Russian Chemical Bulletin, International Edition, Vol. 62, No. 3, pp. 792—796, March, 2013792

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0791—0795, March, 2013.

1066�5285/13/6203�792 © 2013 Springer Science+Business Media, Inc.

Intramolecular cyclization of acetylene�containing�amino carboxylates and �amino phosphonates:

synthesis of �CF3�substituted dehydroprolines and their P�analogs*

M. A. Zotova, T. P. Vasil´eva, and S. N. Osipov

A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,28 ul. Vavilova, 119991 Moscow, Russian Federation.Fax: +7 (499) 135 5085. E�mail: osipov@ineos.ac.ru

CF3�Containing �arylpropargyl��amino carboxylates and �arylpropargyl��amino phos�phonates on treatment with the Brønsted or Lewis acids undergo cyclization involving the freeNH2 group and triple bond to yield the corresponding dehydroprolines and their phosphorusanalogs.

Key words: organofluorine compounds, �amino acids, �amino phosphonates, catalysis,heterocyclization, dehydroprolines.

During recent years, the functionally substituted pro�lines1, including their unsaturated derivatives, found wideapplication in bioorganic chemistry as the conformation�ally rigid amino acids for specific modification of bio�active peptides and peptidomimetics.2 Among them, the5�aryl substituted prolines were found to be especiallypromising starting compounds in the synthesis of poten�tial drug substances.3

In addition, it is known that introduction of �trifluo�romethyl�containing �amino acids into the strategicallyimportant positions of bioactive peptides can improve sig�nificantly their metabolic stability, lipophilicity, and se�lectivity of bonding to bioreceptors due to the electron�withdrawing nature, a large hydrophobic volume of theCF3 group, and the ability of fluorine atoms to form hydro�gen bonds.4 Therefore, the development of efficient syn�thetic methods for novel representatives of �CF3��aminoacids, specifically, conformationally rigid derivatives andanalogs of proline, is a topical problem from both thefundamental and practical points of view.

Recently, we developed an efficient method to convertCF3�containing �propargyl derivatives 1 into �aryl�alkynyl��amino carboxylates 2 (see Ref. 5) and relatedphosphonates 3 (see Ref. 6, Scheme 1) using the palladi�um�catalyzed Sonogashira cross�coupling.

Continuing the studies in the field of organofluorineamino acids and amino phosphonates, in the present workwe report on further application of the acetylene deriva�tives 2 and 3 for the preparation of novel CF3�containingdehydroprolines and their phosphorus analogs. Intramo�

lecular heterocyclization of compounds 2 and 3 was car�ried out by the catalysis with Brønsted and Lewis acids.

First, we found that, during removal of the tert�butoxy�carbonyl (Boc) protection group from the amine func�tionality of compound 2a by the standard treatment withtrifluoroacetic acid in dichloromethane at room tempera�ture for 1 h, a 3 : 1 mixture of the expected product 4a andits intramolecular cyclization product 5a was formed, re�spectively (Scheme 2). It is obvious that cyclization 45proceeds by involving the free amino group and triple bond.

* Dedicated to the Academician of the Russian Academy ofSciences I. P. Beletskaya on occassion of her anniversary.

Scheme 1

Reagents: i. ArI, PdCl2(PPh3)2/CuI, 5 mol.%; ii. Et3N/DMF,X = CO2Me; iii. Pri

2NH/MeCN, X = P(O)(OEt)2.

CF3�Substituted dehydroprolines Russ.Chem.Bull., Int.Ed., Vol. 62, No. 3, March, 2013 793

Compounds 4a and 5a were separated by column chromato�graphy on silica gel.

It should be noted that the formaion of cyclic product 5under these conditions is a quite unusual phenomenon,since, according to the literature data,7 the analogous intra�molecular processes occur upon the triple bond activa�tion, typically, with silver or palladium salts. Therefore,we made an attempt to carry out the complete conversionof 4a into 5a without using the conventional Lewis acids.Unfortunately, variation of the reaction conditions (tem�perature, time, and solvent) and the nature of Brønstedacid (p�toluene�, methane� or trifluoromethane sulfonic

