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One-pot three-component reaction of C60, amino acid and fluorinated benzaldehyde to C60-pyrrolidine derivatives
Journal of Fluorine Chemistry 126 (2005) 349–353 www.elsevier.com/locate/fluor
One-pot three-component reaction of C60, amino acid and fluorinated benzaldehyde to C60-pyrrolidine derivatives Sheng Wang a, Jian-min Zhang a,*, Li-ping Song a,b, Hu Jiang a, Shi-zheng Zhu b,* a
Department of Chemistry, School of Science, Shanghai University, No. 99 Shangda Road, Shanghai 200436, China b State Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China Received 10 October 2004; received in revised form 24 December 2004; accepted 25 December 2004 Available online 7 March 2005
Abstract A series of fluorinated 2,5-disubstituted C60-pyrrolidine derivatives were synthesized via one-pot three-component reaction of C60, amino acid and fluorinated benzaldehyde under reflux in toluene or microwave irradiation. The cis- and trans-isomers could be isolated by chromatography and fully confirmed by 1H NMR. # 2005 Elsevier B.V. All rights reserved. Keywords: C60; Amino acid; Fluorinated benzaldehyde; 1,3-Dipolar cycloaddition; C60-pyrrolidines
1. Introduction Functionalization of fullerenes has drawn much attention recently because of fullerene derivatives have shown to exhibit many interesting properties, which are promising in material sciences and/or life sciences [1]. Cycloaddition reaction of fullerenes was intensively studied because the electron-withdrawing nature of each pyeacyclene unit in fullerene makes it an ideal dienophile and dipolarphile [2]. Among the numerous methods for functionalizing fullerenes, 1,3-dipolar cycloadditions have been extensively applied [3]. For example, the reaction of azomethine ylide with C60 results in the formation of heterocyclic derivatives called fulleropyrrolidines [4], which are frequently employed in these studies [5]. Although a large number of fulleropyrrolidine have been reported in the literatures [6], to the best of our knowledge, the reaction of C60 with 1,3-dipoles derived from amino acid and fluorinated benzaldehyde has not been reported. It is well known that replacement of hydrogen with fluorine atom frequently confer bioactivity to organic molecules in terms * Corresponding author. Fax: +86 21 64166128. E-mail address: [email protected] (S.-z. Zhu). 0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2004.12.018
of life sciences [7]. In this paper, we wish to report the synthesis of fulleropyrrolindine derivatives by one-pot threecomponent reaction of C60, amino acid and fluorinated benzaldehyde.
2. Results and discussions In our initial study, the ratio of starting materials in onepot three-component reaction was briefly investigated. Reaction of C60 with 1 equiv. of leucine and 1 equiv. of pentafluorobenzaldehyde took place smoothly in reflux toluene, after stirring for 10 h, general work-up afforded a mixture of cis- and trans-isomers of fulleropyrrolidine derivatives, which could be isolated by chromatography on silica gel (Scheme 1). However, the yields were quite lower (entry 1, Table 1). In order to improve the yields, different ratio of starting material was applied. As shown in Table 1, the amounts of leucine and pentafluorobenzaldehyde were increased up to 2 equiv., the yields of desired products were slightly increased (entry 2, Table 1). The better yields were obtained when 4 equiv. of leucine and 2 equiv. of pentafluorobenzaledhyde were used. However, by comparison, reaction of C60 with large excess of leucine (6 equiv.) and
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S. Wang et al. / Journal of Fluorine Chemistry 126 (2005) 349–353
Scheme 1.
Table 1 Preparation of compounds 3 and 4 using conventional heating Entry
1 2 3 4 5 6 a b c
Reactantsa
Productsb
1
1 R1
2 R2
1/2/C60
cis (yield%)
trans (yield%)
i-Bu i-Bu i-Bu i-Bu i-Pr PhCH2
C6F5– C6F5– C6F5– C6F5– C6F5– p-FC6H4–
1:1:1 2:2:1 4:2:1 6:3:1 4:2:1 4:2:1
3aa (5) 3aa (7) 3aa (12) 3aa (13) 3ba (23) 3cb (22)
4aa (8) 4aa (13) 4aa (20) 4aa (20) 4ba (14) 4cb (20)
H NMR (CS2/CDCl3)c
cis (d H2,H5)
trans (d H2,H5)
6.34
5.28
6.22
4.92
6.28 6.13
4.82 5.34
6.16 5.63
4.76 4.97
All reactions were carried out in toluene. Isolated yield based on C60. Pyrrolidine 2,5-protons.
