FULL PAPER

DOI: 10.1002/ejoc.201402158

Synthesis of Trifluoromethyl-Substituted 3-Azabicyclo[n.1.0]alkanes:Advanced Building Blocks for Drug Discovery

Olexiy S. Artamonov,[a] Evgeniy Y. Slobodyanyuk,[b] Dmitriy M. Volochnyuk,[a]

Igor V. Komarov,[c] Andrey A. Tolmachev,[b,d] and Pavel K. Mykhailiuk*[b,d]

Keywords: Fluorine / Synthetic methods / Trifluoromethyldiazomethane / Nitrogen heterocycles / Drug discovery

Five CF3-substituted 3-azabicyclo[n.1.0]alkanes were syn-thesized by CuCl-mediated trifluoromethylcyclopropanation

Introduction

Fluorine is very popular in modern drug discovery: itoccurs in approximately 20% of all pharmaceuticals, andthis fact cannot be explained by mere coincidence or bias incomposing the compound sets for biological screening.[1a]

Incorporating the CF3 group, for example, into organiccompounds may be beneficial for their pharmacologicalcharacteristics, because it affects lipophilicity, solubility,stability of the compounds, molecular conformation, andpKa of the functional groups.[1,2] Consequently, at least 45FDA-approved drugs contain a CF3 group.[3] Therefore,CF3-substituted building blocks play a key role in moderndrug design. Trifluoromethyl-substituted cyclic amines areespecially attractive for this purpose. During the past dec-ade, chemists have used 3- and 4-(trifluoromethyl)piperid-ines (1 and 2) in more than one hundred drug discoveryprojects (Figure 1).[4,5]

Other CF3-substituted saturated cyclic amines were usedless in drug discovery; some of them remain unknown.[6] Inour opinion, this situation is illogical: many medicinal pro-jects fail, because chemists cannot optimize biological ac-tivity of the ligands by fine-tuning their structure,[7] partlyowing to the low structural diversity of the available build-ing blocks.[8] Therefore, we became interested in synthesiz-

[a] Institute of Organic Chemistry, National Academy of Sciencesof Ukraine,Murmanska Street 5, 02660 Kyiv-94, Ukraine

[b] Department of Chemistry, Taras Shevchenko NationalUniversity of Kyiv,Volodymyrska Street 64, Kyiv 01601, Ukrainehttp://www.chem.univ.kiev.ua

[c] Institute of High Technologies, Taras Shevchenko NationalUniversity of Kyiv,Volodymyrska Street 60, 01601 Kyiv, Ukraine

[d] Enamine Ltd.,Vul. Oleksandra Matrosova 23, 01103 Kyiv, UkraineE-mail: Pavel.Mykhailiuk@gmail.com

Pavel.Mykhailiuk@mail.enamine.netwww.enamine.netSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201402158.

© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2014, 3592–35993592

reaction of the corresponding cyclic enamides withCF3CHN2.

Figure 1. Some biologically active derivatives of 3- and 4-trifluoro-methylpiperidines.

ing new CF3-substituted saturated cyclic amines.[9] We re-cently reported the synthesis of amine 3, which is a confor-mationally restricted analogue of piperidine 1 (Fig-ure 2).[9a,10] In continuation of this work, we prepared con-formationally restricted analogues/homologues of isomericpiperidine 2. By using the same principles as for 3, namely,incorporation of the cyclopropane ring into the molecules,we constructed amines 4–6, the synthesis of which we re-port herein.

Figure 2. Structure of amines 1–6.

Trifluoromethyl-Substituted 3-Azabicyclo[n.1.0]alkanes

Results and Discussion

Synthetic Strategy

Recently, we applied a CuCl-mediated trifluoromethylcy-clopropanation reaction of a 4,5-dehydroproline derivativewith CF3CHN2 (Scheme 1a)[11] in the synthesis of a CF3-substituted proline analogue.

Scheme 1. (a) Literature synthesis of a CF3-substituted proline ana-logue;[11] (b) retrosynthetic analysis of amines 4–6.

