HETEROCYCLES

Paper | Special issue | Vol. 80, No. 2, 2010, pp. 1091-1102
Received, 31st July, 2009, Accepted, 15th September, 2009, Published online, 16th September, 2009.
DOI: 10.3987/COM-09-S(S)91

■ Three-Component Reactions with 3-Phenyl-1-azabicyclo[1.1.0]butane, Dimethyl Dicyanofumarate, and Primary Aromatic Amines

Grzegorz Mlostoń* and Heinz Heimgartner*

Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190,
CH-8057 Zürich, Switzerland

Abstract

The three-component reaction of 3-phenyl-1-azabicyclo[1.1.0]butane (1a) with 2,3-dicyanofumarates (DCFM) and primary aromatic amines in dichloromethane at room temperature yielded mixtures of (Z)-2-arylamino-3-cyanofumarates (7) and the corresponding (E)-2-(azetidin-1-yl)-3-cyanomaleates (6) and (9). In the case of anisidine (8d), higher oligomers containing three or four azetidine residues, e.g. 10a, were also formed. With more nucleophilic aliphatic amines, only 1:1 adducts of type 7 were obtained. The reaction course can be rationalized by the formation of intermediate zwitterions (11) via addition of the N-nucleophiles onto DCFM. The results show that the nucleophilicity of 1a toward DCFM is lower than that of aliphatic amines but exceeds that of aromatic amines.

INTRODUCTION
Reactions of 1-azabicyclo[1.1.0]butanes (1) leading to azetidine derivatives are of continual interest.1,2 In some of our recent papers, reactions of 1 with diverse electrophiles, such as sulfanyl and sulfinyl chlorides3 as well as chlorodithioformates,4 were described. In analogy to other reactions of 1 with electrophilic agents, e.g. azido and chloroformates,5 the only products obtained were azetidine derivatives of type 2–4 (Scheme 1). On the other hand, the reaction with the electron deficient dicyanofumarates yielded a mixture of stereoisomeric 1-azabicyclo[2.1.1]hexane dicarboxylates (5).6 In this case, the reaction was shown to occur via an intermediate zwitterion which was trapped quantitatively with methanol or morpholine to give enamines of type 6.7,8

The successful trapping reactions evidence that 3-phenyl-1-azabicyclo[1.1.0]butane (1a) exceeds both methanol and morpholine in the nucleophilicity towards the electron poor C=C bond. Whereas methanol does not react with dicyanofumarates at room temperature, a Michael type addition of morpholine, and also of other secondary and primary amines, followed by elimination of HCN to give enamines of type 7 was observed under the same conditions.8 Interestingly, N-methylaniline did not react with dimethyl dicyanofumarate even at elevated temperature. Furthermore, a three-component reaction with equimolar amounts of 1a, cyclohexylamine (8a), and dimethyl dicyanofumarate (DCFM)9 resulted in the formation of only a 1:1 product, i.e., the enamine (7a)7 (Scheme 2), and not even traces of the expected 1:1:1 product of type 6 were observed. This result suggests that 8a reacts faster with DCFM than 1a and prompted us to examine analogous three-component reactions with less nucleophilic primary aromatic amines.