acid) was not successful. The maximum conversion 4a5awas 55% when using a CF3CO2H—TsOH (30 : 1) mix�ture. At the same time, the first attempt of catalysis withsilver triflate (5 mol.%) resulted in the complete conver�sion of 4a. The reaction was carried out in acetonitrile atroom temperature and completed within 4 h. In addition,we found that the optimum conditions in terms of thetotal yield of 5a (based on two steps starting from acetyl�ene 3a) are as follows: 1) treatment of the N�Boc�protect�ed acetylene 3a with an excess of CF3CO2H in CH2Cl2 toform a mixture of 4a and 5a; 2) removal of the solvent andexcess of acid in vacuo; 3) treatment of the crude mixtureof 4a and 5a with AgOTf (5 mol.%) in MeCN. The analo�gous results were achieved also in the case of other aryl�acetylene amino esters 2b—d (see Scheme 2). The singleexception is the case of p�nitro derivative 2e, when the4e : 5e ratio exceeded 10 : 1.

Taking into account the fact that �amino phospho�nates are important bioisosteres of the corresponding aminoacids and often demonstrate unique biological properties,8

it seemed interesting to expand the developed method tothe phosphorus analogs of dehydroproline. For this pur�pose, the available N�Cbz�substituted �arylpropargyl��CF3��amino phosphonates 3 (Cbz is benzyloxycarbon�yl) were used as the starting compounds (Scheme 3). Sincethe standard removal of the Cbz group by catalytic hydro�genation on Pd/C is impossible without affecting the triplebond, we applied another method using a known combi�nation of p�toluene sulfonic and trifluoroacetic acids.9

The reaction was found to be accompanied by cycliza�tion to the desired cyclic products 7a—e at room tempera�ture in high yields (see Scheme 3). Typically, the reactionis completed within 8—10 h, except for the p�nitro deriva�tive 3e for which the reaction was completed after stirringfor 24 h at the same temperature (if this process is termi�nated after 4 h, the intermediate phosphonate 6e is isolat�ed in 81% yield).

This reaction is the first example of intramolecularcyclization of propargyl�containing amines upon the Brøn�sted acid catalysis without the metal�catalyzed activation

Scheme 3

Reagents and conditions: i. CF3CO2H, TsOH•H2O, CH2Cl2, 20 C.

Compound Ar Yield (%) Compound Ar Yield (%)7a Ph 75 7d 2�MeC6H4 777b 4�MeOC6H4 88 7e 4�O2NC6H4 827c 4�MeC6H4 76

Scheme 2

Reagents and conditions: i. CF3CO2H, CH2Cl2, 20 C; ii. 5 mol.%AgOTf/MeCN, 20 C.

Compound Ar Yield (%)5a Ph 855b 4�MeOC6H4 805c 4�MeC6H4 785d 2�MeC6H4 725e 4�O2NC6H4 90

Zotova et al.794 Russ.Chem.Bull., Int.Ed., Vol. 62, No. 3, March, 2013

of the triple bond. The difference from the carboxylateanalogs 4 is likely due to the electronic and steric effects ofthe phosphonate group in the intermediate amino phos�phonate 6.

To demonstrate that it is possible to synthesize theCF3 derivatives of 5�arylproline, we performed catalytichydrogenation of the double bond in dehydroproline 5b.The reaction was performed in methanol in the hydrogenatmosphere at room temperature to afford the correspond�ing proline 8 in 65% yield after purification on silica col�umn (Scheme 4).

Scheme 4

Reagents: H2, Pd/C (5 mol.%), MeOH.

To conclude, we studied the intramolecular cycliza�tion of the CF3�containing �arylpropargyl��aminocarb�oxylates and �arylpropargyl��amino phosphonates in�volving the free NH2 group and internal triple bond. Thecyclization was found to proceed partially (for carboxy�lates) or completely (in the case of amino phosphonates)upon the Brønsted acid activation of triple bond. Asa result, we obtained a series of novel functional deriva�tives of dehydroproline and their phosphorus analogs,which have a high potential of application in bioorganicand medical chemistry.

Experimental

NMR spectra were recorded on Bruker Avance�300, BrukerAvance�400, and Bruker Avance�600 instruments with workingfrequencies of 300, 400, and 600 MHz (1H); 101 or 151 MHz(13C) relative to Me4Si; 282 or 376 MHz (19F) relative toCF3CO2H; and 121 or 161 MHz (31P) relative to H3PO4. Theelemental analyses of the compounds obtained was performed atthe Laboratory of Elemental Analysis, INEOS RAS. All solventsused were purified according to the standard procedures. Col�umn chromatography was performed on a Kieselgel 60 (Merck)silica gel.