We planned to construct amines 4–6 similarly from thecorresponding N-tert-butoxycarbonyl (Boc) enamides(Scheme 1b).[12–14]

Chemistry

Synthesis of amine 4 started from azetidinol 7. Tosyl-ation of the hydroxy group, followed by addition of KOtBugave enamide 8 according to a literature protocol(Scheme 2).[15] Next, we attempted the trifluoromethyl-cyclopropanation reaction. In the experimental setup,gaseous CF3CHN2 was generated from CF3CH2NH2·HCland NaNO2 in water. It was blown off from the generatingflask with an argon flow into a reaction vessel with alkene

Figure 3. Molecular structure of compound 9a (two projections) obtained by X-ray crystallography. Thermal ellipsoids are shown at 30%probability level.[18]

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8 in dichloromethane containing the catalyst – dry CuCl(see Supporting Information). The reaction was monitoredby 1H NMR spectroscopy. After the starting material haddisappeared (ca. 5 equiv. of CF3CHN2 were required), thereaction mixture was concentrated and the product purifiedby column chromatography to obtain cyclopropane 9a in25 % yield.

Scheme 2. Synthesis of amines 4a·TFA (TFA = trifluoroacetic acid)and 11·HCl.

Presumably, the steric strain of the 3-azabicyclo[2.1.0]-pentane skeleton (fused three- and four-membered rings) isthe main reason for the low yield of the product. X-raycrystallographic analysis of 9a (Figure 3) supported thissuggestion: the sum of bond angles at the N atom is 341°,indicating that the pyramidalized N atom conjugates withthe carbonyl group inefficiently, resembling the twisted

P. K. Mykhailiuk et al.FULL PAPERamide bonds in bridgehead lactams.[16] The compound,however, was stable in air at room temperature. Cleavingthe N-Boc group in 9a with a solution of HCl in methanol

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gave a complex mixture. Presumably, the chloride anion at-tacked the cyclopropane ring of the initially formed prod-uct.[17] Therefore, we tried removing the N-Boc group byavoiding strong nucleophiles in the media. Treatment of asolution of 9a in dichloromethane with trifluoroacetic acid(TFA) gave desired amine 4a·TFA in quantitative yield.

Hydrogenation of compound 9a in the presence of 10 %Pd/C at room temperature (15 atm) smoothly gave pyrrolid-ine derivative 10. It is interesting to note that less strained(trifluoromethyl)cyclopropanes are known to be resistanttowards hydrogenation.[19] We next cleaved the N-Bocgroup in 10 by HCl/methanol to afford 4-(trifluoromethyl)-pyrrolidine (11·HCl). During the last decade, amine 11 hasbecome popular in both drug discovery and agrochemistryprojects,[20] but we only recently comprehensively describedits synthesis.[21,9b]

Synthesis of amine 5 started from pyrrolidone 12. Re-duction of the carbonyl group in 12 with LiBHEt3 followedby addition of (CF3CO)2O/N,N-diisopropylethylamine(DIPEA)/4-(dimethylamino)pyridine (DMAP) gave en-amide 13 according to a literature protocol (Scheme 3).[22]

Relative to 8, compound 13 smoothly reacted withCF3CHN2 under the same conditions to afford products14a/14b (1.5:1.0). We obtained individual isomers 14a (50%yield) and 14b (33% yield) by column chromatography.Standard acidic cleavage of the N-Boc group gave amines5a·HCl and 5b·HCl in 98 and 96 % yield, respectively.

Consequently, we synthesized amines 6 according to thesame strategy (Scheme 4). Enamide 16 was obtained by re-duction of the carbonyl group in 15 followed by dehy-dration according to the literature in 68% yield. Reaction of16 with CF3CHN2 in the presence of dry CuCl as a catalystafforded cyclopropanes 17a/17b (2.5:1.0) in 61 % yield. Weseparated the diastereomers by column chromatography.Acidic cleavage of the N-Boc group in 17a/17b afforded tar-get amines 6a·HCl and 6b·HCl in excellent yields.

It is worth noting that the protocols for amines 4–6 werescalable and allowed up to 10 g of the target products to besynthesized.

