& Synthetic Methods

Generation of C2F5CHN2 In Situ and Its First Reaction:[3+2] Cycloaddition with Alkenes

Pavel K. Mykhailiuk *[a, b]

Abstract: The novel chemical reagent, C2F5CHN2, is generat-ed in situ from C2F5CH2NH2·HCl and sodium nitrite. It reactswith mono- and disubstituted electron-deficient alkenes at

room temperature to afford C2F5-pyrazolines in excellentyields.

Introduction

Incorporation of fluorine-containing groups into organic mole-cules affects their physicochemical and biological properties.[1, 2]

About 20 % of all pharmaceutical and agrochemical agentscontain at least one fluorine atom;[1, 2] the trifluoromethylgroup is particularly abundant.[3] In recent years, the larger andmore lipophilic trifluoromethyl analogues[4]—C2F5

[5] and SF5[6]—

have attracted considerable attention. Pentafluoroethylatedderivatives often exhibit superior properties relative to their tri-fluoromethylated counterparts.[7] Therefore, many bioactivecompounds, including several drugs, contain a C2F5 group(Figure 1).[8] However, methods to introduce the C2F5 moietyinto organic molecules are scarce relative to methods to incor-porate a trifluoromethyl group: chemists mostly exploit directpentafluoroethylation[9, 10] and underestimate C2F5-containingbuilding blocks.[11] Hence, novel reagents and reactions to syn-thesize C2F5-substituted compounds are of value.

In contrast to the well-established reagent CF3CHN2,[12] theconceptually attractive analogue C2F5CHN2 remains unknown.So far, only one paper mentions a transformation that mayhave proceeded via this intermediate. In 2007, Zhang and col-leagues synthesized the C2F5-pyrazoline shown in Figure 2 byreaction of C2F5CH=NNTos with an alkene and NaH (36 %yield).[13] However, the authors neither considered the reactionmechanism, nor comprehensively characterized the product.Pyrazolines play a role in materials science, organic synthesis,and medical research (Figure 2),[14, 15] hence the C2F5-pyrazolinesare attractive targets. In this context, I have generated the

novel chemical reagent C2F5CHN2 from C2F5CH2NH2·HCl andsodium nitrite and studied its first representative reaction,[3+2] cycloaddition with alkenes to give C2F5-pyrazolines.

Figure 1. Bioactive compounds with a C2F5 group.[8]

Figure 2. Bioactive pyrazolines.[14]

[a] Dr. P. K. MykhailiukOrganic Chemistry DepartmentTaras Shevchenko National University of KyivVolodymyrska 64, 01601 Kyiv (Ukraine)

[b] Dr. P. K. MykhailiukEnamine Ltd.Matrosova 23, 01103 Kyiv (Ukraine)E-mail : Pavel.Mykhailiuk@gmail.com

Pavel.Mykhailiuk@mail.enamine.net

Supporting information for this article is available on the WWW underhttp ://dx.doi.org/10.1002/chem.201304840.

Chem. Eur. J. 2014, 20, 1 – 7 � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim1 &&

These are not the final page numbers! ��

Full PaperDOI: 10.1002/chem.201304840

Results and Discussion

Diazo compounds are ubiquitous in chemistry.[16] The use of di-azoalkanes, however, is limited relative to their aromatic coun-terparts because of their volatility, toxicity, and tendency to ex-plode.[17] Therefore, in recent years, researchers have devel-oped procedures to generate and use these dangerous speciesin situ.[18, 19]

Diazotization of aliphatic amines with electron-withdrawing groups (EWGs) leads to diazoalkane-s.[16a, b] In the early 2000s, the research teams of Brad-dock and Charette independently prepared ethyldia-zoacetate in situ from the parent amino ester hydro-chloride salt and used it in cyclopropanation reac-tions (Scheme 1).[20] Subsequently, Carreira and col-leagues used this methodology to synthesizetrifluoromethyldiazomethane and applied this re-agent to several reactions.[21, 22] Because the electron-ic properties of the C2F5 and CF3 groups are similar,[1a]