Cyclization of acetylene carboxylates 2 to dehydroprolines 5(general procedure). To a solution of compound 2 (0.54 mmol)in dry CH2Cl2 (2 mL), CF3CO2H (0.2 mL, 2.61 mmol) wasadded. The resulted mixture was stirred for 3—4 h at room tem�

perature. The solvent and the excess of acid were removedin vacuo and the residue was dissolved in water (5 mL) andneutralized with sodium carbonate until pH 7. The product wasextracted with ethyl acetate (2×10 mL), the organic layer wasremoved and dried over MgSO4. After removal of the solvent,the mixture of amino ester 4 and dehydroproline 5 (typically, ina ratio of 3 : 1 according to the 19F NMR spectral data) wasdissolved in dry acetonitrile (1.3 mL), AgOTf (4.2 mg, 0.017 mmol)was added, and the mixture was stirred for 4—5 h at ~20 C. Thesolvent was removed in vacuo and the product was isolated afterchromatography on silica column (the eluent was petroleumether—EtOAc).

Methyl 2�amino�5�phenyl�2�trifluoromethylpent�4�ynoate(4a). The yield was 41%, oil. 1H NMR (300 MHz, CDCl3), :2.19 (br.s, 2 H, NH2); 2.88 (d, 1 H, CH2, J = 14.5 Hz); 3.14 (d, 1 H,CH2, J = 14.5 Hz); 3.82 (s, 3 H, OMe); 7.44 (m, 5 H, Ar). 19F NMR(282 MHz, CDCl3), : 1.12 (s, 3 F, CF3). 13C NMR (101 MHz,CDCl3), : 24.3 (d, J = 1.7 Hz); 52.8, 65.6 (q, J = 27.4 Hz); 81.8,85.5, 122.5, 123.0 (q, J = 233.7 Hz); 128.3, 128.2, 132.5, 133.0,166.7. Found (%): C, 57.34; H, 4.77; N, 5.34. C13H12F3NO2.Calculated (%): C, 57.57; H, 4.46; N, 5.16.

Methyl 2�amino�5�(4�nitrophenyl)�2�trifluoromethylpent�4�ynoate (4e). The yield was 75%, oil. 1H NMR (300 MHz,CDCl3), : 2.22 (br.s, 2 H, NH2); 2.98 (d, 1 H, CH2, J = 16.9 Hz);3.24 (d, 1 H, CH2, J = 16.9 Hz); 3.87 (s, 3 H, OMe); 7.51 (d, 2 H,Ar, J = 8.8 Hz); 8.14 (d, 2 H, Ar, J = 8.9 Hz). 19F NMR (282MHz, CDCl3): 0.42 (s, 3 F, CF3). 13C NMR (101 MHz, CDCl3),: 24.5 (d, J = 1.8 Hz); 52.7, 63.0 (q, J = 27.4 Hz); 81.7, 86.5,122.5, 123.0 (q, J = 287.8 Hz); 128.3, 131.5, 146.3, 167.4.Found (%): C, 48.94; H, 3.22; N, 9.08. C13H11F3N2O4. Calcu�lated (%): C, 49.37; H, 3.51; N, 8.86.

Methyl 5�phenyl�2�trifluoromethyl�3,4�dihydro�2H�pyrrole�2�carboxylate (5a). The yield was 85%, oil. 1H NMR (300 MHz,CDCl3), : 2.23—2.35 (m, 1 H, CH2); 2.37—2.53 (m, 1 H, CH2);3.06 (t, 2 H, CH2, J = 7.9 Hz); 3.67 (s, 3 H, OMe); 7.20—7.41(m, 3 H, Ar); 7.71—7.85 (m, 2 H, Ar). 19F NMR (282 MHz,CDCl3), : 2.88 (s, 3 F, CF3). 13C NMR (101 MHz, CDCl3),: 28.0 (d, J = 1.3 Hz); 36.0, 53.2, 85.3 (q, J = 27.2 Hz); 124.6(q, J = 282.5 Hz); 128.5, 128.6, 131.9, 132.9, 168.4, 180.1.Found (%): C, 57.29; H, 4.17; N, 5.44. C13H12F3NO2. Calculat�ed (%): C, 57.57; H, 4.46; N, 5.16.