RESULTS AND DISCUSSION
In the first series of three-component reactions, a mixture of equimolar amounts of 1a and the corresponding primary amine, e.g. cyclohexylamine (8a), in dichloromethane at room temperature was treated with one mole equivalent of DCFM, dissolved in the same solvent. As depicted in Scheme 2, the mixture contained the enamine (7a) along with unchanged 1a. After chromatographic purification, the already described compound (7a)8 was obtained in 88% yield. The replacement of cyclohexylamine (8a) in the reaction mixture by benzylamine (8b) gave also an enamine (7b)10 as the sole product of this reaction. Similarly to the case with 8a, the yield of the enamine (7b), being the product of the two-component reaction, was high and was determined to 85%. Product (7b) was also obtained in the two-component reaction of 8b with DCFM (94%). The results of the experiments with 8a and 8b showed that aliphatic primary amines with high nucleophilicity react faster with DCFM than 1a, and no competition of the two nucleophiles, present in the solution in identical mol ratios, was observed.
The analogous reaction with aniline (8c) led to a more complex mixture and, according to the 1H-NMR analysis, 1a was completely consumed. The chromatographic separation gave three fractions. The compound isolated from the least polar fraction in 9% yield was identified as the enamine (7c).8 The second fraction contained the 1:1:1 product (6b) as the major component (31%) of the reaction. Its 1H-NMR spectrum was characterized by the presence of two MeO signals at 3.73 and 3.91 ppm and two AB systems at 4.38/4.63 ppm with J = 10.1 Hz and 4.91/4.96 ppm with J = 11.3Hz, respectively, for two CH2 groups of the azetidine ring. In addition, a set of multiplets of 10 aromatic H-atoms confirmed the structure of 6b (Scheme 3). The most polar fraction gave a colorless solid (9a) in 5% yield, which displayed a similar 1H-NMR spectrum as 6b, but differed by the presence of an additional AB system for two azetidine CH2 groups located at 3.5/3.7 ppm. Furthermore, the integration of the aromatic H-atoms confirmed the presence of three Ph residues.
The ESI-MS revealed the [M+Na]+ peak of 6b at m/z 414 and for 9a at m/z 545, thus confirming the structures of a 1:1:1 and 1:2:1 product of type 6 and 9, respectively. The configuration of the C=C bonds of 6 and 9 is described as (E) based on the assumption presented in note 10. The simultaneous formation of 6b and 9a suggests that the secondary step of the reaction occurs via competitive attack of aniline versus 1a onto the initially formed zwitterion. The low yield of 7c in comparison with 6b + 9a evidences that 1a is a more prone nucleophile in the reaction with DCFM.

Similar to aniline, the three-component reaction with anisidine (8d) led to the complete conversion of 1a, and the separation of the mixture gave the corresponding products (7d), (6c) and (9b) (Scheme 3) in a ratio comparable with that observed in the case of aniline (8c).11 With the aim of increasing the yield of the ‘oligoazetidine’ (9b), the stoichiometry of the reaction was modified, and a twofold (Procedure B) as well as a threefold amount (Procedure C) of 1a was used in the following two experiments. In both cases, the formation of the 1:1 product (7d) was completely suppressed and, according to the 1H-NMR spectra of the crude mixtures, significant amounts of 1a were still present. The chromatographic separation yielded in each case 6c along with 9b and a third, even more polar fraction. In comparison with the results of the reaction with equimolar amounts of starting materials, the yields of the isolated products were increased in favor of 9b. The most polar fraction, after additional purification, was analyzed by means of 1H-NMR spectroscopy, and the data obtained confirm the structure of the ‘oligoazetidine’ (10a).12

In order to examine the scope of the three-component reactions with 1a, DCFM, and an aromatic amine, the 4-trifluoromethyl- (8e) and 4-nitroaniline were included in the study. In spite of the fact that the basicity of the former is significantly lower when compared with aniline (pKBH+ = 2.5 versus 4.6), the results of the reaction with equimolar amounts of reactants was comparable with that obtained for aniline, i.e. products (7e), (6d) and (9c) were isolated after chromatographic workup. In contrast, the reaction with 4-nitroaniline (pKBP+ = 1.0) led to a complex mixture. After 30 min, 1a was no more present in the mixture, but after attempted chromatographic separation, apart from 4-nitroaniline no defined product could be isolated.
As already mentioned, N-methylaniline did not react with DCMF.8 However, the three-component reaction with 1a, carried out in the typical manner, led to a single product. After isolation in 96% yield, its structure was elucidated as the 1:1:1 product (6e). In this case, neither the 1:1 nor the 1:2:1 product was formed.

CONCLUSIONS
The present study showed that the reactivity of 3-phenyl-1-azabicyclobutane (1a) as a Michael donor towards DCFM is comparable with that of primary aromatic amines. On the other hand, cyclohexylamine (8a) reacts much faster with DCFM, and in a competition experiment, neither the 1:1:1 product nor higher ‘oligomers’ 9 or 10 were formed. The reactivity of benzylamine (8b) is comparable with that of cyclohexylamine (8a). As evidenced in earlier studies, the reaction of 1a with DCFM occurs via a zwitterion 11, which can be trapped by a nucleophile followed by elimination of HCN.7 On the other hand, elimination of CN– from 11 could lead to the cation 12 (Scheme 4), which than can be intercepted by the nucleophile. Depending on the type of the nucleophile, the trapping product stabilizes by deprotonation (with methanol, primary and secondary amines) or, in the case of 1a as the nucleophile, an oligomerization of the azetidine unit occurs. In each step of this oligomerization, 1a and the aromatic amine compete as nucleophiles. A similar oligomerization was reported for the reactions of 3-ethyl and 3-phenyl-1-azabicyclo[1.1.0]butanes with tosyl azide.13,14

