aqueous 60% NaOH and C2H5OH (2 mL) was refluxed for 90 h. About 20 mL of water was added into the reaction mixture, then hydrochloric acid was added to weak-acid medium. The mixture was extracted with CH2Cl2 (4 mL  5 mL). The extracts were washed with water, dried (Na2SO4) and concentrated. The residue was recrystallized from pentanediethyl ether mixture to give white crystals of 15 (80%). White crystals: mp 114–115 8C; IR (KBr, n (cm 1)): 3400– 2500 (OH), 1700 (C O); 1H NMR (DMSO-d6): d 1.50 (m, 2H, norAd), 1.62–1.84 (m, 8H, norAd), 2.16 (m, 2H, norAd), 2.34 (t, 2H, 3JH,F = 21.6 Hz, CH2RF), 2.38 (s, 2H, CH2COOH), 11.98 (bs, 1H, OH); 13C NMR (CDCl3): d 33.4 (s, C-9), 35.8 (t, 2 JC,F = 20.5 Hz, CH2RF), 35.8 (s, C-1,5), 41.4 (s, CH2COOH), 46.7 (s, C-3 or C-7), 48.4 (s, C-2,4), 49.2 (s, C-6,8), 49.6 (s, C-3 or C-7), 178.2 (s, CO); 19F NMR (DMSO-d6): d 127.1 (m, 2F, CH2CF2), 111.8 (m, 2F, CF2CF3), 79.5 (m, 3F, CF3); EIMS 70 eV, m/z (%): 362 [M]+ (55), 316 [M HCO2H]+ (13), 302 [M CH3CO2H]+ (22), 60 [CH3CO2H]+ (100). Anal. Calcd. for C15H17F7O2: C, 49.7; H, 4.7. Found: C, 49.7; H, 4.8. Acknowledgments This work was supported in part by the Deutsche Forschungsgemeinschaft (436 UKR 17/3/04) and the Ukrainian State Fund for Fundamental Research. AAF is grateful to the University of Giessen for computing facilities. MVP gratefully acknowledges Dr. A.A. Kolomeitsev and Dr. O. Shyshkov for their helpful discussions and advices.

References [1] R. Filler, Y. Kobayashi, L.M. Yagupolskii, Organofluorine Compounds in Medical Chemistry and Biological Applications, Elsevier, Amsterdam, 1993; J.P. Be´gue´, D. Bonnet-Delpon, Chimie bioorganique et me´dicinale du fluor, CNRS Editions, Paris, 2005. [2] J.T. Welch, Tetrahedron 43 (1987) 3123–3197. [3] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry, John Wiley and Sons, New York, 1991. [4] M.A. McClinton, D.A. McClinton, Tetrahedron 48 (1992) 6555–6666. [5] N.O. Brace, J. Fluorine Chem. 93 (1999) 1–25. [6] N.O. Brace, J. Fluorine Chem. 96 (1999) 101–127. [7] C. Amato, C. Naud, P. Calas, A. Commeyras, J. Fluorine Chem. 113 (2002) 55–63. [8] A.-R. Li, Q.-Y. Chen, Synthesis (1997) 1481–1488. [9] O.N. Zefirova, E.V. Selunina, N.V. Averina, N.V. Zyk, N.S. Zefirov, Zh. Org. Khim. 38 (2002) 1176–1180; O.N. Zefirova, E.V. Selunina, N.V. Averina, N.V. Zyk, N.S. Zefirov, Russ. J. Org. Chem. 38 (2002) 1125–1129. [10] O.N. Zefirova, E.V. Selunina, V.V. Nuriev, N.V. Zyk, N.S. Zefirov, Zh. Org. Khim. 39 (2003) 880–882; O.N. Zefirova, E.V. Selunina, V.V. Nuriev, N.V. Zyk, N.S. Zefirov, Russ. J. Org. Chem. 39 (2003) 831–833. [11] J. Shimada, F. Suzuki, H. Nonaka, A. Ishii, J. Med. Chem. 35 (1992) 924– 930. [12] E.B. Villhauer, J.A. Brinkman, G.B. Naderi, B.F. Burkey, B.E. Dunning, K. Prasad, B.L. Mangold, M.E. Russell, T.E. Hughes, J. Med. Chem. 46 (2003) 2774–2789. [13] M.I. Dawson, D.L. Harris, G. Liu, P.D. Hobbs, C.W. Lange, L. Jong, N. Bruey-Sedano, S.Y. James, X. Zhang, V.J. Peterson, M. Leid, L. Farhana, A.K. Rishi, J.A. Fontana, J. Med. Chem. 47 (2004) 3518– 3536. [14] V.J. Jasys, F. Lombardo, T.A. Appleton, J. Bordner, M. Ziliox, R.A. Volkmann, J. Am. Chem. Soc. 122 (2000) 466–473. [15] G.N. Pershin, N.S. Bogdanova, Chemotherapy of Viral Infections, Meditsina, Moscow, 1973, 142 pp. (in Russian); G.N. Pershin, N.S. Bogdanova, Chem. Abstr 79 (1973), 121991 pp.. [16] P.A. Krasutskii, Y.A. Serguchev, A.G. Yurchenko, A.V. Khotkevich, Teor. Eksp. Khim. 19 (1983) 229–232; P.A. Krasutskii, Y.A. Serguchev, A.G. Yurchenko, A.V. Khotkevich, Theor. Exp. Chem. (Engl. Transl.) 19 (1983) 206–209. [17] P.A. Krasutskii, A.V. Khotkevich, Y.A. Serguchev, A.G. Yurchenko, Teor. Eksp. Khim. 21 (1985) 52–56; P.A. Krasutskii, A.V. Khotkevich, Y.A. Serguchev, A.G. Yurchenko, Theor. Exp. Chem. (Engl. Transl.) 21 (1985) 48–52. [18] P.A. Krasutskii, N.B. Ambrosienko, V.N. Rodionov, A.G. Yurchenko, Z.N. Parnes, G.I. Bolestova, Zh. Org. Khim. 21 (1985) 1465–1470; P.A. Krasutskii, N.B. Ambrosienko, V.N. Rodionov, A.G. Yurchenko, Z.N. Parnes, G.I. Bolestova, Chem. Abstr. 104 (1986), 186041h. [19] Y.A. Serguchev, M.V. Ponomarenko, L.F. Lourie, A.N. Chernega, J. Fluorine Chem. 123 (2003) 207–215. [20] Yu.A. Serguchev, L.F. Lourie, M.V. Ponomarenko, Mendeleev Commun. (2002) 23–25. [21] A.G. Yurchenko, L.A. Zosim, N.L. Dovgan’, N.S. Verpovsky, Tetrahedron Lett. (1976) 4843–4846. [22] N.L. Dovgan’, I.R. Likhotvorik, A.G. Yurchenko, I.V. Lisovskaya, N.S. Verpovskii, Vestnik Kievskogo Politekhnicheskogo Instituta, Khim. Mash. i Tekhnologiya 22 (1985) 14–19; N.L. Dovgan’, I.R. Likhotvorik, A.G. Yurchenko, I.V. Lisovskaya, N.S. Verpovskii, Chem. Abstr. (1987) 175816e. [23] V.K. Gubernatorov, B.E. Kogai, V.A. Sokolenko, Izv. Akad. Nauk SSSR. ser. khim. (1983) 1874–1876; V.K. Gubernatorov, B.E. Kogai, V.A. Sokolenko, Chem. Abstr. (1983) 194486a. [24] V.K. Gubernatorov, B.E. Kogai, E.D. Korniets, V.A. Sokolenko, Zh. Org. Khim. 19 (1983) 2209–2210; V.K. Gubernatorov, B.E. Kogai, E.D. Korniets, V.A. Sokolenko, Chem. Abstr. 100 (1984) 209277v.