Methyl 5�(4�methoxyphenyl)�2�trifluoromethyl�3,4�dihydro�2H�pyrrole�2�carboxylate (5b). The yield was 80%, oil. 1H NMR(300 MHz, CDCl3), : 2.33—2.55 (m, 2 H, CH2); 3.08—3.15(m, 2 H, CH2); 3.73 (s, 3 H, OMe); 3.74 (s, 3 H, OMe);6.79—6.81 (m, 2 H, Ar); 7.76—7.79 (m, 2 H, Ar). 19F NMR(188 MHz, CDCl3), : 1.96 (s, 3 F, CF3). 13C NMR (101 MHz,CDCl3), : 27.8, 36.0, 53.3, 55.3, 84.8 (q, J = 27.1 Hz); 113.9,124.5 (q, J = 282.9 Hz); 125.2, 130.2, 162.8, 168.5, 180.4.Found (%): C, 55.97; H, 4.46; N, 4.87. C14H14F3NO3. Calculat�ed (%): C, 55.82; H, 4.68; N, 4.65.

Methyl 5�(4�methylphenyl)�2�trifluoromethyl�3,4�dihydro�2H�pyrrole�2�carboxylate (5c). The yield was 78%, oil. 1H NMR(300 MHz, CDCl3), : 2.46 (s, 3 H, Me); 2.48—2.69 (m, 2 H,CH2); 3.26 (t, 2 H, CH2, J = 7.0 Hz); 3.88 (s, 3 H, OMe);7.28—7.32 (m, 2 H, Ar); 7.86—7.89 (m, 2 H, Ar). 19F NMR(282 MHz, CDCl3), : 2.86 (s, 3 F, CF3). 13C NMR (101 MHz,CDCl3), : 21.6, 28.0, 36.0, 53.3, 85.2 (d, J = 26.8 Hz); 124.6(q, J = 282.3 Hz); 128.6, 129.3, 130.2, 142.5, 168.5, 180.0.Found (%): C, 58.73; H, 5.06; N, 5.04. C14H14F3NO2. Calculat�ed (%): C, 58.95; H, 4.95; N, 4.91.

CF3�Substituted dehydroprolines Russ.Chem.Bull., Int.Ed., Vol. 62, No. 3, March, 2013 795

Methyl 5�(2�methylphenyl)�2�trifluoromethyl�3,4�dihydro�2H�pyrrole�2�carboxylate (5d). The yield was 72%, oil. 1H NMR(600 MHz, CDCl3), : 2.40—2.48 (m, 1 H, CH2); 2.51—2.60(m, 1 H, CH2); 2.57 (s, 3 H, Me); 3.13—3.21 (m, 1 H, CH2);3.22—3.30 (m, 1 H, CH2); 3.86 (s, 3 H, OMe); 7.20—7.33 (m, 2 H,Ar); 7.35 (td, 1 H, Ar, J = 7.5 Hz, J = 1.2 Hz); 7.49 (dd, 1 H, Ar,J = 7.7 Hz, J = 0.9 Hz). 19F NMR (282 MHz, CDCl3), : 2.81(s, 3 F, CF3). 13C NMR (151 MHz, CDCl3), : 21.5, 27.7, 39.2,53.2, 85.6 (q, J = 27.1 Hz); 124.5 (q, J = 282.3 Hz); 125.6, 129.1,130.3, 131.6, 132.9, 138.2, 168.4, 182.2. Found (%): C, 59.16;H, 5.08; N, 4.69. C14H14F3NO4. Calculated (%): C, 58.95;H, 4.95; N, 4.91.

