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Fast diastereoselective Baylis–Hillman reaction by nitroalkenes: synthesis of di- and triene derivatives
Tetrahedron 60 (2004) 4995–4999
Fast diastereoselective Baylis – Hillman reaction by nitroalkenes: synthesis of di- and triene derivatives Roberto Ballini,* Luciano Barboni, Giovanna Bosica, Dennis Fiorini, Emanuela Mignini and Alessandro Palmieri Dipartimento di Scienze Chimiche, Universita` di Camerino, Via S. Agostino 1, I-62032 Camerino, Italy Received 3 March 2004; revised 8 April 2004; accepted 13 April 2004
Abstract—The Baylis – Hillman reaction is performed using nitroalkenes as activated alkenes, ethyl-2-bromomethylacrylate as electrophilic acceptor and DBU as catalyst base. Nitro dienes are obtained in good yields and very short reaction times. Moreover, starting from appropriate nitroalkenes it is possible to realize one pot the synthesis of trienic systems. q 2004 Elsevier Ltd. All rights reserved.
1. Introduction Among the various reactions leading to the formation of carbon – carbon bond, the Baylis – Hillman reaction is doubtless one of the most fascinating ones, due to the simplicity through which it is possible to obtain high densely functionalizated products starting from small molecules. The above reaction is a three component reaction resulting in the construction of a carbon –carbon bond between the a-position of an activated alkene and an electrophilic carbon under the influence of a catalyst (most commonly tertiary amines). A variety of activated alkenes have been used such as alkyl vinyl ketones, alkyl (aryl) acrylates, acrylonitrile, vinyl sulfones, acrylamides, allenic esters, vinyl sulfonates, vinyl phosphonates and acrolein.1,2 Aliphatic nitro compounds have proven to be valuable intermediates, and the chemical literature continuously reports progress in their utilization for the synthesis of a variety of targets. Moreover, these compounds are very powerful synthetic tools because they facilitate the carbon – carbon bond-forming processes.3 Surprisingly little attention has been given to conjugated nitroolefines as activated alkenes; anyhow there are two pioneering works of Ono et al. where nitroolefines are reacted with aldehydes or with a,b-unsaturated compounds,4,5 with the need of long reaction times. Following our studies in the chemistry of aliphatic nitro compounds we wish here to present an extension of these Keywords: Baylis–Hillman reaction; Michael reaction; Nitroalkenes; Nitro dienes; Allylic nitro compounds. * Corresponding author. Tel.: þ39-0737-402270; fax: þ39-0737-402297; e-mail address: [email protected] 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.04.030
forerunner works exploiting the reactivity of nitroolefines with a particular carbon electrophile specie, the allyl bromide 2, whose use has been little explored in the Baylis – Hillman reaction;6 moreover nothing has been done regarding the study of its behavior with nitroolefins.
Scheme 1. Table 1. Preparation of nitro dienes 3a–h Entry 1 2 3 4 5 6 7 8
1, 3
R1
R2
R3
Yield (%) of 3
1a, 3a 1b, 3b 1c, 3c 1d, 3d 1e, 3e 1f, 3f 1g, 3g 1h, 3h
Me Me Et Et Pr –(CH2)3 – MeOCCH2CH2 MeOOC(CH2)4
Me H H H H
Me Et Et n-Bu H H Et Et
63 82 80 77 80 82 84 94
H H
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2. Results and discussion Treatment of 1 equiv. of the nitroalkenes 1a – h with 1 equiv. of ethyl-2-bromomethylacrylate 2 (Scheme 1), in the presence of DBU (2 equiv.) in acetonitrile and at room temperature affords after 30 min the nitro dienic systems 3a – h in good yields (63 –94%, Table 1). The choice of DBU as base7 dramatically improves the efficiency of the method since the reaction can be performed under very short reaction times (30 min) respect to the pioneering work of Ono (24 – 72 h).5 It is noteworthy that a variety of nitroalkenes could be successfully employed, even those having other functionalities (entry 7, 8). A plausible mechanism for the formation of 3 is presented in the Scheme 2 (by analogy with Ref. 6). Both the nitroolefin 1 and the bromide 2 are nucleofilically attacked by DBU resulting in the zwitter ionic complexes 4 and 5; the complex 5 acts as an enolate specie giving the Michael attack to the complex 4 and leading to the dipolar product 6. Finally, 6 undergoes a base-assisted elimination of the conjugate acid of DBU giving diastereoselectively the nitro dienes 3 with E configuration, as evidenced by the H5 –H6 coupling constants (14 –16 Hz). The compounds 3 contain at least four different functionalities such as: (i) an ester moiety, (ii) an electron rich C – C double bond, (iii) an electron poor C –C double bond, and (iv) a nitro group, so that they can be submitted to several further transformations. Of great interest is the possibility to realize
Scheme 3.