I considered that the previously unreported reagentC2F5CHN2 could be synthesized by diazotization ofC2F5CH2NH2·HCl.[23]

Diazoalkanes react rapidly with alkenes that con-tain EWGs.[16b, d] Therefore, the active alkene 1 withtwo EWGs was selected to trap the putative speciesC2F5CHN2. In the experimental setup, NaNO2

(4.0 equiv) was added to a suspension ofC2F5CH2NH2·HCl[23] (3.0 equiv) in dichloromethane/water at 0 8C under air. The reaction mixture wasstirred for 10 min, during which time the organiclayer became yellow in color, followed by addition ofmaleimide 1 (1.0 equiv). After 72 h at room tempera-ture, a mixture of 1D-/2D-pyrazolines 1 a/1 b was ob-tained in quantitative yield. Subsequently, the experi-mental conditions were optimized to reduce theamount of C2F5CH2NH2·HCl to 1.5 equivalents with-out any effect on the reaction conversion (Table 1).

Maleimides 2–6 also reacted with C2F5CHN2

(Table 2). In each experiment a mixture of 1D- (2 a–5 a) and 2D-pyrazolines (2 b–5 b) was obtained in 97–99 % yield (Table 2, entries 2–5). In the reaction ofmaleimide 6, 6 b was obtained exclusively, in 99%yield (Table 2, entry 6). The 1D-/2D-isomer ratio corre-lated well with the electronic properties of the malei-mide N-substituent. Greater electron-withdrawing

Scheme 1. In situ generation of diazoalkanes from electron-defi-cient amines.

Table 1. Reaction optimization.

Entry C2F5CH2NH2·HCl [equiv] NaNO2 [equiv] Conversion [%]

1 3.0 4.0 1002 2.0 3.0 1003 1.5 3.0 1004 1.3 3.0 95

Table 2. Reaction scope.

Entry Alkene Product Ratio Yield [%][a]

1 1 1 a/1 b 1:0.14 99[b]

2 2 2 a/2 b 1:5.6 98[b]

3 3 3 a/3 b 1:3.7 99[b]

4 4 4 a/4 b 1:0.9 97[b]

5 5 5 a/5 b 1:1.5 99[b]

6 6 6 b – 99

7 7 no reaction –

[a] Isolated yield. [b] Yield of the isomeric mixture.

Chem. Eur. J. 2014, 20, 1 – 7 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2&&

�� These are not the final page numbers!

Full Paper

power led to a higher content of the 2D-pyrazoline isomer:1 (12 %)<4 (47 %)<2 (85 %)<6 (100 %). However, 2D-pyrazo-lines of type c did not form; the putative bicyclic alkenes mayhave been too strained according to Bredt’s rule.[24] The trisub-stituted alkene 7 did not react because of the steric clash.

To comprehensively study the reaction scope, the monosub-stituted alkenes 8–17 were also tested (Table 3). Substrates 8–14 with strong EWGs reacted completely with C2F5CHN2

(Table 3, entries 1–7). However, alkenes with either weak EWGs(15) or electron-donating groups (EDGs; 16, 17) did not react(Table 3, entries 8–10). These results suggest that the reactionbetween C2F5CHN2 and alkenes belongs to the class of type I[3+2] cycloadditions:[16b] it is accelerated by EWGs and deceler-ated by EDGs on the alkene.

The reaction is regioselective:it leads to a single regioisomerwith the substituents at posi-tions 3 and 5 of the pyrazolinecore (Figure 3). Moreover, themore thermodynamically stable2D-pyrazolines (c) with conju-gated N=C and double/triplebonds of the EWG were pre-dominantly formed. Only alkene9 afforded the minor isomer 9 a(12 %) alongside product 9 c(Table 3, entry 2).