Methyl 5�(4�nitrophenyl)�2�trifluoromethyl�3,4�dihydro�2H�pyrrole�2�carboxylate (5e). The yield was 90%, oil. 1H NMR(300 MHz, CDCl3), : 2.53—2.89 (m, 2 H, CH2); 3.21—3.52(m, 2 H, CH2); 3.93 (s, 3 H, OMe); 8.14 (d, 2 H, Ar, J = 8.9 Hz);8.28 (d, 2 H, Ar, J = 8.9 Hz). 19F NMR (282 MHz, CDCl3),: 2.85 (s, 3 F, CF3). 13C NMR (101 MHz, CDCl3), : 27.9, 36.8,53.8, 85.4 (q, J = 27.4 Hz); 123.9, 124.2 (q, J = 283.0 Hz); 129.6,138.1, 150.0, 167.8, 180.3. Found (%): C, 49.64; H, 3.82; N, 8.98.C13H11F3N2O4. Calculated (%): C, 49.37; H, 3.51; N, 8.86.

Cyclization of acetylene phosphonates 3 to phosphorylpyrro�lines 7 (general procedure). A solution of compound 3 (0.2 mmol)and p�toluene sulfonic acid monohydrate (0.06 g, 0.314 mmol)in CH2Cl2 (1 mL) and CF3CO2H (1.17 g, 10 mmol) was stirredfor 1 day at ~20 C. After the reaciton has been completed (19F NMRspectral monitoring), the solvent was removed in vacuo and theresidue was dissolved in water and neutralized with sodium bi�carbonate until pH 7. The product was extracted with ethyl acet�ate (2×3 mL) and the organic layer was dried over MgSO4. Thesolvent was removed in vacuo and the product was isolated bycolumn chromatography (the eluent was CH2Cl2—EtOAc).

Diethyl [1�amino�4�(4�nitrophenyl)�1�trifluoromethylbut�3�yn�1�yl]phosphonate (6e). The yield was 81%, oil. 1H NMR(400 MHz, CDCl3), : 1.35 (td, 6 H, Me, J = 7.0 Hz, J = 1.1 Hz);2.02 (s, 2 H, NH2); 2.94—3.28 (m, 2 H, CH2); 4.12—4.38 (m, 4 H,OCH2); 7.46—7.58 (m, 2 H, Ar); 8.10—8.18 (m, 2 H, Ar).19F NMR (282 MHz, CDCl3), : 3.73 (s, 3 F, CF3). 31P NMR(161 MHz, CDCl3), : 15.66 (q, J = 3.6 Hz). 13C NMR (101 MHz,CDCl3), : 16.4 (t, J = 5.7 Hz); 24.1, 58.8 (dq, J = 158.0 Hz,J = 27.2 Hz); 64.2 (dd, J = 41.2 Hz, J = 7.2 Hz); 82.9, 87.9(d, J = 12.6 Hz); 123.5, 125.2 (qd, J = 285.8 Hz, J = 7.3 Hz);129.8, 132.4, 147.2. Found (%): C, 45.40; H, 4.72; N, 6.88.C15H18F3N2O5P. Calculated (%): C, 45.69; H, 4.60; N, 7.10.

Diethyl (5�phenyl�2�trifluoromethyl�3,4�dihydro�2H�pyrrol�2�yl)phosphonate (7a). The yield was 75%, oil. 1H NMR(600 MHz, acetone�d6), : 1.30 (dt, 6 H, Me, J = 11.8 Hz,J = 7.1 Hz); 2.28—2.40 (m, 1 H, CH2); 2.56—2.69 (m, 1 H,CH2); 3.21—3.44 (m, 1 H, CH2); 3.32—3.39 (m, 1 H, CH2);4.09—4.29 (m, 4 H, OCH2); 7.47—7.52 (m, 2 H, Ar); 7.54—7.58(m, 1 H, Ar); 7.95—7.99 (m, 2 H, Ar). 19F NMR (282 MHz,CD3OD), : 7.07 (d, 3 F, CF3, J = 4.6 Hz). 31P NMR (121 MHz,acetone�d6), : 17.96 (q, J = 4.6 Hz). 13C NMR (151 MHz,acetone�d6), : 17.1 (t, J = 6.0 Hz); 27.8 (d, J = 1.8 Hz); 37.1,64.4 (d, J = 7.2 Hz); 64.8 (d, J = 6.6 Hz); 83.7 (dq, J = 27.2 Hz,J = 157.5 Hz); 126.7 (qd, J = 2.9 Hz, J = 280.8 Hz); 129.5,129.9, 132.9, 134.5 (d, J = 2.8 Hz); 181.3 (d, J = 11.3 Hz).Found (%): C, 51.21; H, 5.27; N, 4.19. C15H19F3NO3P. Calcu�lated (%): C, 51.58; H, 5.48; N, 4.01.