the one-pot preparation of triene derivatives 7 by the appropriate choice of the starting nitroalkenes (Scheme 3). In fact we observed that if 1-alkyl-1-nitro-4-phenyl-1butenes 1i,j are employed, the Baylis –Hillman reaction could give, directly, the compounds 7i,j as diastereoisomeric mixtures (Scheme 3). As the 1H and 13C NMR spectra of the diastereomeric mixture 7j showed better separated sets of signals respect to the 7i spectra, they could be used for the determination of the configuration of the C4 –C5 and the C6 – C7 double bonds. The data showed that the major stereoisomer was, as expected, the 4E,6E. In particular, the E configuration of the C6 –C7 double bond could be established on the basis of the H6 –H7 coupling constant (15.6 Hz for both the diastereoisomers), whereas the C4 –C5 configuration was established on the basis of the C3 and C8 chemical shifts. In fact, both the C3 and C8 are deshielded when they are trans respect to
Scheme 2.
Figure 1.
R. Ballini et al. / Tetrahedron 60 (2004) 4995–4999
the stirene moiety, as indicated in Figure 1 and according to the data reported for similar compounds.8a,9 Moreover, the NOESY spectrum of the 7j mixture showed two remarkably different sets of NOE correlations for the two diastereoisomers. The cross peaks evidenced that for both the diastereoisomers the preferred conformation of the C5– C6 single bond was the s-trans. In particular, as depicted in Figure 1, the 4E isomer showed the H3 – H5 and the H6 – H8 NOE correlations, whereas the 4Z isomer exhibited the H3 – H6 and the H5 – H8 NOE correlations. Compounds 7 are very interesting materials from synthetic point of view because these molecules are recurring structural unit in natural targets of relevant interest and in molecules showing important pharmacological activities.8 In these cases the energetic gain due to the conjugation of the styrene moiety allows the final spontaneous elimination of nitrous acid leading to trienes 7i,j. The formation of 7i,j is strongly helped by heating at reflux and is accomplished in 8 h. Anyway the dienic products 3i,j could be still obtained and charaterized by stopping the reaction as soon as they were formed.
3. Conclusions We have reported a new application of the Baylis – Hillman reaction for the diastereoselective, fast, one-pot synthesis of di- and triene derivatives. This procedure works with different conjugated nitroalkenes and affords the title compounds in good yields.
4. Experimental 4.1. General 13
C and 1H NMR spectra were recorded in CDCl3 or in C6D6 at 200 MHz on a Varian Gemini instrument; the use of C6D6 was necessary in the cases in which using CDCl3 olefinic protons signals could not be separated; J values are given in Hz. IR spectra were recorded with a Perkin – Elmer 257 spectrophotometer. Mass spectra were determined on a capillary GC/MS operating in split mode with helium carrier gas and fitted with a mass selective detector (MSD). The nitroalkenes used were commercially available or prepared according to literature procedures.10 The reactions were monitored by TLC. Microanalysis were performed using a Fisons model EA 1108. All the products were purified by flash chromatography on Merck silica gel (cyclohexane/ ethyl acetate). 4.2. General procedure for the preparation of nitrodienes 3a– h The nitroalkene 1 (1 mmol) and the bromide 2 (193 mg, 138 ml, 1 mmol) are dissolved in MeCN (15 ml) and then DBU is added (304 mg, 299 ml, 2 mmol); the obtained solution is magnetically stirred at room temperature for 30 min, then is concentrated under reduced pressure and charged into a flash chromatographic column (cyclohexane/ ethyl acetate) giving the pure compound 3.
