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Tetrahedron xxx (2013) 1e5

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Tetrahedron
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Brønsted acid catalyzed azlactone ring opening by nucleophiles
Adriane A. Pereira a, Pedro P. de Castro a, Amanda C. de Mello a, Bruno R.V. Ferreira b, Marcos N. Eberlin b, *, Giovanni W. Amarante a, *
a b

Department of Chemistry, Federal University of Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil Institute of Chemistry, ThoMSon Mass Spectrometry Laboratory, University of CampinasdUNICAMP, Campinas, SP, Brazil

a r t i c l e i n f o
Article history: Received 18 October 2013 Received in revised form 5 November 2013 Accepted 13 November 2013 Available online xxx Keywords: Azlactones Alcohols Amines ESI(þ)-MS/MS Organocatalysis Brønsted acid

a b s t r a c t
Brønsted acid catalyzed azlactone ring opening in the presence of different nucleophiles leading to the efficient synthesis of protected amides and amino esters is presented. Sixteen compounds were synthesized in good to excellent isolated yields. Mechanism investigation by using ESI(þ)-MS/MS revealed that the CSA catalyst promotes azlactone activation for electrophilic attack facilitating therefore the attack of the nucleophile that leads to ring opening and protonation. Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction Over the past years a major area in organic chemistry has been the development of efficient catalytic reactions able to form biologically functional amino acids and small peptides.1 For such goal, azlactones have been attractive since they may serve as protected amino acids, which can be used in the synthesis of natural or synthetic bioactive molecules.2 Our research group has explored the potential of azlactones as pro-nucleophiles in the presence of Michael acceptors by using an organocatalytic approach.3 The multi-functional heterocyclic azlactone structure, however, confers to such molecules a diverse chemistry reacting as electrophiles via two distinct sites (Fig. 1). This structural versatility is very important since it could be applied in peptide-type synthesis. But

Electrophile sites
R1 O N O

azlactone can also suffer nucleophile attack, as shown for instance by Wang and co-workers, who described a Brønsted acid functioning as a catalyst for the asymmetric dynamic kinetic resolution following by opening of azlactone rings in the presence of a nucleophile. However, only a few azlactone rings and a particular alcohol were well tolerated in their optimized reaction condition.4 Recently, Connon and Palacio showed that cinchona derivatives are suitable organocatalysts for the highly enantioselective dynamic kinetic resolution of azlactones by thiolysis. Moderate to high levels of enantioselectivity were achieved by using this catalytic system.5 We envisioned therefore that the use of Brønsted acid catalysis could be an attractive, metal-free strategy to activate azlactones toward nucleophile attack, and that this reaction could also be useful to prepare protected amino acid derivatives. In this communication, we show that indeed (þ/À)-camphorsulfonic acid (CSA) functions as an effective Brønsted acid catalyst for the azlactone ring via nucleophile attack. 2. Results and discussion Our studies initiated by reacting azlactone6 2 and octanol in the presence of 10 mol % of CSA as catalyst. To our delight, the desired product 6 was isolated in 88% yield (Scheme 1). After optimization of the reaction conditions, we found that replacing octanol with DCM as solvent provided the best reaction conditions. We also note that no reaction was observed in the absence of the CSA catalyst.

pro-nucleophile
R

Fig. 1. General structure of azlactones.