Next, the steric requirementsof the reaction were investigat-ed. Diverse di- and tri-substitut-ed alkenes (19–28) with at leastone strong EWG (�CO2R (R =

alkyl) or �COMe) were selected(Table 4). The 1,1-disubstitutedsubstrates smoothly gave thecorresponding 1D-pyrazolines19 a–22 a, irrespective of theelectronic nature of the secondsubstituent (Table 4, entries 1–4). The 1,2-disubstituted sub-strates, however, were lessactive. Alkenes 23 and 24 withEWGs as the second substituentreacted completely withC2F5CHN2 to afford the 2D-pyra-zolines 23 c and 24 c, respective-ly (Table 4, entries 5 and 6),whereas alkenes 25 and 26 with

Table 3. Reaction scope.

Entry Alkene Product Yield [%][a]

1 8 8 c 97

2 9 9 c[b] 98

3 10 10 c 99

4 11 11 c 97

5 12 12 c 95

6 13 13 c 95

7 14 14 c 98

8 15 no reaction –

9 16 no reaction –

10 17 no reaction –

[a] Isolated yields. [b] Contains isomer 9 a, 98 % (9 a/9 c = 12:88).

Figure 3. X-ray crystallographic analysis of compounds 8 c, 10 c, 11 c, 13 c,and 19 a.[25]

Chem. Eur. J. 2014, 20, 1 – 7 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim3 &&

These are not the final page numbers! ��

Full Paper

an EDG as the second substituent gave 25 c and 26 c, respec-tively (Table 4, entries 7 and 8). Even after 7 d, the reactionconversion was only 16 or 26 % for 25 and 26, respectively. Tri-substituted alkenes 27 and 28, with three EWGs, remained un-changed (Table 4, entries 9 and 10). This data shows thatC2F5CHN2 only reacts with mono- and disubstituted alkenes.

Relative to the well-characterized reagent CF3CHN2,[26]

C2F5CHN2 is less active in [3+2] cycloaddition reactions with al-kenes because of steric reasons (C2F5 is larger than CF3). For ex-ample, under identical conditions, CF3CHN2 generated in situreacted with substrates 15 and 25.[27]

The reaction described above makes pentafluoroethyl-sub-stituted 1D- and 2D-pyrazoline building blocks synthetically ac-

cessible and paves the way fortheir exploration as bioactiveanalogues of their non-fluori-nated counterparts shown inFigure 2.[14, 15] 1D-Pyrazolines iso-merize into the 2D-isomersunder acidic conditions.[28] Inthis context, treatment of the1D-/2D-pyrazoline mixtures ob-tained from the experimentsdescribed in Table 1 (1 a/1 b–5 a/5 b) with a catalytic amountof trifluoroacetic acid in di-chloromethane afforded thepure 2D-isomers 1 b–5 b in ex-cellent yields (Scheme 2; alsosee the Supporting Informa-tion).

Conclusion

The novel chemical reagentC2F5CHN2 has been generatedin situ from C2F5CH2NH2·HCl andNaNO2 in water/dichlorome-thane at 0 8C. The first represen-tative reaction of C2F5CHN2—type I [3+2] cycloaddition withalkenes—has been studied. Atroom temperature, C2F5CHN2

smoothly reacts with mono-and 1,1-disubstituted alkenes,activated by at least one strongEWG, and with 1,2-disubstitutedalkenes with two EWGs.C2F5CHN2 is less active thanCF3CHN2 because of steric con-straints. The synthetic protocolis practical; the reaction worksunder air, at room temperature,without any catalysts, and incommon solvents (H2O/CH2Cl2).Moreover, the products are ob-

tained in excellent yields without the need for further purifica-tion. Given the importance of both the C2F5 and pyrazolinefragments in chemistry, the synthesized compounds are prom-ising target molecules.

Table 4. Reaction scope.

Entry Alkene Product Yield [%][a]

1 19 19 a 99

2 20 20 a 95[b]

3 21 21 a 96

4 22 22 a 97

5 23 23 c 98[c]

6 24 24 c 98

7 25 25 c 16[d]

8 26 26 c 26[d]

9 27 no reaction

10 28 no reaction

[a] Isolated yields. [b] A mixture of pyrazoline 20 a and pyrazole 29 (2:1) was obtained (see the Supporting In-formation). [c] Reaction time = 7 d, approximately 7 % of cis-isomer, 98% combined yield. [d] Reaction time =

7 d. Reaction conversion, determined by 1H NMR spectroscopy.