Assignment of Stereoconfiguration

We determined the relative configuration of compounds9a, 14a and 17a by 2D-NMR experiments (see SupportingInformation). Figure 4 shows the key correlations in theNOESY spectra. We did not observe corresponding corre-lations in isomers 14b and 17b. Subsequently, we proved thestructure of compound 9a by X-ray crystallography (Fig-ure 3).

Discussion

In all bioactive compounds shown in the Figure 1, thetrifluoromethyl fragment served as a metabolically stable li-pophilic group involved in the hydrophobic interaction withthe biological target. A proper ligand-receptor steric matchenhances the ligand efficiency in such cases.[23] Therefore,

Trifluoromethyl-Substituted 3-Azabicyclo[n.1.0]alkanes

Scheme 3. Synthesis of amines 5a·HCl and 5b·HCl.

Scheme 4. Synthesis of isomeric amines 6a·HCl and 6b·HCl.

Figure 4. Key correlations in the NOESY spectra of compounds9a, 14a, 17a.

we suggest that amines 3a–6a, 6b, 11 will complement exi-sting building blocks 1 and 2 in drug design by the follow-ing features:

(1) Structural diversity. Amines 1, 2 and 3a–6a and 6b,and 11 have a different arrangement of the trifluoromethylsubstituent with regard to the nitrogen atom (Figure 5),which might be used in fine-tuning the ligand structure tooptimize its interaction with biological targets.

(2) Conformational restriction. Fixation of the biolo-gically active conformation can, in principle, increase theligand activity and selectivity.[24] For example, Vacher andcolleagues recently showed that cyclopropane-containingcompound 18 exhibited an affinity of two orders of magni-tude higher to the α-adrenergic receptor relative to theknown drug Atipamezole (Figure 6).[25] In this context, thesynthesized amines are the ideal candidates for the diver-sity-oriented conformational-restriction strategy.[24e]

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(3) Isomeric/homologous topology. In structure-activityrelationship studies, scientists often use isomeric/homolo-gous building blocks, because this approach changes mostdramatically the molecular shape whilst keeping the mo-lecular weight (almost) constant.

Conclusions

We designed and synthesized new CF3-substituted satu-rated cyclic amines 4a, 5a, 5b, 6a, 6b, and 11. The synthesisincluded the CuCl-mediated trifluoromethylcyclopropan-ation reaction of cyclic enamides 8, 13 and 16 withCF3CHN2. We suggest that the synthesized building blockswill find practical application in drug discovery, like theircongeners, (trifluoromethyl)piperidines 1 and 2.

Experimental SectionGeneral: Solvents were purified according to standard procedures.All reactions were performed under argon. Compound 8 was pre-pared from 7 according to a literature procedure.[15] Compounds13 and 16 were synthesized from amides 12 and 15, respectively,according to literature protocols.[22] All other starting materialswere purchased from commercial suppliers. Analytical TLC wasperformed with Polychrom SI F254 plates. Column chromatog-raphy was performed with silica gel (230–400 mesh) as the station-ary phase. 1H, 19F, 13C NMR spectra were recorded at 499.9, 470.3,

P. K. Mykhailiuk et al.FULL PAPER

Figure 6. Literature example of the conformational-restrictionstrategy in drug discovery.[25]

and 124.9 MHz, respectively. Chemical shifts are reported relativeto TMS (1H, 13C) or CFCl3 (19F) as internal standards. MS analy-ses were done with an Agilent 1100 LCMSD SL instrument [chemi-cal ionization (APCI), electrospray ionization (ESI)] or an Agilent5890 Series II 5972 GC–MS instrument [electron impact ionization(EI)].