EXPERIMENTAL
General remarks. Melting points were determined in a capillary using a MEL-TEMP II apparatus (Aldrich) and are uncorrected. IR spectra were recorded with a FT-IR NEXUS instrument as KBr pellets or as films, and the positions of absorption bands are given in cm–1. 1H-NMR and 13C-NMR spectra were recorded on a BRUKER-AC-300 (1H at 300 MHz and 13C at 75 MHz) instrument in CDCl3 solutions using TMS (δ = 0 ppm) as an internal standard; chemical shifts (δ) in ppm. The multiplicity of the 13C signals was deduced from DEPT spectra. MS spectra were recorded on a LKB-2091 or Finnigan SSQ-700 spectrometer using electrospray (ESI) method; m/z (rel. %). ESI-HR-MS on Finnigan MAT-95. Elemental analyses were performed in the Analytical Laboratory of the University of Zurich or in the Laboratory of the Polish Academy of Sciences (CBMiM) in Łódź.

Starting materials. For the preparation of the starting materials, known procedures were applied: 3-phenyl-1-azabicyclo[1.1.0]butane (1c),15 and dimethyl 2,3-dicyanofumarates (DCFM).9 Amines 8a–e were used as commercial reagents and purified before usage according to standard procedures.

Reactions of dimethyl dicyanofumarate (DCFM) with amines 8b, 8d and 8e. – General procedure. To a magnetically stirred solution of DCFM (184 mg, 1 mmol) in 2 mL of the appropriate solvent (MeOH or CH2Cl2), the corresponding amine 8 (1.1 mmol) was added in small portions at rt. The stirring was continued at rt and the progress of the reaction was monitored by TLC and 1H-NMR spectroscopy. When the amine 8 was completely consumed, the solvent was evaporated and the product 7 was isolated by means of preparative layer chromatography on plates coated with SiO2 using a mixture of petroleum ether and CH2Cl2 (1:9) or petroleum ether and AcOEt (8:2) as the eluent. Additional crystallization afforded analytically pure sample. Reported yields refer to the product isolated after chromatography. In the case of 7b, crystalline product was also obtained by crystallization of the crude material from MeOH.

Dimethyl (Z)-2-benzylamino-3-cyanobutanedioate (7b). Solvent used for the reaction: CH2Cl2; reaction time: 30 min. Yield: 258 mg (94%). Colorless crystals, mp 102–104 ºC (MeOH). IR (KBr): 3257m (NH), 2956w, 2215vs (C≡N), 1747vs (C=O), 1687vs (C=O), 1598vs (C=C), 1451br.m, 1274vs, 1255s, 1198m, 1159w, 1063m, 1008w, 788s, 749m, 698m. 1H-NMR (CDCl3): 9.70 (br.s, NH); 7.10–7.50 (m, 5 arom. H); 4.45 (d, 2JH,H = 7.5 Hz, CH2); 3.90, 3.76 (2s, 2 MeO). 13C-NMR (CDCl3): 168.1, 161,3, 161.0 (3s, 2 C=O, =C(2)); 135.2 (s, 1 arom. C); 128.9, 128.4, 127.4 (3d, 5 arom. CH); 116.3 (s, CN); 71.1 (s, =C(3)); 53.6, 51.8 (2q, 2 MeO); 49.7 (t, CH2). ESI-MS: 298 (16), 297 (100, [M+Na]+), 275 (6, [M+1]+). Anal. Calcd for C14H14N2O4: C, 61.31; H 5.14; N 10.21. Found: C, 61.31; H, 5.03; N, 10.25.