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4.2.1. Compound 3a. Oil. IR (neat) 1720, 1630, 1543 cm21; 1H NMR (CDCl3) d 1.30 (t, 3H, J¼7.3 Hz); 1.59 (s, 3H), 1.64 (s, 3H), 1.76 (s, 3H), 3.12 (d, 2H, J¼ 1.8 Hz), 4.21 (q, 2H, J¼7.3 Hz), 5.40 (bs, 1H), 5.57 (s, 1H), 6.28 (bs, 1H); 13C NMR (CDCl3) d 167.1, 139.5, 135.1, 129.9, 125.0, 91.1, 61.4, 41.8, 27.4, 24.2, 18.8, 14.3; EI MS 195, 179, 149, 121 (100%), 79. Anal. calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81. Found: C, 59.98; H, 7.77; N, 5.65. 4.2.2. Compound 3b. Oil. IR (neat) 1719, 1629, 1542 cm21; 1H NMR (C6D6) d 0.71 (t, 3H, J¼7.5 Hz); 0.88 (t, 3H, J¼7.1 Hz), 1.41 (s, 3H), 1.60– 1.76 (m, 2H), 2.90 (d, 1H, J¼13.7 Hz), 3.00 (d, 1H, J¼13.7 Hz), 3.88 (q, 2H, J¼7.1 Hz), 5.23 (d, 1H, J¼1.1 Hz), 5.38 (dt, 1H, J¼ 15.7, 6.2 Hz), 5.68 (dt, 1H, J¼15.7, 1.5 Hz); 13C NMR (CDCl3) d 166.9, 135.8, 135.1, 130.0, 128.4, 91.4, 61.3, 40.8, 25.5, 21.3, 14.3, 13.1; EI MS 195, 149, 121 (100%), 93, 79. Anal. calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81. Found: C, 60.01; H, 8.12; N, 5.68. 4.2.3. Compound 3c. Oil. IR (neat) 1716, 1630, 1538 cm21; H NMR (CDCl3) d 0.87 (t, 3H, J¼7.3 Hz); 1.00 (t, 3H, J¼7.3 Hz), 1.29 (t, 3H, J¼7.2 Hz), 1.81 –2.20 (m, 4H), 3.02 (dd, 1H, J¼14.3, 0.7 Hz), 3.16 (dd, 1H, J¼14.3, 0.7 Hz), 4.17 (q, 2H, J¼7.2 Hz), 5.53 (bs, 1H), 5.60– 5.82 (m, 2H), 6.26 (bs, 1H); 13C NMR (CDCl3) d 167.1, 135.7, 135.4, 129.2, 125.8, 95.3, 61.3, 38.8, 29.9, 25.8, 14.3, 13.2, 8.6; EI MS 209, 163, 135 (100%), 93, 79. Anal. calcd for C13H21NO4: C, 61.16; H, 8.29; N, 5.49. Found: C, 61.34; H, 8.11; N, 5.25.