* Corresponding authors. E-mail addresses: eberlin@iqm.unicamp.br (M.N. Eberlin), giovanni.amarante@ufjf.edu.br (G.W. Amarante). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.11.037

Please cite this article in press as: Pereira, A. A.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.11.037

(A) ESI(þ)-MS of the azlactone 2 and CD3OD reaction solution in the presence of CSA as catalyst.1016/j. Conclusion Efficient Brønsted acid catalyzed azlactone ring opening via electrophilic attack in the presence of different nucleophiles has been presented. D2O was used as the nucleophile. after 5 min of reaction. Although no diastereoselectivity was observed. [2þCSAþH]þ was also intercepted. 2. 2B). respectively (Fig. 2C). 24 h O H3C(H2C)7X R H N O 1R=H 2 R = Me 3 R = iPr 4 R = iBu 5 R = Bn 6 R = Me.2 mmol of azlactone. To this end. Fig. / Tetrahedron xxx (2013) 1e5 O R N O Ph CH3(CH2)7XH 10 mol% CSA CH2Cl2. which were attributed to 23. As before. following by nucleophilic attack. X = O (78%) An ion of m/z 211 corresponding to the final product 22 [22þH]þ (Fig. which suggested that de-protonation. 0.. the last reaction step. 0. and 25. another key species of m/z 408 corresponding to the association of the azlactone and the catalyst. A secondary alcohol also worked quite well and even a tertiary alcohol was well tolerated. X = NH (55%) 12 R = iBu. Reactions were carried out using 0. and 105. A. Different lipophilic alcohols and amines could also be used in this reaction condition with medium to high yields (Schemes 1 and 2). (B) ESI(þ)MS/MS of the ion of m/z 211. suggesting that CSA is responsible for the protonation and de-protonation step.A.02 mmol of CSA (10 mol %). 1). sugar-based derivatives were also found to provide the acyclic products in high yields. In addition. X= NH (64%) 13 R = Bn. The transfer of charged reaction intermediates directly from reaction solutions to the gas phase by electrospray ionization (ESI) followed by (tandem) mass spectrometry characterization ESI(þ)-MS/MS7 was therefore used in an attempt to intercept potential intermediates involved in the catalytic cycle. Mechanism investigation via ESI(þ)-MS/MS revealed azlactone activation by the catalyst CSA to form an ion pairing intermediate. The reaction was also found to tolerate different azlactones (1e5). Several amines and alcohols can be applied in this reaction condition. and 0.doi. diluted in acetonitrile. The development of O Me N 2 O Ph CD3OD or D2O 10 mol % CSA CH2Cl2 O RO (D) no deuterium H incorporated N Ph Eq. X = O (74%) 10 R = Me. First. Opening of azlactone ring by others nucleophiles. 24 h O Nu O O H N Me O OH O O O Nu: 15 HOCH2(CH2)6CH2OH (75%) 16 C6H5NH2 (43%) 17 (CH3)2CHOH (78%) 18 t-BuOH (57%) 19 O NH2 O O O O (72%) 21 (79%) OH (91%) Scheme 2. No H/D exchange for these two ions was noted. 148. m/z = 195 ð1Þ Please cite this article in press as: Pereira. 22. A. In the second experiment. X = O (82%) 8 R = iBu. the sterically bulky azlactone 3 provided the desired product 7 in 82% yield. providing protected amino esters and amides derivatives in good to excellent yields. We then turned our attention to understanding the basics of this reaction by investigating its mechanism. 1 Me O R = -CD3.11. Its collision-induced dissociation (CID) showed fragment ions of m/z 176. No H/D exchange occurs when D2O is used with no deuterium incorporation in the final product. and directly analyzed by ESI(þ)-MS (Eq.tet.2 M in azlactone).037 . 1).2 M in azlactone).02 mmol of CSA (10 mol %). X = O (88%) 7 R = iPr.2 mmol of azlactone. the two ions [2þCSAþH]þ of m/z 408 and [26þH]þ of m/z 195 were intercepted (Eq. Reactions were carried out using 0. which facilitates nucleophilic attack at the carbonyl carbon and then the final CSA protonation (Scheme 3). 2A) was intercepted. The mechanism seems therefore to proceed through azlactone activation via N-protonation and CSA binding at the NHþ center (ion pairing). for example. Pereira et al. Scheme 1.21 mmol of nucleophile (0.21 mmol of nucleophile (0. Tetrahedron (2013). 3. which fully agrees with the proposed H-bonded proton dimmer structure in which protonation of 2 occurs at the most basic ring nitrogen. O Me N O Ph 20 Nucleophile (Nu). m/z = 211 R = -D . two experiments were carried out.2013. 26. X = NH (93%) 11 R = iPr. et al. is also promoted by the catalyst. giving the desired product 13 in 57% isolated yield. X = O (59%) 9 R = Bn. and 0. (C) ESI(þ)-MS/MS of the ion of m/z 408. Opening of the azlactone ring by lipophilic alcohols and amines. X = NH (96%) 14 R = H. 24..org/10. 10 mol % CSA CH2Cl2. that is. an aliquot was taken from the crude mixture of azlactone 2 and CD3OD in the presence of 10 mol % of CSA. http://dx.2 A. Its ESI(þ)-MS/MS showed as the unique fragment an ion of m/z 176 due to the neutral loss of CSA (Fig.