Dimethyl (Z)-3-cyano-2-[(4-methoxyphenyl)amino]butanedioate (7d). Solvent used for the reaction: CH2Cl2; reaction time: 4 d. Yield: 127 mg (44%). Colorless crystals, mp 93–95 ºC (MeOH). IR (KBr): 2215vs (C≡N), 1745vs (C=O), 1682vs (C=O), 1598vs (C=C), 1581s, 1510s, 1436m, 1275br.s (C–O), 1255br.s (C–O), 1035s, 849w, 778m. 1H-NMR (CDCl3): 10.90 (br.s, NH); 7.06, 6.88 (AB, J = 9 Hz, 4 arom. H); 3.85, 3.81, 3.78 (3s, 3 MeO). 13C-NMR (CDCl3): 168.2, 161.4, 159.5, 159.0 (4s, 2 C=O, =C(2), 1 arom. C); 129.9 (s, 1 arom. C); 125.0, 114.8 (2d, 4 arom. CH); 116.0 (s, CN); 73.5 (s, =C(3)); 55.5, 53.7, 52.3 (3q, 3 MeO). ESI-MS (MeOH): 314 (18), 313 (100, [M+Na]+), 292 (10), 291 (62, [M+1]+), 259 (52), 245 (14), 231 (11). HR-ESI-MS: 313.0793 (calcd. 313.0795 for C14H14N2NaO5, [M+Na]+), 291.0973 (calcd. 291.0976 for C14H15N2O5, [(M+1]+). Anal. Calcd for C14H14N2O5: C, 57.93; H 4.86; N 9.65. Found: C, 57.43; H, 4.80; N, 9.46.

Dimethyl (Z)-3-cyano-2-[(4-trifluoromethylphenyl)amino]butanedioate (7e). Solvent used for the reaction: MeOH; reaction time: 8 d. Yield: 138 mg (42%). Colorless crystals, mp 117–119 ºC (MeOH). IR (KBr): 2218s (C≡N), 1751s (C=O), 1686s (C=O), 1609s, 1579vs (C=C), 1442m, 1325vs, 1275vs (C–O), 1120s, 1068s, 1027w, 850w, 798w. 1H-NMR (CDCl3): 11.20 (br.s, NH); 7.63, 7.20 (AB, J = 8.5 Hz, 4 arom. H); 3.88, 3.86 (2s, 2 MeO). 13C-NMR (CDCl3): 167.8, 161.2, 157.8 (3s, 2 C=O, =C(2)); 140.2 (s, 1 arom. C); 124.4 (q, 1JC,F = 398 Hz, CF3); 127.1 (q, 3JC,F = 3.6 Hz, 2 arom. CH); 122.4 (d, 2 arom. CH); 126.7 (q, 2JC,F = 166.7 Hz, 1 arom. C); 115.2 (s, CN); 76.7 (s, =C(3)); 54.0, 52.7, 52.3 (3q, 3 MeO). Anal. Calcd for C14H11F3N2O4: C, 51.23; H 3.37; N 8.53. Found: C, 51.00; H, 3.33; N, 8.38.

Three component reactions with 1a, DCFM and variable amounts of amine 8. – General procedure. To a magnetically stirred solution of 1a (131 mg, 1 mmol) and the corresponding amine (1 mmol (procedure A), 2 mmol (procedure B) or 3 mmol (procedure C)) in 3 mL of abs. CH2Cl2, the powdered, crystalline DCFM (194 mg, 1 mmol) was added in small portions. Stirring was continued for 30 min to complete the reaction. Subsequently, the solvent was evaporated to dryness and the mixture obtained was controlled by 1H-NMR spectroscopy. In all cases, no diagnostic multiplets of 1a (2.79–2.76 and 1.54–1.51 ppm for 2 CH2) were found in the spectra evidencing thereby full conversion of the starting material. Mixtures of products were separated chromatographically on SiO2 columns or preparative plates coated with SiO2. Mixtures of petroleum ether with AcOEt (8:2) or CH2Cl2 and MeOH (99:1) were used as eluents. The isolated solid products were additionally purified by crystallization.

Reaction with cyclohexylamine (8a) (procedure A). Column chromatography (SiO2, CHCl3) afforded crystalline 7a as a sole product.

Dimethyl (Z)-3-cyano-2-(cyclohexylamino)butanedioate (7a). Yield: 235 mg (88%). Colorless crystals, mp 102–105 ºC (MeOH) (ref.8: mp 100–104 ºC).

Reaction with benzylamine (8b) (procedure A). Separation was achieved by column chromatography (SiO2, CH2Cl2).

Dimethyl (Z)-2-benzylamino-3-cyanobutanedioate (7b). Yield: 233 mg (85%). Colorless crystals, mp 102–104 °C.