Scheme 2. Acidic isomerization of 1D-pyrazolines into 2D-pyrazolines.

Chem. Eur. J. 2014, 20, 1 – 7 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim4&&

�� These are not the final page numbers!

Full Paper

I believe that, with this practical generation procedure, sci-entists will soon explore C2F5CHN2 in other chemical reactions(e.g. cyclopropanation, carbene insertion, cycloaddition with al-kynes) and its use will become as prominent as other diazoal-kanes, such as CH2N2,[29] CF3CHN2,[21, 22, 30, 31] and N2CHCO2Et.[32]

Experimental Section

General procedure

Sodium nitrite (33 mg, 0.48 mmol, 3.0 equiv) was added at 0 8C toa stirring suspension of C2F5CH2NH2·HCl (45 mg, 0.24 mmol,1.5 equiv) in CH2Cl2 (2.0 mL)/water (0.1 mL). The reaction mixturewas vigorously stirred for 10 min at 0 8C, followed by addition ofalkene (0.16 mmol, 1.0 equiv) at this temperature. After 1 h, thecooling bath was removed and the reaction mixture was stirred for72 h at rt. Water (1.0 mL) and CH2Cl2 (3 mL) were added. The or-ganic layer was separated. The aqueous layer was washed withCH2Cl2 (2 � 3 mL). The combined organic layers were dried overNa2SO4 and evaporated under vacuum to provide the pure prod-uct.

Acknowledgements

I am grateful to Prof. O. V. Shishkin for X-ray studies, O. Ishenkoand V. Stepanenko for provision of C2F5CH2NH2, Dr. A. Kysel, R.Iminov, B. Chalyk, O. Mashkov, A. Scherbatyuk, and S. Yasik forprovision of alkenes, Prof. A. Tolmachev for financial support,O. Babii, Dr. V. Kubyshkin, and Prof. Anne S. Ulrich for helpfuldiscussions, Cyrille Thinnes for proofreading of the manuscript,and Prof. Kristin Sainani for inspiration in her “Writing in theSciences” course.

Keywords: cycloaddition · diazo compounds · fluorine · in situgeneration · pyrazolines

[1] a) Bioorganic and Medicinal Chemistry of Fluorine (Eds. : J.-P. B�gu�, D.Bonnet-Delpon), Wiley, New Jersey, 2008 ; b) Fluorine in MedicinalChemistry and Chemical Biology (Ed. : I. Ojima), Blackwell Publishing,2009 ; c) Fluorine in Pharmaceutical and Medicinal Chemistry: From Bio-physical Aspects to Clinical Applications (Eds. : V. Gouverneur, K. M�ller),Imperial College Press, London, 2012.

[2] Selected reviews: a) H.-J. Bçhm, D. Banner, S. Bendels, M. Kansy, B.Kuhn, K. M�ller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637;b) C. Isanbor, D. O’Hagan, J. Fluorine Chem. 2006, 127, 303; c) K. L. Kirk,Org. Process Res. Dev. 2008, 12, 305; d) S. Purser, P. R. Moore, S. Swallow,V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320; e) W. K. Hagmann, J. Med.Chem. 2008, 51, 4359.

[3] At least 45 drugs contain the CF3 group: D. S. Wishart, C. Knox, A. C.Guo, D. Cheng, S. Shrivastaya, D. Tzur, B. Gautam, M. Hassanali, NucleicAcids Res. 2007, 36, D901.

[4] Lipophilic groups can enhance hydrophobic ligand – receptor interac-tions: C. Bissantz, B. Kuhn, M. Stahl, J. Med. Chem. 2010, 53, 5061.

[5] Pharmaceutical companies often biologically screen compounds withsix or less fluorine atoms, therefore, CF3 and C2F5 groups are commonlypresent in medicinal research, whereas the higher homologues (C3F7,C4F9, etc.) are not.