tert-Butyl trans-5-(Trifluoromethyl)-2-azabicyclo[2.1.0]pentane-2-carboxylate (9a): A solution of 3,3,3-trifluoroethylamine hydro-chloride (5.55 g, 80.5 mmol, 5 equiv.) in water was slowly added(ca. 1–2 h) to a stirred mixture of sodium nitrite (10.87 g,80.5 mmol, 5 equiv.; solution in water) and dodecane (also see Sup-porting Information). Upon addition, the CF3CHN2 formed wasgradually blown off by an inert gas from the generator flask andpassed through a drying tube (MgSO4) into a vessel containing astirred mixture of 8 (2.5 g, 16.1 mmol), anhydrous CuCl (0.3 g) inCH2Cl2 (50 mL). CAUTION: Danger of explosion! Do not useground glass joints! The reaction was monitored by means of 1HNMR spectroscopy. After the starting material had disappeared,trifluoromethyldiazomethane bubbling was immediately stopped.The reaction mixture was filtered off and concentrated in vacuo.The oily residue was submitted to flash column chromatography.Elution with hexane/EtOAc mixture (5:1) afforded compound 9a(0.96 g, 4.0 mmol, 25% yield) as a yellowish solid. M.p. 37–38 °C,Rf = 0.45 (hexane/EtOAc = 5:1). 1H NMR (500 MHz; CDCl3,Me4Si): δ = 4.05 (dd, J = 9.0, 3.0 Hz, 1 H, NCHH), 3.96 (d, J =3.0 Hz, 1 H, NCH), 3.50 (d, J = 9.0 Hz, 1 H, NCHH), 2.15 (m, 1H, 4-CH), 1.91 (q, J = 7.0 Hz, 1 H, CHCF3), 1.49 [s, 9 H, (CH3)3C] ppm. 13C NMR (125 MHz; CDCl3, Me4Si): δ = 156.9 (s,NCOO), 124.75 (q, 1JC,F = 270.0 Hz, CF3), 80.6 [s, OC(CH3)3],52.2 (s, NCH2), 49.7 (s, NCH), 28.7 (q, 2JC,F = 35.0 Hz, CHCF3),28.2 [s, OC(CH3)3], 10.9 (q, 3JC,F = 2.5 Hz, 4-CH) ppm. 19F NMR(470 MHz; CDCl3, Me4Si): δ = –63.86, –65.50 (2 br. s, CF3) ppm.MS: m/z = 237 [M]+. C10H14F3NO2 (237.22): calcd. C 50.63, H5.95, N 5.90; found C 50.30, H 6.11, N 5.81.

Figure 5. Schematic geometric analysis of compounds 1, 2 (left) and amines 3a–6a and 6b, and 11 (right). Gray bars schematicallyrepresent the position of the CF3 group relative to the nitrogen atom.

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trans-5-(Trifluoromethyl)-2-azabicyclo[2.1.0]pentane–TrifluoroaceticAcid (4a·TFA): Compound 9a (30 mg, 0.126 mmol) was dissolvedin CH2Cl2 (2 mL) followed by addition of trifluoroacetic acid(58 mg, 0.508 mmol). The reaction mixture was stirred at a roomtemperature for 3 h (monitored by TLC; hexane/EtOAc, 5:1). Thesolvent was removed in vacuo to give pure 4a·TFA (32 mg,0.126 mmol, quant.) as an oil. 1H NMR (500 MHz; D2O, Me4Si):δ = 4.11 (d, 2JHH = 10.5 Hz, 1 H, NCHH), 4.08 (s, 1 H, NCH),3.50 (d, 2JHH = 10.5 Hz, 1 H, NCHH), 2.63 (q, 3JHF = 6.5 Hz, 1H, CHCF3), 2.56 (s, 1 H, 4-CH) ppm. 13C NMR (125 MHz; D2O,Me4Si): δ = 161.8 (s, CF3COO), 122.8 (q, 1JC,F = 270.0 Hz, CF3),114.5 (q, 1JC,F = 251.0 Hz, CF3COO), 49.6 (s, NCH2), 37.3 (q, 3JCF

= 3.8 Hz, NCH), 25.1 (q, 2JC,F = 35.0 Hz, CHCF3), 16.9 (q, 3JC,F

= 1.3 Hz, 4-CH) ppm. 19F NMR (470 MHz; D2O, Me4Si): δ =–66.35 (d, 3JFH = 7.5 Hz, CF3), –76.44 (s, CF3COO) ppm.