Reaction with aniline (8c) (procedure A). Separation was achieved on preparative plates coated with SiO2; a mixture of CH2Cl2 and MeOH (99:1) was used as the eluent.

Dimethyl (Z)-3-cyano-2-(phenylamino)butanedioate (7c). Isolated as the least polar fraction. Yield: 24 mg (9%). Colorless crystals, mp 89–92 °C (ref.8: mp 90–92 °C). IR and 1H-NMR data fit well with that described in the literature.8

Dimethyl (E)-3-cyano-2-[3-phenyl-3-(phenylamino)azetidin-1-yl]butanedioate (6b). Isolated as the more polar fraction. Yield: 159 mg (31%). Colorless crystals, mp 181–183 °C (MeOH). IR (KBr): 3365s (NH), 2953w, 2201m (C≡N), 1750s (C=O), 1707s (C=O), 1572vs (C=C), 1496w, 1435m, 1294s, 1269s, 1190m, 1146m, 1021w, 754m, 699m. 1H-NMR (CDCl3): 7.60–6.65 (m, 8 arom. H); 6.29 (d, 2JH,H = 8.0 Hz, 2 arom. H); 4.85 (br.s, NH); 4.97, 4.90 (AB, 2JH,H = 11.3 Hz, CH2); 4.62, 4.38 (AB, 2JH,H = 11.3 Hz, CH2); 3.91, 3.73 (2s, 2 MeO). 13C-NMR (CDCl3): 161.9, 161.7, 158.4 (3s, 2 C=O, =C(2)); 143.6, 140.6 (2s, 2 arom. C); 129.2, 129.1, 128.0, 125.1, 118.7, 114.3 (6d, 10 arom. CH); 116.6 (s, CN); 70.9 (s, =C(3)); 67.6, 65.8 (2t, 2 CH2); 59.0 (s, Cq); 53.7, 52.1 (2q, 2 MeO). ESI-MS (MeOH): 415 (23), 414 (100, [M+Na]+), 352 (39), 299 (9), 230 (11). Anal. Calcd for C22H21N3O4: C, 67.51; H 5.41; N 10.73. Found: C, 66.98; H, 5.19; N, 10.68.

Dimethyl (E)-3-cyano-2-{3-phenyl-3-[3-phenyl-3-(phenylamino)azetidin-1-yl]azetidin-1-yl}butanedioate (9a). Isolated as the most polar fraction. Yield: 29 mg (5%). Colorless solid, mp 125–130 °C (MeOH). IR (KBr): 3397br.m (NH), 2952w, 2206m (C≡N), 1748s (C=O), 1707s (C=O), 1603m, 1566vs (C=C), 1497m, 1447br.m, 1308m, 1260br.s, 1195m, 1133s, 1025w, 760s, 700s. 1H-NMR(CDCl3): 7.60–6.60 (m, 13 arom. H); 6.27 (d, 2JH,H = 8.0 Hz, 2 arom. H); 4.93, 4.92 (AB, 2JH,H = 15 Hz, CH2); 4.45 (br.s, CH2); 3.92, 3.74 (2s, 2 MeO); 3.70 (m, 2H); 3.50 (m, 2H). 13C-NMR (CDCl3): 164.9, 161.7, 158.2 (3s, 2 C=O, =C(2)); 144.6, 142.8, 137.8 (3s, 3 arom. C); 128.9, 128.7, 128.5, 128.2, 127.0, 126.5, 125.4, 117.7, 114.2 (9d, 15 arom. CH); 116.6 (s, CN); 70.6 (s, =C(3)); 61.0, 60.9, 60.7, 60.2 (4t, 4 CH2); 65.9, 63.2 (2s, 2 Cq); 53.6, 52.1 (2q, 2 MeO). ESI-MS (MeOH): 546 (16), 545 (48, [M+Na]+), 524 (39), 523 (100, [M+1]+), 431 (10), 430 (33), 299 (13), 298 (65). HR-ESI-MS: 545.2159 (calcd. 545.2159 for C31H30N4NaO4, [M+Na]+), 523.2340 (calcd. 523.2340 for C31H31N4O4, [(M+1]+).