86 (m.7. J¼7. 1H. 2H.7.53e7. HRMS: calcd for [C21H33NO3]þ ([MþH]þ): m/z 348. CDCl3) d (ppm): 173.78 (qu. 4. 25. / Tetrahedron xxx (2013) 1e5 3 O R R 1 O N H Ph X O (+/-)-CSA O Ph N R O O O S O R2 R1 H X R N H O Ph O Ph O mixture was then diluted in CH2Cl2 (10 mL) and washed with saturated solution of sodium bicarbonate (5 mL). 131.9. 74%).A.5.32e3. 29. quintet. Analytical thin layer chromatography (TLC) was performed on Merck precoated glass-backed TLC plates (silica gel 60 F254) and visualized by UV lamp (254 nm).2. J¼6.60 (qu. 2856. Pereira et al. 30. 4. et al. 3H).10e3.42 (m. 128.1. 2958.5. 4H).35 (m.2. 2H). 67.1. 1H. 1.7 Hz. 3H). J¼7.80e7. d. 128.42e7. 38. 7.3. 3.7.78 (d. found 306. 7. 1. 1H. UK) QTof instrument of ESIQTof configuration with 5000 mass resolution and 50 ppm mass accuracy in the TOF mass analyzer.8 Hz). 30. The following typical operating conditions were used: 3 kV capillary voltage.6 Hz).91e0. IR (KBr. 18. 7. 38. 134.2.037 .5.19 (m. J¼7. 13C NMR (75 MHz. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 9 (84 mg. 1633. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 10 (219 mg.51e7. 3.88 (d. J¼6. 23.5 Hz). 2927. 10H). 93%). 167. CDCl3) d (ppm): 7. J¼6. 1. and J.80 (dd.0. CDCl3) d (ppm): 7. 2H).3. Octyl 2-(benzamido)-4-methylpentanoate (8). 1534.61 (m. J¼4.0 Hz). 11. 1741.41(m.32 (m. http://dx. 128. 1. 2873. 13C NMR (75 MHz. Unless otherwise noted.0.4. Octyl 2-(benzamido)-3-phenylpropanoate (9). 4.0. 0.4. 4. 1191. 0. coupling constant in hertz (Hz).2 mmol of azlactone was added. all reagents were obtained commercially and used without further purification.79 (m.68 (d.9.2.28e1. HRMS: calcd for [C20H31NO3]þ ([MþH]þ): m/z 334.7. The purified products were then fully characterized by the conventional elemental analysis. 29. 8H). 2876.51e1. quartet. 1644.2285. 1H.9 Hz). 2960.13 (m.0.68 (d. 57. 38.doi.9.84 (m. 1210. 67. 4.0. unless stated otherwise.org/10. 22. 1737.80 (m.2 M in azlactone. 134. A. Mass-selection was performed by Q1 using a unitary m/z window. 1529.26 ppm) and 13C NMR spectra were referenced to CDCl3 (77. 39.85 (qu. CDCl3) d (ppm): 172. Octyl 2-(benzamido)-3-methylbutanoate (7). 4. 14. 4. 29. 134. 2H).88 (m. 2927.3. 5H). Tetrahedron (2013).5 Hz).3. found 348.9. 2H). 68.0.43e1.11. 131.8. found 334. To this solution. 1H and 13C spectra were recorded on a Bruker DPX-300 spectrometer. 3H). all reaction mixtures were carried out in flame-dried glassware under a positive pressure of dry nitrogen. 7.97e0. 4. J¼7. 11.16e4. All 13C spectra were measured with complete proton decoupling.1. 38. 1534. J¼8.2.8.54e7.5.3. J¼8.2539. 14. 1H NMR spectra were referenced to CDCl3 (7. J¼6. CDCl3) d (ppm): 173.6. 22.01 (m. 30.59 (d. 2. 6. 127. 29. 22. qu.9.02 (m.2.38e1. J¼7. 4. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 7 (62 mg. 127.9. Characterization data 4.76 (m. 4.23 ppm).2069. 1H NMR (300 MHz.48e7. 13C NMR (75 MHz.1.1.9. Experimental section 4. and collisions were performed in the rf-only hexapole collision cell.0. 2925.2. 1H NMR (300 MHz. 13C NMR (75 MHz.5. 