tert-Butyl 3-(Trifluoromethyl)pyrrolidine-1-carboxylate (10): Com-pound 9a (200 mg, 0.84 mmol) was dissolved in MeOH (2 mL),and the solution was hydrogenated for 12 h (15 atm, 20 °C) in thepresence of 10% Pd/C (5 mg) as a catalyst. The reaction mixturewas filtered, and the filtrate was concentrated in vacuo to give purecompound 10 (201 mg, 0.84 mmol, 100 % yield) as an oil. 1H NMR(500 MHz; CDCl3, Me4Si): δ = 3.53–3.35 (2 br. s, 4 H, CH2NCH2),2.87 (m, 1 H, CHCF3), 2.12–2.01 (2 br. s, 2 H, CH2) ppm. 13CNMR (125 MHz; CDCl3, Me4Si; 2 rotamers): δ = 154.1 (s, NCOO),126.81 (q, 1JC,F = 276.3 Hz, CF3), 79.8 [s, OC(CH3)3], 45.0, 44.8 (2s, CH2NCH2), 42.5 (q, 2JC,F = 27.5 Hz, CHCF3), 28.4 [s, OC-(CH3)3], 25.4 (br. s, CH2) ppm. 19F NMR (470 MHz; CDCl3,Me4Si): δ = –71.95 (2 br. s, CF3) ppm. MS: m/z = 239 [M]+.

3-(Trifluoromethyl)pyrrolidine Hydrochloride (11·HCl): Compound10 (150 mg, 0.63 mmol) was dissolved in a saturated solution ofdry HCl in MeOH (1 mL). The reaction mixture was stirred atroom temperature for 6 h. The solvent was removed in vacuo, andEt2O (1 mL) was added to the residue. The precipitate was filteredoff to give pure 11·HCl (102 mg, 0.58 mmol, 92% yield) as a whitesolid. M.p. � 200 °C. 1H NMR (500 MHz; D2O, Me4Si): δ = 2.15(m, 1 H), 2.29 (m, 1 H), 3.32 (m, 2 H), 3.42 (m, 2 H), 3.55 (m, 1H) ppm. 13C NMR (125 MHz; D2O, Me4Si): δ = 24.3 (CH2CH),40.8 (q, J = 30.1 Hz, CHCF3), 44.6 (CH2N), 45.7 (CH2N), 126.5(q, J = 277.2 Hz, CF3) ppm. 19F NMR (477 MHz; DMSO, Me4Si):δ = –69.1 (d, J = 8.1 Hz) ppm. MS (CI): m/z = 140 [M – Cl + 1]+.C5H9ClF3N (175.58): calcd. C 34.20, H 5.17, Cl 20.19, N 7.98;found C 34.11, H 5.22, Cl 20.25, N 8.13.

Trifluoromethyl-Substituted 3-Azabicyclo[n.1.0]alkanes

tert-Butyl trans-6-(Trifluoromethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (14a), tert-Butyl cis-6-(Trifluoromethyl)-2-azabicy-clo[3.1.0]hexane-2-carboxylate (14b): CF3CHN2 (5 equiv.; obtainedas described above) was gradually blown off by an inert gas fromthe generator flask and passed through a drying tube (MgSO4) intoa vessel containing a stirred mixture of 13 (2.5 g, 14.8 mmol), anhy-drous CuCl (0.3 g) in CH2Cl2 (50 mL). The reaction was monitoredby 1H NMR spectroscopy. After the starting material had disap-peared, trifluoromethyldiazomethane bubbling was immediatelystopped. The reaction mixture was filtered off and concentrated invacuo. The oily residue was submitted to flash column chromatog-raphy. Elution with hexane/EtOAc mixture (5:1) afforded com-pound 14a (1.9 g, 7.9 mmol, 50% yield) as a white solid. M.p. 64–65 °C. Rf = 0.4 (hexane/EtOAc, 5:1). 1H NMR (500 MHz; CDCl3,Me4Si): δ = 3.66 (t, J = 12.5 Hz, 2 H, NCH2), 2.97 (br. s, 1 H,NCH), 2.19 (m, 1 H, CHH), 2.04 (t, J = 12.5 Hz, 1 H, CHH), 1.95(br. s, 1 H, CHCHCF3), 1.57 (br. s, 1 H, CHCF3), 1.45 [s, 9 H,(CH3)3C] ppm. 13C NMR (125 MHz; CDCl3, Me4Si): δ = 154.8 (s,NCOO), 124.8 (q, 1JC,F = 268.8 Hz, CF3), 80.2 [s, OC(CH3)3], 44.0(s, NCH2), 38.7 (s, NCH), 28.4 [s, OC(CH3)3], 25.1 (s), 20.2 (s),15.0 (s) ppm. 19F NMR (470 MHz; CDCl3, Me4Si): δ = –67.65,–67.90 (2 br. s, CF3) ppm. MS: m/z = 251 [M]+. C11H16F3NO2