Reaction with anisidine (8d) (procedures A, B and C). Separation of the crude mixture was achieved on preparative plates coated with SiO2; a mixture of CH2Cl2 and AcOEt (7:3) was used as the eluent.

Dimethyl (Z)-3-cyano-2-[(4-methoxyphenyl)amino]butanedioate (7d). Isolated as the least polar fraction. Yield: 29 mg (10%) (procedure A), traces (procedure B), and not found (procedure C). Colorless crystals, mp 93–95 °C (MeOH) ; according to IR and 1H-NMR data identical with the substance isolated form the two-component reaction.

Dimethyl (E)-3-cyano-2-{3-phenyl-3-[(4-methoxyphenyl)amino]azetidin-1-yl}butanedioate (6c). Isolated as the second polar fraction. Yield: 225 mg (53%) (procedure A), 96 mg (23%) (procedure B), and 124 mg (29%) (procedure C). Colorless crystals, mp 106–109 ºC (dec.) (MeOH). IR (KB): 3406m (NH), 2952w, 2207m (C≡N), 1747s (C=O), 1705s (C=O), 1566vs (C=C), 1513s, 1457m, 1436m, 1278br.vs, 1196m, 1135m, 1037m, 823m, 764m, 702w. 1H-NMR (CDCl3): 7.60–7.25 (m, 5 arom. H); 6.76, 6.29 (AB, 3JH,H = 8.5 Hz, 4 arom. H); 4.95, 4.80 (AB, 2JH,H = 11.5 Hz, CH2); 4.55, 4.35 (AB, 2JH,H = 10.5 Hz, CH2); 3.90, 3.70, 3.65 (3s, 3 MeO). 13C-NMR (CDCl3): 164.9, 161.7, 158.5 (3s, 2 C=O, =C(2)); 153.0, 140.9, 137.3 (3s, 3 arom. C); 129.1, 128.0, 125.3, 116.0, 114.9 (5d, 10 arom. CH); 116.5 (s, CN); 71.0 (s, =C(3)); 67.5, 65.9 (2t, 2 CH2); 56.6 (s, Cq); 55.6, 53.8, 52.2 (3q, 3 MeO). ESI-MS (MeOH): 445 (37), 444 (100, [M+Na]+), 393 (9), 225 (14). Anal. Calcd for C23H23N3O5: C, 65.55; H 5.50; N 9.97. Found: C, 65.45; H, 5.28; N, 9.60.

Dimethyl (E)-3-cyano-2-{3-phenyl-3-[3-(4-methoxyphenyl)amino-3-phenylazetidin-1-yl]azetidin- 1-yl}butanedioate (9b). Isolated as the third polar fraction. Yield: 60 mg (11%) (procedure A), 64 mg (12%) (procedure B), and 95 mg (17%) (procedure C). Colorless crystals, mp 111–116 °C (dec.) (MeOH). IR (neat): 3393m (NH), 2951w, 2205m (C≡N), 1748s (C=O), 1706s (C=O), 1566vs (C=C), 1512s, 1447m, 1307m, 1249br.s, 1132m, 1030m, 910w, 822w, 763w, 734w, 701w. 1H-NMR (CDCl3): 7.60–7.10 (m, 10 arom. H); 6.65, 6.25 (AB, 3JH,H = 7.5 Hz, 4 arom. H); 4.95, 4.45 (2 br.s, 2 CH2); 3.90, 3.73, 3.65 (3s, MeO); 3.66, 3.52 (AB, 2JH,H = 6.5 Hz, 2 CH2). 13C-NMR (CDCl3): 165.0, 161.8, 158.3 (3s, 2 C=O, =C(2)); 152.4, 138.6, 137.9 (3s, 3 arom. C); 128.8, 128.6, 128.3, 127.1, 126.5, 125.6, 115.8, 114.6 (8d, 10 arom. CH); 116.6 (s, CN); 70.8 (s, =C(3)); 61.8, 60.6 (2t, 2 CH2); 61.0 (t, 2 CH2), 60.3, 55.6 (2s, 2 Cq); 54.8, 53.7, 52.1 (3q, 3 MeO). ESI-MS (MeOH): 575 (11, [M+Na]+), 554 (36), 553 (100, [M+1]+), 430 (31). HR-ESI-MS: 575.2259 (calcd. 575.2265 for C32H32N4NaO5, [M+Na]+), 553.2442 (calcd. 553.2446 for C32H33N4O5, [(M+1]+).