pentafluorobenzaldehyde (3 equiv.) did not improve the yields drastically, whereas it caused trouble in separation. The reaction conditions and reaction results are listed in Table 1. The structures assignment of two cis- and trans-isomers is based on their 1H NMR spectrum data. Wilson et al. have previously reported that 1H NMR of the cis- and transisomers showed distinctive chemical shifts for the pyrrolidine methine protons, and the signals of the cis-isomers always appear further downfield than the corresponding signals for the trans-isomer [8]. In our case, similar different chemical shifts were also observed. For example, the signals of two pyrrodine methines protons in compound 4aa were at d 6.22 and 4.92, whereas for the corresponding compound 3aa, these two signals were at d 6.34 and 5.28, respectively, which appeared at further downfield than those of 4aa. Similarly, the corresponding pyrrolidine methine signals for 4ba appeared at d 6.16 and 4.76, whereas for the corresponding 3ba, these two signals were at d 6.28 and 4.82, respectively. Therefore, we assigned compound 3aa as the 2,5-cis-isomer and 4aa as the 2,5-trans-isomer based on the 1H NMR, where the more downfield signals was assigned to cis-isomer. This result is consistent with TLC analysis on silica gel because the smaller Rf value of 3aa suggests that 3aa possesses higher polarity. However, the proton bonding to the nitrogen atom was not found in either 1 H NMR spectra, these observations were in agreement with the previous work [6]. It is interesting to noted that the 19F NMR spectra (282 MHz, CS2/CDCl3 = 4/1) of 3aa, 4aa, 3ba
and 4ba exhibited four signals, which indicated that there existed the inter-molecular hydrogen bond between the one of two fluorine atoms in the ortho-position of the phenyl group and hydrogen bonding with the pyrrolidine nitrogen atom (Fig. 1), resulting in two fluorine atoms in the
Fig. 1. H F inter-molecular hydrogen bond.
S. Wang et al. / Journal of Fluorine Chemistry 126 (2005) 349–353
ortho-position of phenyl group appeared different chemical shifts. It should be indicated that the reaction of C60 either with 1c and 2a, 1a and 2b, or with 1b and 2b, unfortunately, the obtained cis- and trans-isomers mixture could not be separated by chromatography. However, for 1c/2a reaction system, 1H NMR of isomers mixture elucidated the cis-/trans-ratio is 71/29, based on the 1H NMR integrals of the characteristic protons in 3-, 5-positions of pyrrolidine moiety, with the total yield of 36%. Similarly, for 1a/2b and 1b/2b systems, the cis-/trans-ratios are 68/32 and 53/47, with the total yields of 22% and 16%, respectively. Under the same reaction conditions, other amino acids such as 2-phenylglycin were also used in this reaction, attempt to separate the cis- and trans-isomers failed because of their similar polarity. Microwave assisted organic synthesis is known to achieve spectacular accelerations in many reactions as a consequence of a heating rate that cannot be reproduced by classical heating, problems of reversibility or decomposition of reagent and/or products have been nicely solved using this methodology [9]. 1,3-Dipolar cycloadditions were easily performed under microwave irradiation [10]. Cruz et al. have recently described the first application of microwave irradiation to the preparation of a functionalized C60, and a series of Diels–Alder reaction and 1,3-dipolar cycloadditions involving C60 have been achieved [11]. More recently, we have successfully prepared 2-pentafluorophenylquinoline derivatives by microwave prompted one-pot threecomponent reaction [12]. Consequently, we considered it of interest to investigate the potential of microwave irradiation in the preparation of fullerene derivatives when this type of reaction is involved. Based on the previous investigation of microwave promoted one-pot three-component reaction to C60-pyrrolidine derivatives [13], this three-component reaction was carried out in a modified domestic microwave oven. Reaction of C60 with Leucine and pentafluorobenzaldehyde in o-dichlorobenzene as solvent for 50 m at 80 W produced the same cycloadducts 3aa and 4aa in 11% and 26%, respectively. Reaction conditions and reaction results are listed in Table 2. In principle, a reduction of reaction times and the improvement of yields are the benefits of microwave irradiation reaction. With this aim of view, in order to improve the yields obtained by microwave irradiation, we tried to change microwave irradiation time and irradiation
351
power, and found that neither increasing the irradiation power nor prolonged the irradiation time could improve the yields significantly. In some cases, longer reaction times result in lower yields probably due to the formation of other non-identified decomposition products. It is remarkable that in the microwave irradiation conditions indicated in Table 2, although microwave irradiation did not significantly improve the yields in comparison with conventional heating, actually, it reduced the reaction time to 1 h. In summary, under the thermal conditions or microwave irradiations, a series of fluorinated 2,5-disubstituted C60pyrrolidine derivatives were synthesized via 1,3-dipolar cycloadditions of C60 with fluorinated 1,3-dipoles derived in situ from corresponding amino acid and fluorinated benzaldehyde. It provides a convenient route to prepare C60-derivatives bearing fluorinated five-membered heterocycles. Reactions of C60 with other 1,3-dipoles such as fluorine-containing nitrile imines and nitrile oxides are now under investigation. These results will be published elsewhere.