(251.25): calcd. C 52.59, H 6.42, N 5.57; found C 52.80, H 6.54, N5.33. Further elution gave isomer 14b (1.3 g, 5.2 mmol, 33% yield)as an oil. Rf = 0.3 (hexane/EtOAc, 5:1). 1H NMR (500 MHz;CDCl3, Me4Si; 2 N-Boc rotamers): δ = 3.72–3.38 (m, 3 H, NCH +NCH2), 2.26 (m, 1 H), 2.04 (m, 1 H), 1.56 (m, 1 H), 1.48–1.47 [2s, 9 H, (CH3)3C] ppm. 13C NMR (125 MHz; CDCl3, Me4Si; 2 N-Boc rotamers): δ = 155.20, 155.95 (2 s, NCOO), 124.4, 126.55 (2 q,1JC,F = 273.4 Hz, CF3), 79.96, 79.92 [2 s, OC(CH3)3], 49.64, 49.62(2 q, J = 2.5 Hz, NCH), 40.35, 39.97 (2 q, J = 1.3 Hz, NCH2),28.33, 28.28 [2 s, OC(CH3)3], 27.45, 26.88 (2 q, J = 35.0 Hz,CHCF3), 23.36, 22.35, 21.11, 21.09 (4 s, CH2 + CH) ppm. 19FNMR (470 MHz; CDCl3, Me4Si; 2 N-Boc rotamers): δ = –58.59(minor; d, 2JF,H = 4.7 Hz), –58.68 (major; d, 2JF,H = 9.4 Hz, CF3)ppm. MS: m/z = 251 [M]+. C11H16F3NO2 (251.25): calcd. C 52.59,H 6.42, N 5.57; found C 52.64, H 6.21, N 5.22.

trans-6-(Trifluoromethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride(5a·HCl): Compound 14a (3.00 g, 11.9 mmol) was dissolved in asaturated solution of dry HCl in MeOH (20 mL). The reaction mix-ture was stirred at room temperature for 6 h. The solvent was re-moved in vacuo, and Et2O (10 mL) was added to the residue. Theprecipitate was filtered off to give pure 5a·HCl (2.20 g, 11.7 mmol,98% yield) as a white solid. M.p. � 200 °C. 1H NMR (500 MHz;D2O, Me4Si): δ = 3.71 (dd, J = 6.0, 2.0 Hz, 1 H, NCH), 3.49 (t, J= 5.5 Hz, 1 H, NCHH), 2.91 (dd, J = 5.5, 5.0 Hz, 1 H, NCHH),2.38–2.19 (m, 4 H, CH2 + CH + CH) ppm. 13C NMR (125 MHz;D2O, Me4Si): δ = 124.2 (q, 1JC,F = 268.8 Hz, CF3), 42.3 (s, NCH2),36.4 (q, 3JC,F = 3.8 Hz, NHCHCHCF3), 24.5 (s), 20.0 (q, 3JC,F =2.5 Hz, CH2CHCHCF3), 19.8 (q, 2JC,F = 37.5 Hz, CHCF3) ppm.19F NMR (470 MHz; D2O, Me4Si): δ = –66.45 (d, 2JF,H = 4.7 Hz,CF3) ppm. C6H9ClF3N (187.59): calcd. C 38.42, H 4.84, N 7.47;found C 38.51, H 4.72, N 7.27.