Dimethyl (E)-3-cyano-2-(3-phenyl-3-{[3-(4-methoxyphenyl)amino-3-phenylazetidin-1-yl]-3- phenylazetidin-1-yl}azetidin-1-yl)butanedioate (10a). Isolated as the most polar fraction. Yield: not observed (procedure A), traces (procedure B), 21 mg (3%) (procedure C). Colorless, viscous oil. IR (neat): 3382m (NH), 2980s, 2206s (C≡N), 1747vs (C=O), 1705vs (C=O), 1559vs (C=C), 1512s, 1447br.m, 1374m, 1249br.vs, 1134s, 927w, 842m, 762m, 736s, 701s. 1H-NMR (CDCl3): 7.70–7.10 (m, 15 arom. H); 6.63, 6.22 (AB, 3JH,H = 9.0 Hz, 4 arom. H); 4.90, 4.40 (2br.s, 2 CH2); 3.89, 3.74, 3.66 (3s, 3 MeO); 3.70–3.20 (m, 4 CH2). ESI-MS (MeOH): 816 (14), 815 (25), 706 (6, [M+Na]+), 685 (41), 684 (100, [M+1]+), 551 (18), 529 (13), 444 (16), 422 (12). HR-ESI-MS: 815.3903 (calcd. 815.3916 for C50H51N6O5, [M(10a)+1a+1]+), 684.3174 (calcd. 684.3181 for C41H42N5O5, [(M(10a)+1]+).

Reaction with 4-(trifluoromethyl)phenylamine (8e) (procedure A). Separation of the crude mixture was achieved on preparative plates coated with SiO2; a mixture of petroleum ether and AcOEt (8:2) was used as the eluent.

Dimethyl (Z)-3-cyano-2-[(4-trifluoromethylphenyl)amino]butanedioate (7e). Isolated as the least polar fraction. Yield: 53 mg (16%). Colorless crystals, mp 117–119 °C (MeOH).

Dimethyl (E)-3-cyano-2-{3-phenyl-3-[(4-trifluoromethylphenyl)amino]azetidin-1-yl}butanedioate (6d).
Isolated as the second fraction. Yield: 123 mg (27%). Colorless crystals, mp 167–169 °C (MeOH or diisopropylether). IR (KBr): 3366m (NH), 2955w, 2204m (C≡N), 1747s (C=O), 1709s (C=O), 1618m, 1567vs (C=C), 1460m, 1438m, 1327vs, 1287s (C–F), 1261s (C–F), 1194m, 1134br.s, 1067s, 1015br.w, 930w, 830m, 763m, 701m. 1H-NMR (CDCl3): 7.60–7.15 (m, 5 arom. H); 7.35, 6.35 (AB, 3JH,H = 9.0 Hz, 4 arom. H); 4.85 (br.s, NH); 4.95 (br.s, CH2); 4.45 (br.s, CH2); 3.90, 3.70 (2s, 2 MeO). 13C-NMR (CDCl3): 164.8, 161.6, 158.5 (3s, 2 C=O, =C(2)); 164.5, 139.8 (2s, 2 arom. C); 124.5 (q,1JC,F = 270 Hz, CF3); 120.4 (q, 2JC,F = 32.8 Hz, 1 arom. C); 129.3, 128.4, 125.0, 113.6 (4d, 7 arom. CH); 126.7 (q, 3JC,F = 3.7 Hz, 2 arom. CH); 116.6 (s, CN); 71.3 (s, =C(3)); 67.6, 65.6 (2t, 2 CH2); 56.0 (s, Cq); 53.9, 52.3 (2q, 2 MeO). ESI-MS (MeOH): 483 (37), 482 (100, [M+Na]+), 460 (5, [M+1]+), 459 (3, M+). Anal. Calcd for C23H20F3N3O4: C, 60.13; H 4.39; N 9.15. Found: C, 59.68; H, 4.16; N, 8.92.