3. Experimental Solvents were dried before use. 1H NMR and 19F NMR spectra were recorded on a Bruker AM-300 spectrometer with Me4Si and CFCl3 (with upfield negative) as the internal and external standards, respectively. IR spectra were obtained with a Nicolet AV-360 spectrophotometer. Lower resolution mass spectra were obtained on an Applied Biosystems Mariner time-of-flight mass spectrometer using electrospray ionization technique (ESI). Elemental analyses were performed by this Institute. C60 was purchased from Wuhan University (>99.9%). Amino acids were purchased from Sigma Chemical Co. (St. Louis, MO, USA). 3.1. A general procedure for the synthesis of C60-pyrrolidine derivatives 3.1.1. Method A (conventional heating) A mixture of 72 mg of C60 (0.1 mmol), 52.4 mg (0.4 mmol) leucine and 39.2 mg (0.2 mmol) pentafluorobenzaldehyde was dissolved in 70 ml toluene and heated to reflux with stirring for 10 h. After cooling, the solvent was removed by rotary evaporation. Isolation by flash column chromatography on silica gel using toluene and PE (v/v = 1)
Table 2 Preparation of compounds 3 and 4 using microwave irradiation Entry
R1
R2
1 2 3
i-Bu i-Pr PhCH2
C6F5– C6F5– P–F–C6H4–
a b
Microwave irradiationa
Productb
Power (W)
Time (min)
cis (yield%)
trans (yield%)
80 80 80
50 90 60
3aa (11) 3ba (25) 3cb (29)
4aa (26) 4ba (11) 4cb (8)
Microwave irradiations were carried out using a Sanyo, EM-551S/550S, modified domestic microwave oven. Isolated yield based on C60.
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as eluents afforded expected products 11.8 mg of 3aa, 19.7 mg of 4aa. The yield of 3aa and 4aa were 12% and 20%, respectively, based on C60.
(M+ + 1, 15), 720 (C60+, 100). Anal. Calcd. for C71H10F5N: C, 87.75; H, 1.04; N, 1.44. Found: C, 87.49; H, 1.18; N, 1.36%.
3.1.2. Method B (microwave irradiation) A mixture of 72 mg of C60 (0.1 mmol), 52.4 mg leucine (0.4 mmol) and 39.2 mg pentafluorobenzaldehyde (0.2 mmol) was dissolved in 60 ml o-dichlorobenzene and irradiated in a modified domestic microwave oven with 80 W for appropriate time. After cooling, the solvent was removed by rotary evaporation. Isolation by flash column chromatography on silica gel using toluene and PE (v/v = 1) as eluents afforded expected products 10.8 mg of 3aa, 25.6 mg of 4aa. The yield of 3aa and 4aa were 11% and 26%, respectively, based on C60.
3.1.2.5. 3cb cis-2-(4-fluorophenyl)-5-benzyl-C60-pyrrolidine. IR (KBr pellet): 2919, 2847, 1654, 1523, 1502, 1400, 1157, 1117, 574, 527 cm 1. 1H NMR (CS2/CDCl3) d: 7.79– 7.74 (m, 2H), 7.49–7.29 (m, 5H), 7.01 (t, J = 8.4 Hz, 2H), 6.13 (s, 1H), 5.34 (dd, J = 11.7 Hz, J = 3.6 Hz, 1H), 3.97 (t, J = 11.7 Hz, 1H), 3.67 (dd, J = 11.7 Hz, J = 3.6 Hz, 1H). 19F NMR (CS2/CDCl3) d: 111.3 (s, 1F). ESI-MS m/z (%): 948 (M+ + 1, 18), 720 (C60+, 100). Anal. Calcd. for C75H14FN: C, 95.02; H, 1.49; N, 1.48. Found: C, 94.83; H, 1.54; N, 1.29%.