1
4.2.4. Compound 3d. Oil. IR (neat) 1716, 1630, 1538 cm21; 1H NMR (CDCl3) d 0.88 (t, 3H, J¼7.3 Hz); 0.90 (t, 3H, J¼7.2 Hz), 1.30 (t, 3H, J¼7.2 Hz), 1.25 – 1.46 (m, 4H), 1.90– 2.22 (m, 4H), 3.04 (dd, 1H, J¼14.3, 0.7 Hz), 3.16 (dd, 1H, J¼14.3, 0.7 Hz), 4.19 (q, 2H, J¼7.2 Hz), 5.53 (bs, 1H), 5.65 (dt, 1H, J¼16.0, 6.0 Hz), 5.78 (d, 1H, J¼ 16.1 Hz), 6.24 (s, 1H); 13C NMR (CDCl3) d 167.1, 135.4, 134.5, 129.2, 126.6, 95.3, 61.3, 38.7, 32.5, 31.1, 29.9, 22.4, 14.3, 14.1, 8.6; EI MS 252, 237, 179, 123, 93, 79 (100%). Anal. calcd for C15H25NO4: C, 63.58; H, 8.89; N, 4.94. Found: C, 63.75; H, 8.74; N, 5.16. 4.2.5. Compound 3e. Oil. IR (neat) 1718, 1560, 1540 cm21; H NMR (CDCl3) d 0.91 (t, 3H, J¼7.1 Hz); 1.12 –1.46 (m, 2H), 1.29 (t, 3H, J¼7.0 Hz), 1.83– 2.15 (m, 2H), 3.04 (dd, 1H, J¼14.6, 0.7 Hz), 3.17 (dd, 1H, J¼14.6, 0.7 Hz), 4.19 (q, 2H, J¼7.0 Hz), 5.22 (d, 1H, J¼17.6 Hz), 5.35 (d, 1H, J¼ 11.3 Hz), 5.54 (d, 1H, J¼0.7 Hz), 6.19 (dd, 1H, J¼17.8, 11.2 Hz) 6.28 (d, 1H, J¼0.7 Hz); 13C NMR (CDCl3) d 166.9, 135.1, 135.0, 129.5, 117.6, 95.0, 61.3, 38.9, 38.8, 17.3, 14.3, 14.2; EI MS 195, 149, 121 (100%), 93, 79. Anal. calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81. Found: C, 59.89; H, 8.21; N, 5.65. 1
4.2.6. Compound 3f. Oil. IR (neat) 1716, 1633, 1538 cm21; H NMR (CDCl3) d 1.30 (t, 3H, J¼7.1 Hz); 1.46 –2.12 (m, 4H), 2.42 –2.55 (m, 1H), 3.00 (s, 2H), 4.21 (q, 2H, J¼ 7.0 Hz), 5.58 (bs, 1H), 5.91 (m, 1H), 6.06 (m, 1H), 6.31 (s, 1H); 13C NMR (CDCl3) d 166.8, 134.7, 134.2, 130.0, 125.5, 89.4, 61.4, 41.4, 31.4, 24.9, 19.0, 14.3; EI MS 193, 147, 119 (100%), 91, 79. Anal. calcd for C12H17NO4: C, 60.24; H, 7.16; N, 5.85. Found: C, 59.89; H, 6.97; N, 6.03.
1
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4.2.7. Compound 3g. Oil. IR (neat) 1717, 1628, 1539 cm21; 1H NMR (C6D6) d 0.72 (t, 3H, J¼7.2 Hz); 0.92 (t, 3H, J¼7.2 Hz), 1.50 (s, 3H), 1.64 –1.80 (m, 2H), 2.02– 2.16 (m, 2H), 2.22 –2.36 (m, 2H), 2.96 (d, 2H, J¼ 2.2 Hz), 3.88 (q, 2H, J¼7.2 Hz), 5.22 (bs, 1H), 5.35 (dt, 1H, J¼16.1, 6.0 Hz), 5.60 (dd, 1H, J¼16.1, 6.6 Hz), 6.12 (s, 1H); 13C NMR (CDCl3) d 206.8, 166.9, 136.2, 134.8, 130.0, 125.6, 94.3, 61.4, 39.6, 38.4, 30.2, 29.5, 25.8, 14.3, 13.1; EI MS 251, 193, 121, 91, 43 (100%). Anal. calcd for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C, 60.77; H, 8.02; N, 4.51. 