19. singlet.03 (m. 128. Peak multiplicities are designated by the following abbreviations: s. the crude reaction mixture was purified through silica gel chromatography by using ethyl acetate/hexanes as solvents (up to 25% ethyl acetate/hexanes).9. 127.78 (m.9.29 (m. 23. 0. 1. 167.2. 1.2 Hz). CDCl3) d (ppm): 7. 59%). 3H).1.2. 1H).2. Yields refer to chromatographically purified and spectroscopically pure compounds.5 Hz). 2867.2. IR (KBr. 2858.24 (m. 68. t. The reaction Please cite this article in press as: Pereira. 134.7. 4.3. 167.02e0.7. 2852.3. double doublet. IR (KBr.2382. 5H). 23.5. 2951.24 (m.99 (m.5.9. 1H.4.10 (m. 13C NMR (75 MHz. CDCl3) d (ppm): 7. 129. 11H)..0. 29. 82%). 88%).23 (m. IR (KBr.21 mmol of nucleophile. 2927.2 Hz). 4. 1740. 14. 23. 1. 9H). 2H. cmÀ1): 3321. IR (KBr. 1H. 4.0. 1170.82e7.14e4. 1H). cmÀ1): 3303. 1657. 1H. 134.97 (m.1016/j.23e3. dd. 1.43 (m.1. Chemical shifts are reported in parts per million (ppm). 4. 24. N R O H O S R2 O O Ph R2 = O O XHR1 R1-XH N R O H O S R2 O Scheme 3.1. 48.8. an enantioselective version is ongoing and will be reported in due course. 14. 23. 136.2. 51.17 (m.1.4. 6. 53.5. After. General remarks Unless otherwise noted. 6H). After. 2H).49e1. HRMS: calcd for [C24H31NO3]þ ([MþH]þ): m/z 382. 0. J¼8. CH2Cl2 was cannulated at the concentration of 0. 11. 3071. 2960. 2961. 131. found 382. CDCl3) d (ppm): 172.9.23e1. m. 12H).5.03e3. 1526. 27. 131.1. N-(1-(Octylcarbamoyl)ethyl)benzamide (10).2.64e7. 1H).34e2. cmÀ1): 3330. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 6 (123 mg.23 (m. Tandem ESI-MS/MS were collected after 4e32 eV collision-induced dissociation (CID) of massselected ions with argon.9. doublet. 7.81e0.77 (d. 2H). 4. 1. 9H).2433. 128. 3H. cmÀ1): 3278. 131. HRMS: calcd for [C18H27NO3]þ ([MþH]þ): m/z 306.87e4.2.5.82 (d. 1H.2. General procedure for the catalytic azlactone ring opening in the presence of nucleophiles In a flamed screw cap vial and under nitrogen atmosphere. 30.5.75e1. 31. 23. multiplet. followed by mass analysis of product ions by the high-resolution orthogonal reflectron TOF analyzer.1.2. 7.0. 1. 23.2075.86 (m.2013. CDCl3) d (ppm): 172. 2H).A. 167.tet.5. 0.0.. 32. 49. 1H NMR (300 MHz.9. 1H). 6. 6. 1642. 1H. 5. The reaction mixture was kept at room temperature and under nitrogen atmosphere for 24 h. 29.7.9.7. CDCl3) d (ppm): 7.3. 1162.2382. 11. 5H).8. 0.62e1.7 Hz). 2873.7. Mechanism hypothesis for the azlactone activation following by nucleophilic attack. 166. 1H NMR (300 MHz.56 (m. broad. triplet.2725.82 (t. 11H). The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 8 (142 mg. High-resolution mass spectra as well as mechanism investigation were acquired in the positive ion mode using a mass spectrometer Micromass (Manchester. 2H). A. 127. 1546. 1647.9 Hz). 2930. 42. 2858.0. Octyl 2-(benzamido)propanoate (6). 4H). 1 H NMR (300 MHz. 1644.03e4.2. 7. 1749. br.0.0 mol %) of (þ/À)-camphorsulfonic acid was added followed by 0. 127. 2H). 38. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. q.22e7. and desolvation gas temperature of 100  C.4 Hz). 18. cmÀ1): 3313.1. 8 V cone voltage.3.02 mmol (10.39 (m.3.4.