3.1.2.1. 3aa cis-2-pentafluorophenyl-5-[2-(methyl)-propyl]-C60-pyrrolidine. IR (KBr pellet): 2951, 2865, 1652, 1522, 1502, 1458, 1400, 1183, 1013, 574, 527 cm 1. 1H NMR (CS2/CDCl3) d: 6.34 (s, 1H), 5.28 (d, J = 11.26 Hz, 1H), 2.36 (m, 1H), 1.26 (d, J = 6.59 Hz, 6H). 19F NMR (CS2/ CDCl3) d: 137.2 (s, 1F), 138.6 (s, 1F), 151.5 (t, J = 24.1 Hz, 1F), 159.1 (t, J = 22.8 Hz, 2F). ESI-MS m/z (%): 986 (M+ + 1, 10), 720 (C60+, 100). Anal. Calcd. for C72H12F5N: C, 87.72; H, 1.23; N, 1.42. Found: C, 87.27; H, 1.50; N, 1.33%. 3.1.2.2. 4aa trans-2-pentafluorophenyl-5-[2-(methyl)-propyl]-C60-pyrrolidine. IR (KBr pellet) cm 1: 2955, 2861, 1654, 1522, 1504, 1400, 1155, 1031, 574, 527. 1H NMR (CS2/CDCl3) d: 6.22 (s, 1H), 4.92 (d, J = 11.28 Hz, 1H), 2.36 (m, 1H), 1.24 (d, J = 6.59 Hz, 6H). 19F NMR (CS2/CDCl3) d: 136.9 (d, J = 17.8 Hz, 1F), 138.9 (d, J = 24.6 Hz, 1F), 151.3 (t, J = 21.0 Hz, 1F), 158.9 (m, 2F). ESI-MS m/z (%): 986 (M+ + 1, 9), 720 (C60+, 100). Anal. Calcd. for C72H12F5N: C, 87.72; H, 1.23; N, 1.42. Found: C, 87.43; H, 1.44; N, 1.32%. 3.1.2.3. 3ba cis-2-pentafluorophenyl-5-[2-(methyl)-ethyl]C60-pyrrolidine. IR (KBr pellet): 2962, 2924, 1650, 1523, 1512, 1504, 1400, 1154, 1024, 574, 527 cm 1. 1H NMR (CS2/CDCl3) d: 6.28 (s, 1H), 4.82 (d, J = 11.3 Hz, 1H), 3.04 (m, 1H), 1.26 (d, J = 15.9 Hz, 6H). 19F NMR (CS2/CDCl3) d: 137.1 (d, J = 26.3 Hz, 1F), 138.7 (s, 1F), 151.4 (t, J = 20.2 Hz, 1F), 159.1 (m, 2F). ESI-MS m/z (%): 972 (M+ + 1, 14), 720 (C60+, 100). Anal. Calcd. for C71H10F5N: C, 87.75; H, 1.04; N, 1.44. Found: C, 87.32; H, 1.26; N, 1.52%. 3.1.2.4. 4ba trans-2-pentafluorophenyl-5-[2-(methyl)ethyl]-C60-pyrrolidine. IR (KBr pellet): 2962, 1647, 1524, 1502, 1400, 1261, 1096, 1022, 576, 527 cm 1. 1H NMR (CS2/CDCl3) d: 6.16 (s, 1H), 4.76 (d, J = 11.2 Hz, 1H), 3.04 (m, 1H), 1.24 (d, J = 15.6 Hz, 6H). 19F NMR (CS2/ CDCl3) d: 137.0 (s, 1F), 138.9 (s, 1F), 151.2 (t, J = 21.3 Hz, 1F), 158.8 (m, 2F). ESI-MS m/z(%): 972
3.1.2.6. 4cb trans-2-(4-fluorophenyl)-5-benzyl-C60-pyrrolidine. IR (KBr pellet): 2914, 2847, 1654, 1523, 1502, 1400, 1131, 1047, 574, 527 cm 1. 1H NMR (CS2/CDCl3) d: 7.80– 7.76 (m, 2H), 7.53–7.50 (m, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.29–7.25 (m, 1H), 7.00 (t, J = 8.4 Hz, 2H), 5.63 (s, 1H), 4.97 (dd, J = 10.8 Hz, J = 2.4 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.46 (1H, t, J = 12.0 Hz). 19F NMR (CS2/CDCl3) d: 111.2 (s, 1F). ESI-MS m/z (%): 948 (M+ + 1, 16), 720 (C60+, 100). Anal. Calcd. for C75H14FN: C, 95.02; H, 1.49; N, 1.48. Found: C, 94.79; H, 1.51; N, 1.36%.
Acknowledgement The authors thank the National Natural Science Foundation of China (NNSFC) (No. 20372077) and Innovation Foundation of Chinese Academy of Sciences for financial support.
References [1] (a) M. Prato, Fullerene material, in: R. Hirsch (Ed.), Topics in Current Chemistry, 199, Springer, New York, 1999, p. 173; (b) A.W. Jensen, S.R. Wilson, D.I. Schuster, Bioorg. Med. Chem. 4 (1996) 767–779. [2] (a) F. Wudl, Acc. Chem. Res. 25 (1992) 157–161; (b) S. Muthu, P. Maruthamuthu, R. Ragunathan, R.P.R. Vasudeva, C.K. Mathews, Tetrahedron Lett. 35 (1994) 1763–1766. [3] X. Tan, D.I. Schuster, S.R. Wilson, Tetrahedron Lett. 39 (1998) 4187– 4190. [4] M. Maggini, G. Scorrano, M. Prato, J. Am. Chem. Soc. 115 (1993) 9798–9799. [5] S. Zhang, L. Gan, C. Huang, M. Lu, J. Pan, X. He, J. Org. Chem. 67 (2002) 883–891. [6] L.H. Shu, G.W. Wang, S.H. Wu, H.M. Wu, X. He, X.F. Lao, Tetrahedron Lett. 36 (1995) 3871–3874. [7] Y.L. Wang, S.Z. Zhu, Synthesis 13 (2002) 1813–1818, and references therein. [8] S.R. Wilson, Y. Wang, J. Cao, X. Tan, Tetrahedron Lett. 37 (1996) 775–778. [9] F. Langa, P.D.L. Curz, E. Espildora, J.J. Garcia, M.C. Perez, A.D.L. Hoz, Carbon 38 (2000) 1641–1646.