4.2.8. Compound 3h. Oil. IR (neat) 1716, 1628, 1538 cm21; 1H NMR (CDCl3) d 1.00 (t, 3H, J¼7.5 Hz); 1.12– 1.46 (m, 2H), 1.29 (t, 3H, J¼7.1 Hz), 1.53 –1.70 (m, 2H), 1.86 –2.37 (m, 4H), 2.30 (t, 2H, J¼7.5 Hz), 3.02 (d, 1H, J¼14.4 Hz), 3.15 (d, 1H, J¼14.4 Hz), 3.67 (s, 3H), 4.18 (q, 2H, J¼7.1 Hz), 5.53 (bs, 1H), 5.59 – 5.72 (m, 1H), 5.76 (d, 1H, J¼16.2 Hz), 6.26 (bs, 1H); 13C NMR (CDCl3) d 173.9, 167.0, 135.7, 135.2, 129.4, 125.0, 94.7, 61.3, 51.7, 39.1, 36.3, 33.8, 25.8, 25.0, 23.6, 14.3, 13.2; EI MS 310, 294, 237 (100%), 177, 91. Anal. calcd for C17H27NO6: C, 59.81; H, 7.97; N, 4.10. Found: C, 60.03; H, 8.14; N, 3.98. 4.2.9. Compound 3i. Oil. IR (neat) 1718, 1629, 1542 cm21; H NMR (C6D6) d 0.86 (t, 3H, J¼7.3 Hz); 1.35 (s, 3H); 2.90 (d, 2H, J¼3.3 Hz); 2.99 (d, 2H, J¼6.2 Hz); 3.87 (q, 2H, J¼7.3 Hz); 5.2 (d, 1H, J¼1.1 Hz); 5.51 (dt, 1H, J¼15.7, 6.6 Hz); 5.73 (dt, 1H, J¼15.7, 1.5 Hz); 6.11 (d, 1H, J¼ 1.1 Hz); 6.91 –7.15 (m, 5H); 13C NMR (CDCl3) d 166.9, 139.1, 135.0, 133.0, 130.7, 130.2, 128.9, 128.8, 126.7, 91.3, 61.4, 40.8, 38.9, 21.4, 14.4; EI MS 256, 181, 167, 115, 91. Anal. calcd for C17H21NO4: C, 67.29; H, 6.98; N, 4.62. Found: C, 67.11; H, 7.17; N, 4.47.
J¼7.2 Hz), 4.23 (q, 0.3H, J¼7.2 Hz), 5.53– 5.90 (m, 1H), 6.07 (d, 0.83H, J¼10.6 Hz), 6.19 (d, 0.17H, J¼10.6 Hz), 6.25 (d, 1H, J¼1.1 Hz), 6.49 (d, 1H, J¼15.4 Hz), 6.99 (dd, 0.17H, J¼15.4, 10.6 Hz), 7.01 (dd, 0.83H, J¼15.7, 10.6 Hz), 7.16 – 7.43 (m, 5H); 13C NMR (CDCl3) d 167.3, 138.8, 138.0, 136.6, 131.1, 128.8, 127.6, 127.3, 126.4, 126.2, 125.5, 61.0, 41.9, 17.1, 14.4. Anal. calcd for C17H20O2: C, 79.65; H, 7.86. Found: C, 79.90; H, 7.99. 4.3.2. Compound 7j. Diastereomeric mixture 4E,6E and 4Z,6E (2:1): Oil. IR (neat) 2966, 1716, 1628, 1142 cm21; 1H NMR (CDCl3) d 1.07 (t, 2H, J¼7.3 Hz), 1.08 (t, 1H, J¼ 7.3 Hz), 1.30 (t, 1H, J¼7.3 Hz), 1.31 (t, 2H, J¼7.3 Hz), 2.13 (q, 1.33H, J¼7.3 Hz), 2.29 (q, 0.67H, J¼7.3 Hz), 3.14 (s, 0.67H), 3.30 (s, 1.33H), 4.24 (m, 2H), 5.52 (bs, 0.67H), 5.57 (bs, 0.33H), 5.99 (d, 0.33H), 6.20 (d, 0.67H, J¼10.7 Hz), 6.23 (bs, 0.67H), 6.27 (bs, 0.33H), 6.49 (d, 0.33H, J¼ 15.3 Hz), 6.53 (d, 0.67H, J¼15.6 Hz), 6.97 (dd, 0.67H, J¼15.6, 10.7 Hz), 7.02 (dd, 0.33H, J¼15.6, 11.0 Hz), 7.16 – 7.43 (m, 5H); 13C NMR (CDCl3) d 167.5, 167.4, 142.8, 141.7, 138.3, 138.1, 131.5, 131.3, 128.8 (4C), 127.8, 127.4 (2C), 126.7, 126.5 (2C), 126.4, 125.7, 125.6, 125.2, 61.1, 61.0, 39.0, 33.0, 30.3, 24.3, 14.5 (2C), 13.7, 12.9. Anal. calcd for C18H22O2: C, 79.96; H, 8.20. Found: C, 80.21; H, 8.01.