[6] S. Altomonte, M. Zanda, J. Fluorine Chem. 2012, 143, 57.[7] See, for example: a) M. Andrzejewska, L. Y�pez-Mulia, R. Cedillo-Rivera,

A. Tapia, L. Vilpo, J. Vilpo, Z. Kazimierczuk, Eur. J. Med. Chem. 2002, 37,973; b) A. Johansson, A. Poliakov, E. �kerblom, K. Wiklund, G. Lindeberg,S. Winiwarter, U. H. Danielson, B. Samuelsson, A. Hallberg, Bioorg. Med.Chem. 2003, 11, 2551.

[8] a) W. Jonat, T. Bachelot, T. Ruhstaller, I. Kuss, U. Reimann, J. F. Robertson,Ann. Oncol. 2013, 24, 2543; b) J. D. Croxtall, K. McKeage, Drugs 2011, 71,363; c) N. Taka, H. Koga, H. Sato, T. Ishizawa, T. Takahashi, J. Imagawa,Bioorg. Med. Chem. 2000, 8, 1393.

[9] a) J.-A. Ma, D. Cahard, Chem. Rev. 2004, 104, 6119; b) Y. Mac�, E. Magni-er, Eur. J. Org. Chem. 2012, 2479.

[10] Selected papers: a) R. Krishnamurti, D. R. Bellew, G. K. S. Prakash, J. Org.Chem. 1991, 56, 984; b) G. K. S. Prakash, Y. Wang, R. Mogi, J. Hu, T.Mathew, G. A. Olah, Org. Lett. 2010, 12, 2932; c) M. M. Kremlev, W. Tyrra,A. I. Mushta, D. Naumann, Y. L. Yagupolskii, J. Fluorine Chem. 2010, 131,212; d) Y. Li, A. Studer, Angew. Chem. 2012, 124, 8345; Angew. Chem.Int. Ed. 2012, 51, 8221; e) Q. Qi, Q. Shen, L. Lu, J. Fluorine Chem. 2012,133, 115; f) A. Lishchynskyi, V. V. Grushin, J. Am. Chem. Soc. 2013, 135,12584; g) A. Hafner, A. Bihlmeier, M. Nieger, W. Klopper, S. Br�se, J. Org.Chem. 2013, 78, 7938.

[11] For recent examples, see: a) J. Thibonnet, A. Duch�ne, J.-L. Parrain, M.Abarbri, J. Org. Chem. 2004, 69, 4262; b) S. Bigotti, A. Volonterio, M.Zanda, Synlett 2008, 958; c) K. V. Tarasenko, O. V. Manoylenko, V. P.Kukhar, G.-V. Rçschenthaler, I. I. Gerus, Tetrahedron Lett. 2010, 51, 4623;d) B. Duda, S. N. Tverdomed, G.-V. Rçschenthaler, J. Org. Chem. 2011, 76,71; e) T. M. Sokolenko, Y. A. Davydova, Y. L. Yagupolskii, J. Fluorine Chem.2012, 136, 20.

[12] 70 publications (Reaxys database) since the preparation: H. Gilman,R. G. Jones, J. Am. Chem. Soc. 1943, 65, 1458.

[13] X. Zhang, X. Li, G. F. Allan, T. Sbriscia, O. Linton, S. G. Lundeen, Z. Sui, J.Med. Chem. 2007, 50, 3857.

[14] a) M. Shaharyar, M. M. Abdullah, M. A. Bakht, J. Majeed, Eur. J. Med.Chem. 2010, 45, 114; b) X.-H. Liu, P.-C. Lv, B. Li, H.-L. Zhu, B.-A. Song,Aust. J. Chem. 2008, 61, 223; c) L. S. Bai, Y. Wang, X. H. Liu, H. L. Zhu,B. A. Song, Chin. Chem. Lett. 2009, 20, 427; d) M. V. R. Reddy, V. K. Billa,V. R. Pallela, M. R. Mallireddigari, R. Boominathan, J. L. Gabriel, E. P.Reddy, Bioorg. Med. Chem. 2008, 16, 3907.