cis-6-(Trifluoromethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride(5b·HCl): Compound 5b·HCl (0.74 g, 4.0 mmol, 96% yield) wasprepared from 14b (1.00 g, 4.1 mmol) according to the same experi-mental procedure used for the synthesis of 5a. White solid. M.p.� 200 °C. 1H NMR (500 MHz; D2O, Me4Si): δ = 3.64 (m, 2 H,NCH + NCHH), 3.35 (m, 1 H, NCHH), 2.49–2.35 (m, 2 H), 2.30(m, 1 H), 2.13 (m, 1 H) ppm. 13C NMR (125 MHz; D2O, Me4Si):δ = 124.9 (q, 1JC,F = 271.3 Hz, CF3), 47.9 (q, 3JC,F = 2.5 Hz,NHCHCHCF3), 40.2 (s, NCH2), 24.3 (q, 2JC,F = 37.5 Hz, CHCF3),23.7 (s), 23.1 (s) ppm. 19F NMR (470 MHz; D2O, Me4Si): δ =

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–56.98 (quint, J = 11.3 Hz, CF3) ppm. C6H9ClF3N (187.59): calcd.C 38.42, H 4.84, N 7.47; found C 38.33, H 4.65, N 7.30.

tert-Butyl trans-7-(Trifluoromethyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate (17a), tert-Butyl cis-7-(Trifluoromethyl)-2-azabicyclo-[4.1.0]heptane-2-carboxylate (17b): CF3CHN2 (5 equiv.; obtained asdescribed above) was gradually blown off by an inert gas from thegenerator flask and passed through a drying tube (MgSO4) into avessel containing a stirring mixture of 16 (5.0 g, 27.3 mmol) andanhydrous CuCl (0.6 g) in CH2Cl2 (100 mL). The reaction wasmonitored by 1H NMR spectroscopy. After the starting materialhad disappeared, trifluoromethyldiazomethane bubbling was im-mediately stopped. The reaction mixture was filtered off and con-centrated in vacuo. The oily residue was purified by flash columnchromatography with a hexane/EtOAc mixture (9:1) as an eluentto afford a mixture of 17a/17b (61% yield). Rf = 0.4. 100 mg ofthis mixture was separated into the individual isomers by furthercolumn chromatography with a hexane/EtOAc (9:1) mixture as aneluent. Isomer 17a was eluted as an oil. Rf = 0.40 (hexane/EtOAc,9:1). 1H NMR (500 MHz; CDCl3, Me4Si; major N-Boc rotamer):δ = 3.84 (d, J = 13.0 Hz, 1 H, NCHH), 3.17 (dd, J = 8.5, 1.5 Hz,1 H, NCH), 2.55 (t, J = 13.0 Hz, 1 H, NCHH), 1.95 (m, 1 H), 1.84(m, 1 H), 1.68 (m, 2 H), 1.48 [s, 9 H, (CH3)3C], 1.37 (m, 1 H), 1.26(m, 1 H) ppm. 13C NMR (125 MHz; CDCl3, Me4Si; major N-Bocrotamer): δ = 155.8 (s, NCOO), 125.4 (q, 1JC,F = 270.0 Hz, CF3),80.3 [s, OC(CH3)3], 44.0 (s, NCH2), 32.2 (q, 3JCF = 2.5 Hz, NCH),28.3 [s, OC(CH3)3], 25.6 (q, 2JCF = 36.3 Hz, CHCF3), 21.8 (s), 19.3(s), 15.8 (s) ppm. 19F NMR (470 MHz; CDCl3, Me4Si; major N-Boc rotamer): δ = –66.10 (d, J = 7.5 Hz, CF3) ppm. MS: m/z = 265[M]+. C12H18F3NO2 (265.27): calcd. C 54.33, H 6.84, N 5.28; foundC 53.97, H 6.53, N 5.32. Further elution gave isomer 17b as an oil.Rf = 0.35 (hexane/EtOAc, 9:1). 1H NMR (500 MHz; CDCl3,Me4Si; major N-Boc rotamer): δ = 3.31 (m, 1 H), 3.09 (m, 2 H),2.04 (m, 1 H, CHCF3), 1.70–1.40 [m, 14 H, (CH3)3C + CH2 + CH2