Dimethyl (E)-3-cyano-2-{3-phenyl-3-[3-(4-trifluoromethylphenyl)amino-3-phenylazetidin-1-yl]
azetidin-1-yl}butanedioate (9c). Isolated as the third, most polar fraction. Yield: 32 mg (6%). Colorless crystals, mp 97–100 °C (dec.) (MeOH). IR (KBr): 3393m (NH), 2955w, 2207m (C≡N), 1748vs (C=O), 1707s (C=O), 1617s, 1568vs (C=C), 1456br.m, 1325s, 1262br.s, 1191w, 1168w, 1114s, 1066m, 830m, 763m, 701m. 1H-NMR (CDCl3): 7.60–7.15 (m, 10 arom. H); 7.40, 6.40 (AB, 3JH,H = 9.0 Hz, 4 arom. H); 5.55 (br.s, NH); 5.95 (br.s, CH2); 4.70, 4.40 (AB, 2JH,H = 9.8 Hz, CH2); 3.90, 3.70 (2s, 2 MeO); 3.70, 3.50 (AB, 2JH,H = 7.5 Hz, 2 CH2). 13C-NMR (CDCl3): 165.0, 161.8, 158.3 (3s, 2 C=O, =C(2)); 147.4.5, 141.9, 137.5 (3s, 3 arom. C); 124.9 (q,1JC,F = 270 Hz, CF3); 126.4 (q, 3JC,F = 3.7 Hz, 2 arom. CH); 127.4 (q, 2JC,F = 31.0 Hz, 1 arom. C); 129.4, 128.9, 128.8, 127.4, 126.5, 126.0, 125.4, 113.5 (7d, 12 arom. CH); 114.9 (s, CN); 71.4 (s, =C(3)); 68.6, 67.6 (2t, 2 CH2); 66.2 (t, 2 CH2); 60.9, 60.5 (2s, 2 Cq); 53.7, 52.2 (2q, 2 MeO). ESI-MS (MeOH): 629 (22, [M+K]+), 614 (34), 613 (100, [M+Na]+), 592 (31), 591 (87, [M+1]+), 509 (28), 488 (11), 482 (13), 449 (27), 430 (28). HR-ESI-MS: 613.2026 (calcd. 613.2033 for C32H29F3N4NaO4, [M+Na]+), 591.2208 (calcd. 591.22214 for C32H30F3N4O4, [(M+1]+).

Reaction with N-methylaniline (8f). Separation of the crude material was achieved on PLC plates (SiO2) using a mixture of CH2Cl2 and MeOH (99:1) as an eluent and gave 6e as the sole product. The experiment was carried out using 1a, 8f and DCFM in the molar ratio 1:1:1 (procedure A).

Dimethyl (E)-3-cyano-2-{3-[(methyl)(phenyl)amino]-3-phenylazetidin-1-yl}butanedioate (6e). Yield: 387 mg (96%). Colorless crystals, mp 98–100 ºC (dec.) IR (KBr): 2952w, 2206m (C≡N), 1750m (C=O), 1708m (C=O), 1568vs (C=C), 1503m, 1456m, 1436m, 1267br.s, 1135s, 753m, 701m. 1H-NMR (CDCl3): 7.43–7.20 (m, 5 arom. H); 7.17 (t-like, 2 arom. H); 6.78 (t-like, 1 arom. H); 6.37 (d-like, 2 arom. H); 5.10, 4.88 and 4.58, 4.38 (2 AB, J = 11 and 10 Hz, resp., 2 CH2); 3.93, 3.76 (2s, 2 MeO); 3.12 (s, MeN). 13C-NMR (CDCl3): 165.0, 161.7, 158.0 (3s, 2 C=O, =C(2)); 146.4, 140.7 (2s, 2 arom. C); 129.23, 129.17, 128.2, 125.3, 118.5, 114.6 (6d, 10 arom. CH); 116.5 (s, CN); 71.3 (s, =C(3)); 66.0, 65.3 (2t, 2 CH2); 61.5 (s, Cq); 53.8, 52.2 (2q, 2 MeO); 36.9 (q, MeN). ESI-MS (MeOH): 429 (26), 428 (100, [M+Na]+), 406 (10, [M+1]+). HR-ESI-MS: 428.1579 (calcd. 428.1581 for C23H23N3NaO4, [M+Na]+).

ACKNOWLEDGEMENTS
The authors thank Ms Małgorzata Celeda (University of Łódź) for her skilful assistance in the laboratory work. Financial support by the Rector of the University of Łódź (Grant # 505/712) (to G. M.) and F. Hoffmann-La Roche AG, Basel (to H. H.) is acknowledged.

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