79%).8.2224.2699.17 (m. 1H. 0.2 Hz).5.5. J¼8.A.7 Hz).8.18 (m. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 17 (158 mg.4. 2H.79e7. 65.0.2. 48. 1.2229.1. cmÀ1): 3301.08 (m. 4H). 8H). 31.4. 2958.4. 7. 1H NMR (300 MHz. 1H.3. 23.2569. found 515. 32.76 (qu. 7.8.3.6. 11H).9.30e4. 1.5.81 (m. 29.38. 0. 13C NMR (75 MHz. http://dx.74 (d. HRMS: calcd for [C13H17NO3]þ ([MþH]þ): m/z 236. 3.4. 172.30 (m. J¼6. J¼8. 109. 25.2. 1H). 31.06 (q. 168. 68. J¼7. 131. 43%). found 305. 4. 5. 70. 4.28e7.1. CDCl3) d (ppm. 55%).6 Hz). CDCl3) d (ppm): 7. 4. CDCl3) d (ppm): 173. 3H).85 (t. 134.6. 2H). 7.1310. 1.62 (qu.5.2. 1096. 1H. 1.33 (m.43e7. 71. 127. 18.53e7.3.34 (m. J¼8. 1H.7.. 7. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 13 (218 mg.2542.36e1. 4. 127.3. H1. 1H. CDCl3) d (ppm.37e4. 110. N-(1-(Octylcarbamoyl)-3-methylbutyl)benzamide (12).4.11. 29.92 (m. 2927. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 19 (81.2.3. N-(1-(Octylcarbamoyl)-2-methylpropyl)benzamide (11).6.22 (m.43 (d.1496. 1.42 (m. 1642. 4. found 236.4 0 -Di-O-isopropilidene. 9H).8. mixture of diastereomers): 172.org/10.2 Hz).7. CDCl3) d (ppm): 172.5. 27. cmÀ1): 3360. 1H.4 Hz).73 (m. 129. 1H). 3H. 2936. 13C NMR (75 MHz. 29.28. 1H NMR (300 MHz.26 (m. 1H. 3253.7. J¼2. CDCl3) d (ppm): 7. 95. 61.85. N-((1-(60 -Deoxy-1 0.77e7. 40. 3H. 134.2542.1. cmÀ1): 3306. 3H). 1. J¼7.6 Hz). 1H.5 Hz). 78%).1. J¼7..9 Hz).48 (d. 3134.99 (m. HRMS: calcd for [C21H34N2O2]þ ([MþH]þ): m/z 347. IR (KBr.6 Hz). 2853. et al.9.30e1. 2H).3. 3H).8. 3H).2070.47e7.4.0.8.63 (qu. 19. 127. 22. HRMS: calcd for [C22H29NO8]þ ([MþH]þ): m/z 436.9. 6H.46e7. 131.6. cmÀ1): 3333. 14. cmÀ1): 3335.6. 34. 1.14 (m.5.3.3.67. 2853.14.doi. 128.2 Hz). 13C NMR (75 MHz.2.0 (qu. 2924. 1523.45 (d.4. 3H). found 269. 2853. 134. 14.24 (m. CDCl3) d (ppm): 172.3. CDCl3) d (ppm): 7.87 (t. 166. 31.51 (m.38 (m. 29. 3. 2873.7. 4. 2.82e3. 1H. N-(1-(Octylcarbamoyl)-2-phenylethyl)benzamide (13). 1H NMR (300 MHz. 4. 64%).15.2 Hz). 3.a .76 (m. 1H. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 11 (40. 2H). The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 12 (153 mg. 128. 4.1.D -galactopyrane-6 0 -yl-2(benzamido)propanoate (20).5 Hz). 14. 22.1. 1H.4. 1H).9. 14. 1. 48. mixture of diastereomers): 7. 1174.48e5. 7.99e6. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 14 (284 mg.2 Hz). 4.33.4. 6.3. found 436. 131.4.06 (d. 131. 167. 8-Hydroxyoctyl 2-(benzamido)propanoate (15). 0. 50. CDCl3) d (ppm): 7. 128.6. 1750. 2856.4 A. 127. 2933.1985. 4. 131.23 (m.57e1. IR (KBr. 8H). 10H). IR (KBr.2 Hz). 18. 1666.2 Hz).6.30 (m.43 (m. 24.21e7.23e3. 22.1. 23H). 4.9.55. 29. 28.5. 131.10.46 (qu. 13C NMR (75 MHz. 167. 127. 4. 7. 78%). 22. 13C NMR (75 MHz. Isopropyl 2-(benzamido)propanoate (17). 29. 4.tet.15 (d.8.1.23e2. 131. 7. 5.1978. 1H). 