Diethyl [5�(4�methoxyphenyl)�2�trifluoromethyl�3,4�di�hydro�2H�pyrrol�2�yl]phosphonate (7b). The yield was 88%, oil.

1H NMR (400 MHz, CDCl3), : 1.23—1.28 (m, 6 H, Me);2.17—2.30 (m, 1 H, CH2); 2.50—2.61 (m, 1 H, CH2); 3.08—3.14(m, 2 H, CH2); 3.76 (s, 3 H, OMe); 4.06—4.26 (m, 4 H, OCH2);6.82—6.86 (m, 2 H, Ar); 7.76—7.79 (m, 2 H, Ar). 19F NMR(188 MHz, CDCl3), : 4.89 (s, 3 F, CF3). 31P NMR (161 MHz,CDCl3), : 15.20 (q, J = 4.6 Hz). 13C NMR (101 MHz, CDCl3),: 16.3 (dd, J = 2.7 Hz, J = 5.7 Hz); 26.7, 36.0, 55.3, 63.5(d, J = 7.4 Hz); 64.2 (d, J = 6.8 Hz); 82.4 (dq, J = 27.3 Hz,J = 159.9 Hz); 113.8, 125.1 (qd, J = 3.7 Hz, J = 281.8 Hz); 126.0(d, J = 2.6 Hz); 130.2, 162.4, 179.1 (d, J = 11.7 Hz). Found (%):C, 50.33; H, 5.90; N, 3.31. C16H21F3NO4P. Calculated (%):C, 50.66; H, 5.58; N, 3.69.

Diethyl [5�(4�methylphenyl)�2�trifluoromethyl�3,4�dihydro�2H�pyrrol�2�yl]phosphonate (7c). The yield was 76%, oil. 1H NMR(400 MHz, CDCl3), : 1.24—1.29 (m, 6 H, Me); 2.19—2.35(m, 1 H, CH2); 2.32 (s, 3 H, Me); 2.58—2.72 (m, 1 H, CH2);3.10—3.16 (m, 2 H, CH2); 4.08—4.24 (m, 4 H, OCH2); 7.15(d, 2 H, Ar, J = 7.9 Hz); 7.72 (d, 2 H, Ar, J = 8.2 Hz). 19F NMR(282 MHz, CDCl3), : 4.84 (s, 3 F, CF3). 31P NMR (161 MHz,CDCl3), : 15.10 (q, J = 4.6 Hz). 13C NMR (101 MHz, CDCl3),: 16.4 (dd, J = 3.5 Hz, J = 5.7 Hz); 21.6, 26.7 (d, J = 1.7 Hz);36.1, 63.6 (d, J = 7.4 Hz); 64.3 (d, J = 6.8 Hz); 82.5 (dq, J = 27.1 Hz,J = 159.3 Hz); 125.1 (qd, J = 3.3 Hz, J = 281.6 Hz); 128.5,129.3, 130.5 (d, J = 2.7 Hz); 142.2, 179.8 (d, J = 11.8 Hz).Found (%): C, 53.07; H, 6.05; N, 3.95. C16H21F3NO3P. Calcu�lated (%): C, 52.89; H, 5.83; N, 3.86.

Diethyl [5�(2�methylphenyl)�2�trifluoromethyl�3,4�dihydro�2H�pyrrol�2�yl]phosphonate (7d). The yield was 77%, oil.1H NMR (600 MHz, CDCl3), : 1.30 (dt, 6 H, Me, J = 7.1 Hz,J = 14.0 Hz); 2.20—2.32 (m, 1 H, CH2); 2.52 (s, 3 H, Me);2.53—2.62 (m, 1 H, CH2); 3.05—3.14 (m, 1 H, CH2); 3.16—3.29(m, 1 H, CH2); 4.04—4.31 (m, 4 H, OCH2); 7.16—7.23 (m, 2 H,Ar); 7.27 (td, 1 H, Ar, J = 7.5 Hz, J = 1.2 Hz); 7.42 (dd, 1 H, Ar,J = 7.6 Hz, J = 0.8 Hz). 19F NMR (282 MHz, CDCl3), : 5.69(d, 3 F, CF3, J = 4.5 Hz). 31P NMR (121 MHz, CDCl3), : 17.30(q, J = 4.2 Hz). 13C NMR (151 MHz, CDCl3), : 16.3 (dd,J = 8.2 Hz, J = 6.0 Hz); 21.9, 26.2, 39.4, 63.4 (d, J = 7.4 Hz);64.1 (d, J = 6.6 Hz); 82.9 (dq, J = 159.5 Hz, J = 27.3 Hz); 125.0(qd, J = 281.5 Hz, J = 2.6 Hz); 125.6, 129.3 (d, J = 1.3 Hz);130.1, 131.5, 133.0 (d, J = 2.4 Hz); 138.4, 182.0 (d, J = 11.9 Hz).Found (%): C, 52.47; H, 5.99; N, 3.94. C16H21F3NO3P. Calcu�lated (%): C, 52.89; H, 5.83; N, 3.86.