S. Wang et al. / Journal of Fluorine Chemistry 126 (2005) 349–353 [10] A.D. Ortiz, E.D. Barra, A.D.L. Hoz, P. Prieto, A. Moreno, F. Langa, T. Prange, A. Neuman, J. Org. Chem. 60 (1995) 4160–4166. [11] P.D.L. Curz, A.D.L. Hoz, F. Langa, Tetrahedron 53 (1997) 2599– 2608.
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[12] J.M. Zhang, W. Yang, L.P. Song, X. Cai, S.Z. Zhu, Tetrahedron Lett. 45 (2004) 5771–5773. [13] J.M. Zhang, W. Yang, P. He, S.Z. Zhu, S. Wang, Synth. Commun. 35 (2005) 89–96.
One-pot three-component reaction of C60, amino acid and fluorinated benzaldehyde to C60-pyrrolidine derivatives Sheng Wang a, Jian-min Zhang a,*, Li-ping Song a,b, Hu Jiang a, Shi-zheng Zhu b,* a
Department of Chemistry, School of Science, Shanghai University, No. 99 Shangda Road, Shanghai 200436, China b State Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China Received 10 October 2004; received in revised form 24 December 2004; accepted 25 December 2004 Available online 7 March 2005
Abstract A series of fluorinated 2,5-disubstituted C60-pyrrolidine derivatives were synthesized via one-pot three-component reaction of C60, amino acid and fluorinated benzaldehyde under reflux in toluene or microwave irradiation. The cis- and trans-isomers could be isolated by chromatography and fully confirmed by 1H NMR. # 2005 Elsevier B.V. All rights reserved. Keywords: C60; Amino acid; Fluorinated benzaldehyde; 1,3-Dipolar cycloaddition; C60-pyrrolidines
1. Introduction Functionalization of fullerenes has drawn much attention recently because of fullerene derivatives have shown to exhibit many interesting properties, which are promising in material sciences and/or life sciences [1]. Cycloaddition reaction of fullerenes was intensively studied because the electron-withdrawing nature of each pyeacyclene unit in fullerene makes it an ideal dienophile and dipolarphile [2]. Among the numerous methods for functionalizing fullerenes, 1,3-dipolar cycloadditions have been extensively applied [3]. For example, the reaction of azomethine ylide with C60 results in the formation of heterocyclic derivatives called fulleropyrrolidines [4], which are frequently employed in these studies [5]. Although a large number of fulleropyrrolidine have been reported in the literatures [6], to the best of our knowledge, the reaction of C60 with 1,3-dipoles derived from amino acid and fluorinated benzaldehyde has not been reported. It is well known that replacement of hydrogen with fluorine atom frequently confer bioactivity to organic molecules in terms * Corresponding author. Fax: +86 21 64166128. E-mail address: [email protected] (S.-z. Zhu). 0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2004.12.018
of life sciences [7]. In this paper, we wish to report the synthesis of fulleropyrrolindine derivatives by one-pot threecomponent reaction of C60, amino acid and fluorinated benzaldehyde.
2. Results and discussions In our initial study, the ratio of starting materials in onepot three-component reaction was briefly investigated. Reaction of C60 with 1 equiv. of leucine and 1 equiv. of pentafluorobenzaldehyde took place smoothly in reflux toluene, after stirring for 10 h, general work-up afforded a mixture of cis- and trans-isomers of fulleropyrrolidine derivatives, which could be isolated by chromatography on silica gel (Scheme 1). However, the yields were quite lower (entry 1, Table 1). In order to improve the yields, different ratio of starting material was applied. As shown in Table 1, the amounts of leucine and pentafluorobenzaldehyde were increased up to 2 equiv., the yields of desired products were slightly increased (entry 2, Table 1). The better yields were obtained when 4 equiv. of leucine and 2 equiv. of pentafluorobenzaledhyde were used. However, by comparison, reaction of C60 with large excess of leucine (6 equiv.) and
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S. Wang et al. / Journal of Fluorine Chemistry 126 (2005) 349–353
Scheme 1.