5.25e1.8. HRMS: calcd for [C28H38N2O7]þ ([MþH]þ): m/z 515.3. 29. 4.8.76e7. 1H. 71.0. found 292.4 Hz).77 (m.3. 3.2974. tert-Butyl 2-(benzamido)propanoate (18).30 (m.6.8. 34. 3.75 (m. 2H). 4. 1650.2. J¼7. 1H).2 Hz). J¼6.46e1.51 (m.8. 128. 1H). 127.5 Hz).38e3. 66. 13 C NMR (75 MHz. 1. 24. 18. 1072. J¼6. 7.3 Hz). 127. 28. CDCl3) d (ppm): 7.9.19 (t.7. J¼5.3.6. CDCl3) d (ppm): 7.50 (m. J¼6. 3.4. 1H). 1525.7. 38. 4H).2. cmÀ1): 3318.3. 49.56 (m. HRMS: calcd for [C24H32N2O2]þ ([MþH]þ): m/z 381.1 Hz).6.6 Hz). 131. J¼6. 3H). 1630. J¼7.7. 1H).11. 1 0.06 (dd. 64.5.9.8 Hz). 4. 120. 134. 2960. Octyl 2-(benzamido)acetate (14). 1645. 2H).44e7.2 Hz). 2927.7.28e1.44 (m.4. 1H.2. A.6.1. 131.83e7.50e1.64 (m.12. HRMS: calcd for [C16H16N2O2]þ ([MþH]þ): m/z 269.48e7.1. 96. 1H). 1H). 1H).8.2. found 322.21 (m. 4. found 381. J¼6. J¼7. CDCl3) d (ppm): 171. 4. 1021. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 16 (130 mg.98. 70. 1H. 3196.5. 12H).17 (d.59 (t. 7. 1.2655. 134. 23. 29. 128. HRMS: calcd for [C17H25NO3]þ ([MþH]þ): m/z 292. 2H.65 (d. HRMS: calcd for [C18H28N2O2]þ ([MþH]þ): m/z 305. 2H.8 Hz). 65.6 mg. 55.50 (t.9.5. 13C NMR (75 MHz.13.8.1.9.7. 166. 96%). 52. 172.14 (t. 1. 108. 1648. J¼7.2.9. J¼7. found 347. 3301.9 Hz). 24.3 mg. J¼8.16e3.8. 12H).5 Hz). 29. 2957.2. J¼4. 2H.2758. 3.68 (d. 96.1. IR (KBr.20 (m. J¼7. IR (KBr. 128. 6.4 mg. 1H). 110.45. 4.12 (m. 127.74 (qu. 24.1. 1635.9. 1647.6 Hz). 13C NMR (75 MHz. 133. 12H). 134. 1260. 29.0.82 (m.8 Hz).3. 1H NMR (300 MHz.4. 0.03e6. HRMS: calcd for [C14H19NO3]þ ([MþH]þ): m/z 250.16. 133.00e3. 1H.1 Hz). 6.4 Hz). 3H. CDCl3) d (ppm): 9.8.11e7. 24.3 Hz). A.4 Hz).5 Hz.73 (qu. 124.93 (m. The product was purified by column chromatography on silica gel Please cite this article in press as: Pereira. 72%). 21.04 (m.3.7.3.80e7.17 (d. 2963. 19. 7. H1. 166.81 (q.8.5. 128. CDCl3) d (ppm): 172. 3244. 1H NMR (300 MHz.7. 59.45e7.60e1. CDCl3) d (ppm. 1723. 1.2.50e7.7. 2930. 5H).62 (m. 4. 1635.06 (m. 39. CDCl3) d (ppm): 7.9. 2H. 7. 7. 25. 1H). 3.3 Hz). 6. 13C NMR (75 MHz. / Tetrahedron xxx (2013) 1e5 18. 127. 62. 1H. 2H). CDCl3) d (ppm. 126. CDCl3) d (ppm): 171. J¼5. 3071. 7.4 0 -di-O-cyclohexylidene.6.48 (d.7. 128.0. 1747.8. 23. 11. 6H). 66. H10. 1H.8.1016/j. 3H. IR (KBr. 4. 3H). 133. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 15 (96. 1.3 Hz).44e1. 1540. 27.49e7. 34. J¼7. 127.37e1. 25. 3. 5. 48. 1635. 30. 5.5. 108. 6H). 109. 4.4.3. 131.2. 1543. J¼7.2653.1.5.4.60e4.2. 18.3.3. 4. 2984. HRMS: calcd for [C20H32N2O2]þ ([MþH]þ): m/z 333. 4H). 134. found 250.79e7. cmÀ1): 3425. 2859.7. 1H NMR (300 MHz. HRMS: calcd for [C18H27NO4]þ ([MþH]þ): m/z 322. IR (KBr.78e6.29e2. 167. 0. 1H NMR (300 MHz. 1.a.8.48 (m. IR (KBr. cmÀ1): 3286. 1H.0. 109. J¼7.1287. 4.1. J¼6. Tetrahedron (2013).82 (m.3. cmÀ1): 3330. 39.49 (qu. 18.98 (m.34 (m. 18. 