1
4.2.10. Compound 3j. Oil. IR (neat) 1718, 1629, 1542 cm21; 1H NMR (C6D6) d 0.63 (t, 3H, J¼7.3 Hz); 0.88 (t, 3H, J¼7.0 Hz); 1.55 –1.95 (m, 2H); 2.89 (d, 1H, J¼14.6 Hz); 3.00 (d, 1H, J¼14.6 Hz); 3.05 (d, 2H, J¼ 6.6 Hz); 3.88 (q, 2H, J¼7.0 Hz); 5.21 (s, 1H); 5.46 (dt, 1H, J¼16.0, 6.6 Hz); 5.74 (dt, 1H, J¼16.0, 1.5 Hz); 6.09 (s, 1H); 6.96– 7.18 (m, 5H); 13C NMR (CDCl3) d 167.0, 139.3, 135.2, 132.8, 129.5, 128.9, 128.8, 128.1, 126.6, 95.2, 61.4, 39.2, 38.8, 30.0, 14.4, 8.7; EI MS 270, 167, 123, 91, 79. Anal. calcd for C18H23NO4: C, 68.10; H, 7.31; N, 4.42. Found: C, 67.93; H, 7.42; N, 4.57. 4.3. General procedure for the preparation of trienes 7i,j The nitroalkene 1i,j (1 mmol) and the bromide 2 (193 mg, 138 ml, 1 mmol) are dissolved in MeCN (15 ml) and then DBU is added (304 mg, 299 ml, 2 mmol); the obtained solution is magnetically stirred at room temperature until the products 3i,j are formed (30 min., TLC); after that the mixture is refluxed for 8 h to yield the products 7i,j each as diastereomeric mixture of 4E,6E and 4Z,6E. The mixture is finally concentrated and submitted to flash chromatographic column (ciclohexane/ethyl acetate). 4.3.1. Compound 7i. Diastereomeric mixture 4E,6E and 4Z,6E (5:1): Oil. IR (neat) 2964, 1715, 1628, 1140 cm21; 1H NMR (CDCl3) d 1.31 (t, 3H, J¼7.2 Hz), 1.83 (s, 0.5H), 1.86 (s, 2.5H), 3.12 (s, 1.7H), 3.28 (s, 0.3H), 4.22 (q, 1.7H,
Acknowledgements The work was carried out in the framework of the National Project ‘Il Mezzo Acquoso nelle Applicazioni Sintetiche dei Nitrocomposti Alifatici’ supported by the Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica, Rome-Italy.
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Fast diastereoselective Baylis – Hillman reaction by nitroalkenes: synthesis of di- and triene derivatives Roberto Ballini,* Luciano Barboni, Giovanna Bosica, Dennis Fiorini, Emanuela Mignini and Alessandro Palmieri Dipartimento di Scienze Chimiche, Universita` di Camerino, Via S. Agostino 1, I-62032 Camerino, Italy Received 3 March 2004; revised 8 April 2004; accepted 13 April 2004
Abstract—The Baylis – Hillman reaction is performed using nitroalkenes as activated alkenes, ethyl-2-bromomethylacrylate as electrophilic acceptor and DBU as catalyst base. Nitro dienes are obtained in good yields and very short reaction times. Moreover, starting from appropriate nitroalkenes it is possible to realize one pot the synthesis of trienic systems. q 2004 Elsevier Ltd. All rights reserved.
1. Introduction Among the various reactions leading to the formation of carbon – carbon bond, the Baylis – Hillman reaction is doubtless one of the most fascinating ones, due to the simplicity through which it is possible to obtain high densely functionalizated products starting from small molecules. The above reaction is a three component reaction resulting in the construction of a carbon –carbon bond between the a-position of an activated alkene and an electrophilic carbon under the influence of a catalyst (most commonly tertiary amines). A variety of activated alkenes have been used such as alkyl vinyl ketones, alkyl (aryl) acrylates, acrylonitrile, vinyl sulfones, acrylamides, allenic esters, vinyl sulfonates, vinyl phosphonates and acrolein.1,2 Aliphatic nitro compounds have proven to be valuable intermediates, and the chemical literature continuously reports progress in their utilization for the synthesis of a variety of targets. Moreover, these compounds are very powerful synthetic tools because they facilitate the carbon – carbon bond-forming processes.3 Surprisingly little attention has been given to conjugated nitroolefines as activated alkenes; anyhow there are two pioneering works of Ono et al. where nitroolefines are reacted with aldehydes or with a,b-unsaturated compounds,4,5 with the need of long reaction times. Following our studies in the chemistry of aliphatic nitro compounds we wish here to present an extension of these Keywords: Baylis–Hillman reaction; Michael reaction; Nitroalkenes; Nitro dienes; Allylic nitro compounds. * Corresponding author. Tel.: þ39-0737-402270; fax: þ39-0737-402297; e-mail address: [email protected] 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.04.030
forerunner works exploiting the reactivity of nitroolefines with a particular carbon electrophile specie, the allyl bromide 2, whose use has been little explored in the Baylis – Hillman reaction;6 moreover nothing has been done regarding the study of its behavior with nitroolefins.