[15] For reviews on bioactive pyrazolines, see: a) S. Kumar, S. Bawa, S.Drabu, R. Kumar, H. Gupta, Recent Pat. Anti-Infect. Drug Discovery 2009,4, 154; b) A. Rahman, A. A. Siddiqui, Int. J. Pharm. Sci. Drug Res. 2010, 2,165; c) X.-H. Liu, B.-F. Ruan, J. Li, F.-H. Chen, B.-A. Song, H.-L. Zhu, P. S.Bhadury, J. Zhao, Mini-Rev. Med. Chem. 2011, 11, 771; d) M. R. Shaaban,A. S. Mayhoub, A. M. Farag, Expert Opin. Ther. Pat. 2012, 22, 253; e) A.Ganesh, Int. J. Pharm. Bio. Sci. 2013, 4, 727.

[16] a) M. Regitz, G. Maas, Diazo Compounds-Properties and Synthesis Aca-demic Press, Orlando, 1986 ; b) H. Zollinger, Diazo Chemistry I and II,Wiley-VCH, Weinheim, 1994 ; c) M. P. Doyle, M. A. McKervey, T. Ye,Modern Catalytic Methods for Organic Synthesis with Diazo Compounds,Wiley, New York, 1998 ; d) G. Maas in Synthetic Applications of 1,3-DipolarCycloaddition Chemistry toward Heterocycles and Natural Products (Eds. :A. Padwa, W. H. Pearson), Wiley, New York, 2002, pp. 539 – 621.

[17] Prudent Practices for Handling Hazardous Chemicals in Laboratories, Na-tional Academy Press, 1981, pp. 57 – 68.

[18] a) J. R. Fulton, V. K. Aggarwal, J. de Vicente, Eur. J. Org. Chem. 2005,1479; b) G. Maas, Angew. Chem. 2009, 121, 8332; Angew. Chem. Int. Ed.2009, 48, 8186.

[19] Selected papers: a) T. G. Archibald, D.-S. Huang, M. H. Pratton, J. C. Bar-nard US5817778, 1998; b) L. D. Proctor, A. J. Warr, Org. Process Res. Dev.2002, 6, 884; c) B. Morandi, E. M. Carreira, Science 2012, 335, 1471;d) L. S. Barkawi, J. D. Cohen, Nat. Protoc. 2010, 5, 1619.

[20] a) A. G. M. Barrett, D. C. Braddock, I. Lenoir, H. Tone, J. Org. Chem. 2001,66, 8260; b) R. P. Wurz, A. B. Charette, Org. Lett. 2002, 4, 4531.

[21] Selected papers: a) B. Morandi, E. M. Carreira, Angew. Chem. 2010, 122,950; Angew. Chem. Int. Ed. 2010, 49, 938; b) B. Morandi, E. M. Carreira,Angew. Chem. 2010, 122, 4390; Angew. Chem. Int. Ed. 2010, 49, 4294;c) B. Morandi, E. M. Carreira, Angew. Chem. 2011, 123, 9251; Angew.Chem. Int. Ed. 2011, 50, 9085; d) B. Morandi, E. M. Carreira, Org. Lett.2011, 13, 5984.

[22] Contribution of other groups: a) Z. Chai, J.-P. Bouillon, D. Cahard, Chem.Commun. 2012, 48, 9471; b) F. Li, J. Nie, L. Sun, Y. Zheng, J.-A. Ma,Angew. Chem.2013, 125, 6375; Angew. Chem. Int. Ed. 2013, 52, 6255;c) M. A. J. Duncton, R. Singh, Org. Lett. 2013, 15, 4284; d) G. A. Molander,L. N. Cavalcanti, Org. Lett. 2013, 15, 3166.

[23] C2F5CH2NH2·HCl was prepared from pentafluoropropyonic acid accord-ing to the literature: D. R. Husted, A. H. Ahlbrecht, J. Am. Chem. Soc.1953, 75, 1605.