M.V. Ponomarenko et al. / Journal of Fluorine Chemistry 127 (2006) 842–849 [25] [26] [27] [28] [29] [30]

Z.-Y. Yang, D.J. Burton, J. Org. Chem. 56 (1991) 5125–5132. Z.-Y. Yang, D.J. Burton, J. Org. Chem. 57 (1992) 5144–5149. R. Engel, Chem. Rev. 77 (1977) 349–367. G.M. Blackburn, Chem. Ind. London (1981) 134–138. Z.-Y. Yang, D.J. Burton, J. Org. Chem. 57 (1992) 4676–4683. V. Pham, W. Zhang, V. Chen, T. Whitney, J. Yao, D. Froese, A.D. Friesen, J.M. Diakur, W. Haque, J. Med. Chem. 46 (2003) 3680–3687. [31] Q.-Y. Chen, Z.-Y. Yang, J. Fluorine Chem. 28 (1985) 399–411. [32] K. Tsuchii, M. Imura, N. Kamada, T. Hirao, A. Ogawa, J. Org. Chem. 69 (2004) 6658–6665. [33] Geometry optimizations, frequency analysis of stationary points, and IRC calculations were carried with Gaussian 03, revision B.03 program package, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, J.A. Montgomery, Jr., T. Vreven, K.N. Kudin, J.C. Burant, J.M. Millam, S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J.E. Knox, H.P. Hratchian, J.B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y. Ayala, K. Morokuma, G.A. Voth, P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S.

[34] [35]

[36]

[37] [38] [39] [40]

849

Dapprich, A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S. Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.W. Wong, C. Gonzalez, J.A. Pople, Gaussian, Inc., Pittsburgh PA, 2003. J.E. Baldwin, R.C. Thomas, L.I. Kruse, L. Silberman, J. Org. Chem. 42 (1977) 3846–3852. H. Becker, W. Berger, G. Domschke, E. Fangha¨nel, J. Faust, M. Fischer, F. Gentz, K. Gewald, R. Gluch, R. Mayer, K. Mu¨ller, D. Pavel, H. Schmidt, K. Schollberg, K. Schwetlick, G. Zeppenfeld, Organikum, in: K. Schwetlick (Ed.), Berlin, 1963. pp. 592. L.F. Tietze, T. Eicher, Reactionen und Synthesen im organisch-chemischen Praktikum und Forschungslaboratorium, Georg Thieme Verlag Stuttgart, New York, 1991. F.N. Stepanow, W.D. Suchowerchow, Angew. Chem. 79 (1967) 860. R. Waschbu¨sch, M. Samadi, P. Savignac, J. Organomet. Chem. 529 (1997) 267–278. H.K. Nair, R.D. Guneratne, A.S. Modak, D.J. Burton, J. Org. Chem. 59 (1994) 2393–2398. V.C.R. McLoughlin, J. Thrower, Tetrahedron 25 (1969) 5921–5940.