Table 1 Preparation of compounds 3 and 4 using conventional heating Entry
1 2 3 4 5 6 a b c
Reactantsa
Productsb
1
1 R1
2 R2
1/2/C60
cis (yield%)
trans (yield%)
i-Bu i-Bu i-Bu i-Bu i-Pr PhCH2
C6F5– C6F5– C6F5– C6F5– C6F5– p-FC6H4–
1:1:1 2:2:1 4:2:1 6:3:1 4:2:1 4:2:1
3aa (5) 3aa (7) 3aa (12) 3aa (13) 3ba (23) 3cb (22)
4aa (8) 4aa (13) 4aa (20) 4aa (20) 4ba (14) 4cb (20)
H NMR (CS2/CDCl3)c
cis (d H2,H5)
trans (d H2,H5)
6.34
5.28
6.22
4.92
6.28 6.13
4.82 5.34
6.16 5.63
4.76 4.97
All reactions were carried out in toluene. Isolated yield based on C60. Pyrrolidine 2,5-protons.
pentafluorobenzaldehyde (3 equiv.) did not improve the yields drastically, whereas it caused trouble in separation. The reaction conditions and reaction results are listed in Table 1. The structures assignment of two cis- and trans-isomers is based on their 1H NMR spectrum data. Wilson et al. have previously reported that 1H NMR of the cis- and transisomers showed distinctive chemical shifts for the pyrrolidine methine protons, and the signals of the cis-isomers always appear further downfield than the corresponding signals for the trans-isomer [8]. In our case, similar different chemical shifts were also observed. For example, the signals of two pyrrodine methines protons in compound 4aa were at d 6.22 and 4.92, whereas for the corresponding compound 3aa, these two signals were at d 6.34 and 5.28, respectively, which appeared at further downfield than those of 4aa. Similarly, the corresponding pyrrolidine methine signals for 4ba appeared at d 6.16 and 4.76, whereas for the corresponding 3ba, these two signals were at d 6.28 and 4.82, respectively. Therefore, we assigned compound 3aa as the 2,5-cis-isomer and 4aa as the 2,5-trans-isomer based on the 1H NMR, where the more downfield signals was assigned to cis-isomer. This result is consistent with TLC analysis on silica gel because the smaller Rf value of 3aa suggests that 3aa possesses higher polarity. However, the proton bonding to the nitrogen atom was not found in either 1 H NMR spectra, these observations were in agreement with the previous work [6]. It is interesting to noted that the 19F NMR spectra (282 MHz, CS2/CDCl3 = 4/1) of 3aa, 4aa, 3ba
and 4ba exhibited four signals, which indicated that there existed the inter-molecular hydrogen bond between the one of two fluorine atoms in the ortho-position of the phenyl group and hydrogen bonding with the pyrrolidine nitrogen atom (Fig. 1), resulting in two fluorine atoms in the
Fig. 1. H F inter-molecular hydrogen bond.
S. Wang et al. / Journal of Fluorine Chemistry 126 (2005) 349–353
ortho-position of phenyl group appeared different chemical shifts. It should be indicated that the reaction of C60 either with 1c and 2a, 1a and 2b, or with 1b and 2b, unfortunately, the obtained cis- and trans-isomers mixture could not be separated by chromatography. However, for 1c/2a reaction system, 1H NMR of isomers mixture elucidated the cis-/trans-ratio is 71/29, based on the 1H NMR integrals of the characteristic protons in 3-, 5-positions of pyrrolidine moiety, with the total yield of 36%. Similarly, for 1a/2b and 1b/2b systems, the cis-/trans-ratios are 68/32 and 53/47, with the total yields of 22% and 16%, respectively. Under the same reaction conditions, other amino acids such as 2-phenylglycin were also used in this reaction, attempt to separate the cis- and trans-isomers failed because of their similar polarity. Microwave assisted organic synthesis is known to achieve spectacular accelerations in many reactions as a consequence of a heating rate that cannot be reproduced by classical heating, problems of reversibility or decomposition of reagent and/or products have been nicely solved using this methodology [9]. 1,3-Dipolar cycloadditions were easily performed under microwave irradiation [10]. Cruz et al. have recently described the first application of microwave irradiation to the preparation of a functionalized C60, and a series of Diels–Alder reaction and 1,3-dipolar cycloadditions involving C60 have been achieved [11]. More recently, we have successfully prepared 2-pentafluorophenylquinoline derivatives by microwave prompted one-pot threecomponent reaction [12]. Consequently, we considered it of interest to investigate the potential of microwave irradiation in the preparation of fullerene derivatives when this type of reaction is involved. Based on the previous investigation of microwave promoted one-pot three-component reaction to C60-pyrrolidine derivatives [13], this three-component reaction was carried out in a modified domestic microwave oven. Reaction of C60 with Leucine and pentafluorobenzaldehyde in o-dichlorobenzene as solvent for 50 m at 80 W produced the same cycloadducts 3aa and 4aa in 11% and 26%, respectively. Reaction conditions and reaction results are listed in Table 2. In principle, a reduction of reaction times and the improvement of yields are the benefits of microwave irradiation reaction. With this aim of view, in order to improve the yields obtained by microwave irradiation, we tried to change microwave irradiation time and irradiation
351
power, and found that neither increasing the irradiation power nor prolonged the irradiation time could improve the yields significantly. In some cases, longer reaction times result in lower yields probably due to the formation of other non-identified decomposition products. It is remarkable that in the microwave irradiation conditions indicated in Table 2, although microwave irradiation did not significantly improve the yields in comparison with conventional heating, actually, it reduced the reaction time to 1 h. In summary, under the thermal conditions or microwave irradiations, a series of fluorinated 2,5-disubstituted C60pyrrolidine derivatives were synthesized via 1,3-dipolar cycloadditions of C60 with fluorinated 1,3-dipoles derived in situ from corresponding amino acid and fluorinated benzaldehyde. It provides a convenient route to prepare C60-derivatives bearing fluorinated five-membered heterocycles. Reactions of C60 with other 1,3-dipoles such as fluorine-containing nitrile imines and nitrile oxides are now under investigation. These results will be published elsewhere.