+ CH] ppm. 13C NMR (125 MHz; CDCl3, Me4Si; major N-Bocrotamer): δ = 155.8 (s, NCOO), 125.4 (q, 1JC,F = 270.0 Hz, CF3),125.7 (q, 1JC,F = 270.0 Hz, CF3), 79.5 [s, OC(CH3)3], 40.4 (s,NCH2), 29.6 (q, 3JCF = 3.7 Hz, NCH), 27.8 [s, OC(CH3)3], 21.3 (q,2JCF = 35.0 Hz, CHCF3), 21.3 (s), 15.4 (s), 14.3 (s) ppm. 19F NMR(470 MHz; CDCl3, Me4Si; major N-Boc rotamer): δ = –56.70 (d, J= 7.5 Hz, CF3) ppm. MS: m/z = 265 [M]+. C12H18F3NO2 (265.27):calcd. C 54.33, H 6.84, N 5.28; found C 54.11, H 6.61, N 5.44.

trans-7-(Trifluoromethyl)-2-azabicyclo[3.1.0]heptane Hydrochloride(6a·HCl): Compound 17a (100 mg, 0.38 mmol) was dissolved in asaturated solution of dry HCl in MeOH (1 mL). The reaction mix-ture was stirred at room temperature for 6 h. The solvent was re-moved in vacuo, and Et2O (1 mL) was added to the residue. Thesolvent was evaporated again to give pure 6a·HCl (74 mg,0.37 mmol, 98% yield) as a white solid. M.p. � 200 °C. 1H NMR(500 MHz; D2O, Me4Si): δ = 3.17 (d, J = 7.0 Hz, 1 H, NCHH),2.99 (m, 1 H, NCH), 2.91 (t, J = 7.0 Hz, 1 H, NCHH), 2.25 (m, 1H), 1.93 (m, 2 H), 1.82 (m, 1 H), 1.68 (m, 1 H), 1.45 (m, 1 H) ppm.13C NMR (125 MHz; D2O, Me4Si): δ = 124.2 (q, 1JC,F = 270.0 Hz,CF3), 40.2 (s, NCH2), 28.8 (q, 3JC,F = 3.8 Hz, NHCHCHCF3), 20.9(q, 2JC,F = 37.5 Hz, CHCF3), 16.5 (s), 15.8 (s), 12.7 (q, 3JC,F =1.3 Hz, CH2CHCHCF3) ppm. 19F NMR (470 MHz; D2O, Me4Si):δ = –66.35 (m, CF3) ppm. C7H11ClF3N (201.62): calcd. C 41.70, H5.50, N 6.95; found C 41.33, H 5.45, N 6.63.

cis-7-(Trifluoromethyl)-2-azabicyclo[3.1.0]heptane Hydrochloride(6b·HCl): Compound 17b (100 mg, 0.38 mmol) was dissolved in asaturated solution of dry HCl in MeOH (1 mL). The reaction mix-ture was stirred at a room temperature for 6 h. The solvent wasremoved in vacuo to give pure 6b·HCl (72 mg, 0.36 mmol, 96%

P. K. Mykhailiuk et al.FULL PAPERyield) as a white solid. M.p. � 200 °C. 1H NMR (500 MHz; D2O,Me4Si): δ = 3.05 (t, J = 7.0 Hz, 1 H), 2.99 (m, 2 H), 2.15 (m, 1 H),1.96 (m, 1 H), 1.72 (m, 2 H), 1.58 (m, 2 H) ppm. 13C NMR(125 MHz; D2O, Me4Si): δ = 125.1 (q, 1JC,F = 270.0 Hz, CF3), 40.8(s, NCH2), 28.1 (s), 19.9 (q, 2JC,F = 36.5 Hz, CHCF3), 16.2 (s), 12.7(s), 10.5 (s) ppm. 19F NMR (470 MHz; D2O, Me4Si): δ = –66.35(d, J = 11.3 Hz, CF3) ppm. C7H11ClF3N (201.62): calcd. C 41.70,H 5.50, N 6.95; found C 41.38, H 5.35, N 6.58.

Supporting Information (see footnote on the first page of this arti-cle): Copies of NMR spectra for all new compounds; 2D NMRspectra for compounds 9a, 14a, 17a.

Acknowledgments

The authors are grateful to Dr. Vitaly Polovinko for 2D NMRexperiments and to Prof. Oleg Shishkin for X-ray crystallographicanalysis.

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Received: February 27, 2014Published Online: April 22, 2014