2H. 2H).33 (m. 7. The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 20 (298 mg.2 Hz). 32.01 (qu.12 (m. 167. 1537. 1744. 167. 18.6.76 (m.0. 2987.8. 1H).1. 7.25e1. 27. 2984. 4. 1 H NMR (300 MHz.1913.2 0 :3 0 . 1540. N-(1-(Phenylcarbamoyl)ethyl)benzamide (16).6.09 (m.0. Pereira et al. 25.3. Adamantan-1-yl-methyl-2-(benzamido)propanoate (21). 70. 70. CDCl3) d (ppm): 171.2 0 :3 0 .32 (m.9. 29.84 (t. 3H). NMR 13C (75 MHz.1971. 1657.1. H10 ). 2.9. 82.9. J¼8.0.5.2 Hz). found 333.81 (t. 49.2.90e 0. J¼6. 29. 1H).0.6. 68.0.56e4.4. 41.1. CDCl3) d (ppm): 170. 1630. 2H. 28. J¼4.26 (m.D -galactopyrane-60 -yl)carbamoyl)ethyl)benzamide (19).77e3.8. mixture of diastereomers): 7. 70. 25. cmÀ1): 3304.2013.16. IR (KBr.66 (qu. 75%).9.9.21 (m. 40.46e7. 7.6.3. 129. 39.19 (m.94 (d.35 (m.78 (d. J¼7. 137. 23. 1H).99 (d. 1. 22.8.1443. 25. 41. 1H).9. 1. 69. 3064. 2936. J¼7.4. 3H.5. 127.0. 1H).3.037 . 1.7.6. 133.87 (d. 7.4. 57%). The product was purified by column chromatography on silica gel (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 18 (203 mg. 4. 9H).20 (s. 1. mixture of diastereomers): 172. 167. 10H). 1H. J¼6.37e1. 6H).8.8. 3H. IR (KBr.1290.85e7.1361. 1544. 138.53e7.57e1. J¼7. 2930. 35. J¼4.22e1. 128.8.31e3.9. J¼7.32 (m.13. 2855. 2955. 48. 7. 14. 3H. 1H. 5.8.74 (m. 70.39 (s. 71. 1H NMR (300 MHz. 39. J¼6. NMR 1H (300 MHz. 66. 7.39 (m. 1H.3.32e3. 2H. 166. 3H).3.23 (m. 132. 7. 7. 2H).98 (d. 1734.1. 1.9.3.5.88. 2H).1.0. 3H).2. 3.1 Hz).2018. 4.5.5. J¼6. 1H.3.

de Almeida (DQ-UFJF) for helpful suggestions.5 Hz). (b) Weber. 2011. Synlett 2011. P.. (f) Amarante. .037 .. Chem. (c) Weber. A. Soc. 131. 3167. 4584. Luparia. H. N. H. (b) Coelho. 37. A. S. G. 2009. 3H).8..0. 6. 18. 105. Chem. D. F. J.. Sorimachi. 2. 1. G.. 16. 10. H. Chem. C. 2007. Tetrahedron Lett. Milagre.037. For the preparation of azlactone rings. Lee.. Coelho. M.. Org.. 129. D. A. see: Melhado. Pascoal. L. Rev.doi.. Acknowledgements We are grateful to FAPEMIG. Quim.5.47 (m. Gong. dEur. N. 1H.. 50. see: (a) Uraguchi. R. S.80 (d. Z.-S. N. Maseras.dEur. IR (KBr. Int. A. M. W. CDCl3) d (ppm): 7. T.-Z. 3. 2009... Paixa Monge. Amarante. N. E. M. W. De Mello. 14H).. Eberlin. D. 2013.1. J. Esteves. M. N. Am.. C.2069. H. Org. W. (k) Alba. C... A. B. 9884. E. García.-Z. (e) Orth. J. 1743. J. Chem. G. Milagre. Chem. G. 120. 2009.. (m) Terada. J. Org... da Silva. Y. R. Birman.. H. M. J¼7. W.01e1.3. Antunes. 52. R. (a) Avila..... F. 5. M. Lin. N.5. Molecules 2009.. 10846. 13C NMR (75 MHz.2013. Sabino.77 (m. Chem. Chem. Chen. F. 1H. K. J. B. D. J. E. Lett.. Nova 2009. 1713.. Moyano. The authors thank Prof.org/10. J. Garden. 3430.25e1.2 Hz). C. J. Mello. A. 3031. 13. Ed. F.. Chem. Rios. R..com. K.. E. 32. H. (a) Na dilla. R.. L...9. Luparia. 7. Pereira et al. R.sciencedirect. 66. 3517. Eur. A. Ueki.73e1.org/10. R. 5398. 