Diethyl [5�(4�nitrophenyl)�2�trifluoromethyl�3,4�dihydro�2H�pyrrol�2�yl]phosphonate (7e). The yield was 82%, oil. 1H NMR(400 MHz, CDCl3), : 1.30—1.42 (m, 6 H, Me); 2.31—2.47(m, 1 H, CH2); 2.64—2.82 (m, 1 H, CH2); 3.15—3.37 (m, 2 H,CH2); 4.12—4.35 (m, 4 H, OCH2); 8.02—8.12 (m, 2 H, Ar);8.24—8.34 (m, 2 H, Ar). 31P NMR (161 MHz, CDCl3), : 14.25(q, J = 4.2 Hz). 19F NMR (282 MHz, CDCl3), : 4.84 (s, 3 F,CF3). 13C NMR (101 MHz, CDCl3), : 16.4 (dd, J = 2.9 Hz,J = 5.7 Hz); 26.9 (d, J = 1.7 Hz); 36.4, 63.8 (d, J = 7.5 Hz); 64.5(d, J = 6.7 Hz); 83.0 (dq, J = 27.7 Hz, J = 158.0 Hz); 123.8,124.2 (qd, J = 1.8 Hz, J = 281.7 Hz); 129.4, 138.5 (d, J = 2.9 Hz);149.7, 178.2 (d, J = 11.8 Hz). Found (%): C, 45.90; H, 4.32;N, 7.38. C15H18F3N2O5P. Calculated (%): C, 45.69; H, 4.60;N, 7.10.

Hydrogenation of dehydroproline 5b. Dehydroproline 5b(100 mg, 0.32 mmol) was dissolved in dry methanol (10 mL) andPd/C (10 mg) was added. The resulted suspension was deairatedand stirred in the hydrogen atmosphere for 1 h at ~20 C. Thecatalyst was filtered off and the solvent was removed in vacuo.

Russian Chemical Bulletin, International Edition, Vol. 62, No. 3, pp. 796—796, March, 2013796

The product was purified by column chromatography (the elu�ent was petroleum ether—EtOAc).

Methyl 5�(4�methoxyphenyl)�2�trifluoromethylpyrrolidine�2�carboxylate (8). The yield was 65%, oil. 1H NMR (300 MHz,CDCl3), : 1.75—1.95 (m, 1 H, CH2); 2.07—2.22 (m, 1 H, CH2);2.25—2.39 (m, 1 H, CH2); 2.45—2.59 (m, 1 H, CH2); 3.12 (br.s,1 H, NH); 3.86 (s, 3 H, OMe); 3.92 (s, 3 H, OMe); 4.38 (dd, 1 H,CH, J = 10.0 Hz, J = 5.7 Hz); 6.92 (d, 2 H, Ar, J = 8.7 Hz); 7.41(d, 2 H, Ar, J = 8.7 Hz). 19F NMR (282 MHz, CDCl3), : 1.57(s, 3 F, CF3). 13C NMR (101 MHz, CDCl3), : 31.3, 35.1, 53.4,55.3, 62.1, 70.6 (q, J = 28.6 Hz); 113.8, 125.1 (q, J = 282.7 Hz);127.6, 135.0, 159.0, 171.5. Found (%): C, 55.06; H, 5.71; N, 4.27.C14H16F3NO3. Calculated (%): C, 55.44; H, 5.32; N, 4.62.

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Received December 26, 2012