3. Experimental Solvents were dried before use. 1H NMR and 19F NMR spectra were recorded on a Bruker AM-300 spectrometer with Me4Si and CFCl3 (with upfield negative) as the internal and external standards, respectively. IR spectra were obtained with a Nicolet AV-360 spectrophotometer. Lower resolution mass spectra were obtained on an Applied Biosystems Mariner time-of-flight mass spectrometer using electrospray ionization technique (ESI). Elemental analyses were performed by this Institute. C60 was purchased from Wuhan University (>99.9%). Amino acids were purchased from Sigma Chemical Co. (St. Louis, MO, USA). 3.1. A general procedure for the synthesis of C60-pyrrolidine derivatives 3.1.1. Method A (conventional heating) A mixture of 72 mg of C60 (0.1 mmol), 52.4 mg (0.4 mmol) leucine and 39.2 mg (0.2 mmol) pentafluorobenzaldehyde was dissolved in 70 ml toluene and heated to reflux with stirring for 10 h. After cooling, the solvent was removed by rotary evaporation. Isolation by flash column chromatography on silica gel using toluene and PE (v/v = 1)
Table 2 Preparation of compounds 3 and 4 using microwave irradiation Entry
R1
R2
1 2 3
i-Bu i-Pr PhCH2
C6F5– C6F5– P–F–C6H4–
a b
Microwave irradiationa
Productb
Power (W)
Time (min)
cis (yield%)
trans (yield%)
80 80 80
50 90 60
3aa (11) 3ba (25) 3cb (29)
4aa (26) 4ba (11) 4cb (8)
Microwave irradiations were carried out using a Sanyo, EM-551S/550S, modified domestic microwave oven. Isolated yield based on C60.
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as eluents afforded expected products 11.8 mg of 3aa, 19.7 mg of 4aa. The yield of 3aa and 4aa were 12% and 20%, respectively, based on C60.
(M+ + 1, 15), 720 (C60+, 100). Anal. Calcd. for C71H10F5N: C, 87.75; H, 1.04; N, 1.44. Found: C, 87.49; H, 1.18; N, 1.36%.
3.1.2. Method B (microwave irradiation) A mixture of 72 mg of C60 (0.1 mmol), 52.4 mg leucine (0.4 mmol) and 39.2 mg pentafluorobenzaldehyde (0.2 mmol) was dissolved in 60 ml o-dichlorobenzene and irradiated in a modified domestic microwave oven with 80 W for appropriate time. After cooling, the solvent was removed by rotary evaporation. Isolation by flash column chromatography on silica gel using toluene and PE (v/v = 1) as eluents afforded expected products 10.8 mg of 3aa, 25.6 mg of 4aa. The yield of 3aa and 4aa were 11% and 26%, respectively, based on C60.
3.1.2.5. 3cb cis-2-(4-fluorophenyl)-5-benzyl-C60-pyrrolidine. IR (KBr pellet): 2919, 2847, 1654, 1523, 1502, 1400, 1157, 1117, 574, 527 cm 1. 1H NMR (CS2/CDCl3) d: 7.79– 7.74 (m, 2H), 7.49–7.29 (m, 5H), 7.01 (t, J = 8.4 Hz, 2H), 6.13 (s, 1H), 5.34 (dd, J = 11.7 Hz, J = 3.6 Hz, 1H), 3.97 (t, J = 11.7 Hz, 1H), 3.67 (dd, J = 11.7 Hz, J = 3.6 Hz, 1H). 19F NMR (CS2/CDCl3) d: 111.3 (s, 1F). ESI-MS m/z (%): 948 (M+ + 1, 18), 720 (C60+, 100). Anal. Calcd. for C75H14FN: C, 95.02; H, 1.49; N, 1.48. Found: C, 94.83; H, 1.54; N, 1.29%.