2010. Santos. M. J. 5963. A.A. 2011. 2012. 1635.. Wang. J. 28. A. (n) Uraguchi. W.. Wang. Diniz. M... W.. 74. CNPq (305489/2012-7). Chem. G.. Soc. Braga... (h) Carrasco-Sanchez. CDCl3) d (ppm): 173. F. S. Chem. F. A. 2906. Gao. Liu.. F. Y.. For our recent view about organocatalytic processes. 2. S. 3H). W. A. A.. Luo. 4. Chem. Am.50e7. H. Correia.-Y. P. 1881. 2010.. CAPES.. R.dEur. De la Pra1. V.. R. Chem. 1308. Sugiyama.1016/j. L. T. M. Coelho. H. Calbet.. Org. H. Lee. S. 2H). L. C.. C. Bunton.. Feng. S. 469. 6.. Eberlin.tet. 2013.11. S. Eur.. S.8. Chem. 12460. J. M. S. 128.2013.  W. Chem. 2005. J. Peters. Milagre.. 2007. 4370. Frey. S. 5354. D. Eberlin. 3. L. Toste. 77. Chem.. 14. (b) Viso. at http://dx.. Org. / Tetrahedron xxx (2013) 1e5 5 (elution: hexanes to hexanes/ethyl acetate 25%) to afford product 21 (90 mg. 39. Flores. 127. M. 2009. found 342. 18. Milagre.2 Hz). M. Coelho. G.. Org.. Simirgiotis. J.. J.. Nome. (i) Dong. (f) Lu. Tetrahedron 2010. and Rede Mineira de Química for financial support. M. H.dEur. http://dx. J¼7. A. J. Eberlin.. Xiao. F. O. Song. C. Org. 133. A. Soc. D... A. Sci. 5011. 1H NMR (300 MHz. ~o. 7. J. M. R. Jautze. Am. References and notes jera. Valero. Please cite this article in press as: Pereira.. 107. 2847. V. Rios. F. C. Supplementary data Copies of IR and NMR spectra for the prepared compounds are available free of charge at www. Catal. B.. 15. P. 10650. H.dEur. S. Benassi. X. J.. 74.-N.. cmÀ1): 3351. J..-F. Ooi. 2010. Tetrahedron (2013). 3989. Eberlin.  3. L. (d) Amarante.96 (m. J... A. G. Wang. N. Mei. Biomol. 326. 132.37 (m.. 1H.tet. N... B. 16. A.80e7.7. (j) Jiang. F. Ooi. Milagre. Chem. G. M. 2012. J¼10. (d) Weber.69 (d. V.. 11. L.... J. A. R. 75. 2013. 1052. Peters. (c) Avila. 48.. 5261.. (a) Machado. 132.-N. 131. 167.2. M. 12638. C. W. Chem. M. 2011. Tanaka. R. 91%). da Penha. J. Chem. Mauro V.2091. (h) Melhado. 3277. G. T.. G. Zhang. J. For azlactones as substrates in catalytic reactions.80 (qu. J¼7. M. 1. G.doi. 2011.. Science 2009. Amarante. Am.11. F. X. Guo. Coelho. Y. O.1. Jørgensen.95 (d... Frey..17 (m. 354. P. Valero. Benassi. 2013. 33. 134.0. 2009. Ueki. A. 2012.-S. Supplementary data associated with this article can be found in the online version. see: (b) Amarante. (c) Amarante. Vaz. 2010. et al. H. (l) Companyo Alba. Gong..1016/j. Am.. Soc. 2775.. H. HRMS: calcd for [C21H27NO3]þ ([MþH]þ): m/z 342.. T.. M. Eberlin. Chem. Moyano. M.2.A. R. E. M. Org. A.. 4. Toste. 9799. S.. Sansano. Synth.. 1443.. 1H. Chem. Font-Bardía.. Fiedler. 4. Peters. F.. S.-W. X. M. P. Angew.. T. Adv. (g) Han. M. Eberlin. 992. Ryu. Rev. M. X. Chem.. ChemCatChem 2012. Ferreira. A. (e) Oh. Soc. D.. A. W. 4. Amarante. Biomol. M.2 Hz). 15. 2012. R. R. Connon. 14792. Eberlin.. 356. M. Z. D. D. Chen. 1H). D. Palacio. 1168.-W. (g) de Souza..