Chem. Eur. J. 2014, 20, 1 – 7 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim5 &&

These are not the final page numbers! ��

Full Paper

[24] J. Bredt, Justus Liebigs Ann. Chem. 1924, 437, 1.[25] CCDC-969845 (8 c), 969842 (10 c), 976074 (13 c), 969844 (11 c), and

969843 (19 a) contain the supplementary crystallographic data for thispaper. These data can be obtained free of charge from The CambridgeCrystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

[26] For [3+2] cycloadditions of CF3CHN2 with alkenes, see: a) J. H. Atherton,R. Fields, J. Chem. Soc. C 1968, 1507; b) R. Fields, J. P. Tomlinson, J. Fluo-rine Chem. 1979, 13, 147.

[27] E. Y. Slobodyanyuk, O. S. Artamonov, O. V. Shishkin, P. K. Mykhailiuk, Eur.J. Org. Chem. 2014, in press (10.1002/ejoc.201301852).

[28] See, for example: a) C.-H. Yang, H.-J. Sherf, R.-H. Wang, J.-C. Wang, J.Chin. Chem. Soc. 2002, 49, 95; b) P. Schiess, H. Stalder, Tetrahedron Lett.1980, 21, 1413.

[29] Diazomethane is used in the synthesis of the drug Nelfinavir(Ref. [19b]).

[30] Our contribution: a) P. K. Mykhailiuk, S. Afonin, A. S. Ulrich, I. V. Komarov,Synthesis 2008, 1757; b) P. K. Mykhailiuk, S. Afonin, G. V. Palamarchuk,

O. V. Shishkin, A. S. Ulrich, I. V. Komarov, Angew. Chem. 2008, 120, 5849;Angew. Chem. Int. Ed. 2008, 47, 5765; c) O. S. Artamonov, P. K. Mykhai-liuk, N. M. Voievoda, D. M. Volochnyuk, I. V. Komarov, Synthesis 2010,443; d) O. S. Artamonov, E. Y. Slobodyanyuk, O. V. Shishkin, I. V. Komarov,P. K. Mykhailiuk, Synthesis 2013, 225.

[31] Other groups: a) P. Le Maux, S. Juillard, G. Simonneaux, Synthesis 2006,10, 1701; b) M. A. J. Duncton, L. Ayala, C. Kaub, S. Janagani, W. T. Ed-wards, N. Orike, K. Ramamoorthy, J. Kincaid, M. G. Kelly, Tetrahedron Lett.2010, 51, 1009; c) I. Su�rez del Villar, A. Gradillas, J. P�rez-Castells, Eur. J.Org. Chem. 2010, 5850.

[32] a) Z. Zhang, J. Wang, Tetrahedron 2008, 64, 6577; b) Y. Zhang, J. Wang,Chem. Commun. 2009, 5350.

Received: December 10, 2013

Published online on && &&, 0000

Chem. Eur. J. 2014, 20, 1 – 7 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim6&&

�� These are not the final page numbers!

Full Paper

FULL PAPER

& Synthetic Methods

P. K. Mykhailiuk *

&& –&&

Generation of C2F5CHN2 In Situ and ItsFirst Reaction: [3+2] Cycloadditionwith Alkenes

Novel reagent : The new chemical re-agent, C2F5CHN2, is generated in situfrom C2F5CH2NH2·HCl and sodium nitrite.It reacts with mono- and disubstituted

electron-deficient alkenes at room tem-perature to afford C2F5-pyrazolines inexcellent yields (see scheme).

A new fluorinated reagent……discovered by scientistsat Enamine Ltd. , that is, C2F5CHN2, is generated in situfrom C2F5CH2NH2·HCl and sodium nitrite. For moredetails see the Full Paper by P. K. Mykhailiuk on page &

& ff.

Chem. Eur. J. 2014, 20, 1 – 7 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim7 &&

These are not the final page numbers! ��

Full Paper