3.1.2.1. 3aa cis-2-pentafluorophenyl-5-[2-(methyl)-propyl]-C60-pyrrolidine. IR (KBr pellet): 2951, 2865, 1652, 1522, 1502, 1458, 1400, 1183, 1013, 574, 527 cm 1. 1H NMR (CS2/CDCl3) d: 6.34 (s, 1H), 5.28 (d, J = 11.26 Hz, 1H), 2.36 (m, 1H), 1.26 (d, J = 6.59 Hz, 6H). 19F NMR (CS2/ CDCl3) d: 137.2 (s, 1F), 138.6 (s, 1F), 151.5 (t, J = 24.1 Hz, 1F), 159.1 (t, J = 22.8 Hz, 2F). ESI-MS m/z (%): 986 (M+ + 1, 10), 720 (C60+, 100). Anal. Calcd. for C72H12F5N: C, 87.72; H, 1.23; N, 1.42. Found: C, 87.27; H, 1.50; N, 1.33%. 3.1.2.2. 4aa trans-2-pentafluorophenyl-5-[2-(methyl)-propyl]-C60-pyrrolidine. IR (KBr pellet) cm 1: 2955, 2861, 1654, 1522, 1504, 1400, 1155, 1031, 574, 527. 1H NMR (CS2/CDCl3) d: 6.22 (s, 1H), 4.92 (d, J = 11.28 Hz, 1H), 2.36 (m, 1H), 1.24 (d, J = 6.59 Hz, 6H). 19F NMR (CS2/CDCl3) d: 136.9 (d, J = 17.8 Hz, 1F), 138.9 (d, J = 24.6 Hz, 1F), 151.3 (t, J = 21.0 Hz, 1F), 158.9 (m, 2F). ESI-MS m/z (%): 986 (M+ + 1, 9), 720 (C60+, 100). Anal. Calcd. for C72H12F5N: C, 87.72; H, 1.23; N, 1.42. Found: C, 87.43; H, 1.44; N, 1.32%. 3.1.2.3. 3ba cis-2-pentafluorophenyl-5-[2-(methyl)-ethyl]C60-pyrrolidine. IR (KBr pellet): 2962, 2924, 1650, 1523, 1512, 1504, 1400, 1154, 1024, 574, 527 cm 1. 1H NMR (CS2/CDCl3) d: 6.28 (s, 1H), 4.82 (d, J = 11.3 Hz, 1H), 3.04 (m, 1H), 1.26 (d, J = 15.9 Hz, 6H). 19F NMR (CS2/CDCl3) d: 137.1 (d, J = 26.3 Hz, 1F), 138.7 (s, 1F), 151.4 (t, J = 20.2 Hz, 1F), 159.1 (m, 2F). ESI-MS m/z (%): 972 (M+ + 1, 14), 720 (C60+, 100). Anal. Calcd. for C71H10F5N: C, 87.75; H, 1.04; N, 1.44. Found: C, 87.32; H, 1.26; N, 1.52%. 3.1.2.4. 4ba trans-2-pentafluorophenyl-5-[2-(methyl)ethyl]-C60-pyrrolidine. IR (KBr pellet): 2962, 1647, 1524, 1502, 1400, 1261, 1096, 1022, 576, 527 cm 1. 1H NMR (CS2/CDCl3) d: 6.16 (s, 1H), 4.76 (d, J = 11.2 Hz, 1H), 3.04 (m, 1H), 1.24 (d, J = 15.6 Hz, 6H). 19F NMR (CS2/ CDCl3) d: 137.0 (s, 1F), 138.9 (s, 1F), 151.2 (t, J = 21.3 Hz, 1F), 158.8 (m, 2F). ESI-MS m/z(%): 972
3.1.2.6. 4cb trans-2-(4-fluorophenyl)-5-benzyl-C60-pyrrolidine. IR (KBr pellet): 2914, 2847, 1654, 1523, 1502, 1400, 1131, 1047, 574, 527 cm 1. 1H NMR (CS2/CDCl3) d: 7.80– 7.76 (m, 2H), 7.53–7.50 (m, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.29–7.25 (m, 1H), 7.00 (t, J = 8.4 Hz, 2H), 5.63 (s, 1H), 4.97 (dd, J = 10.8 Hz, J = 2.4 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.46 (1H, t, J = 12.0 Hz). 19F NMR (CS2/CDCl3) d: 111.2 (s, 1F). ESI-MS m/z (%): 948 (M+ + 1, 16), 720 (C60+, 100). Anal. Calcd. for C75H14FN: C, 95.02; H, 1.49; N, 1.48. Found: C, 94.79; H, 1.51; N, 1.36%.
Acknowledgement The authors thank the National Natural Science Foundation of China (NNSFC) (No. 20372077) and Innovation Foundation of Chinese Academy of Sciences for financial support.
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