Scheme 1. Table 1. Preparation of nitro dienes 3a–h Entry 1 2 3 4 5 6 7 8
1, 3
R1
R2
R3
Yield (%) of 3
1a, 3a 1b, 3b 1c, 3c 1d, 3d 1e, 3e 1f, 3f 1g, 3g 1h, 3h
Me Me Et Et Pr –(CH2)3 – MeOCCH2CH2 MeOOC(CH2)4
Me H H H H
Me Et Et n-Bu H H Et Et
63 82 80 77 80 82 84 94
H H
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2. Results and discussion Treatment of 1 equiv. of the nitroalkenes 1a – h with 1 equiv. of ethyl-2-bromomethylacrylate 2 (Scheme 1), in the presence of DBU (2 equiv.) in acetonitrile and at room temperature affords after 30 min the nitro dienic systems 3a – h in good yields (63 –94%, Table 1). The choice of DBU as base7 dramatically improves the efficiency of the method since the reaction can be performed under very short reaction times (30 min) respect to the pioneering work of Ono (24 – 72 h).5 It is noteworthy that a variety of nitroalkenes could be successfully employed, even those having other functionalities (entry 7, 8). A plausible mechanism for the formation of 3 is presented in the Scheme 2 (by analogy with Ref. 6). Both the nitroolefin 1 and the bromide 2 are nucleofilically attacked by DBU resulting in the zwitter ionic complexes 4 and 5; the complex 5 acts as an enolate specie giving the Michael attack to the complex 4 and leading to the dipolar product 6. Finally, 6 undergoes a base-assisted elimination of the conjugate acid of DBU giving diastereoselectively the nitro dienes 3 with E configuration, as evidenced by the H5 –H6 coupling constants (14 –16 Hz). The compounds 3 contain at least four different functionalities such as: (i) an ester moiety, (ii) an electron rich C – C double bond, (iii) an electron poor C –C double bond, and (iv) a nitro group, so that they can be submitted to several further transformations. Of great interest is the possibility to realize
Scheme 3.
the one-pot preparation of triene derivatives 7 by the appropriate choice of the starting nitroalkenes (Scheme 3). In fact we observed that if 1-alkyl-1-nitro-4-phenyl-1butenes 1i,j are employed, the Baylis –Hillman reaction could give, directly, the compounds 7i,j as diastereoisomeric mixtures (Scheme 3). As the 1H and 13C NMR spectra of the diastereomeric mixture 7j showed better separated sets of signals respect to the 7i spectra, they could be used for the determination of the configuration of the C4 –C5 and the C6 – C7 double bonds. The data showed that the major stereoisomer was, as expected, the 4E,6E. In particular, the E configuration of the C6 –C7 double bond could be established on the basis of the H6 –H7 coupling constant (15.6 Hz for both the diastereoisomers), whereas the C4 –C5 configuration was established on the basis of the C3 and C8 chemical shifts. In fact, both the C3 and C8 are deshielded when they are trans respect to
Scheme 2.
Figure 1.
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the stirene moiety, as indicated in Figure 1 and according to the data reported for similar compounds.8a,9 Moreover, the NOESY spectrum of the 7j mixture showed two remarkably different sets of NOE correlations for the two diastereoisomers. The cross peaks evidenced that for both the diastereoisomers the preferred conformation of the C5– C6 single bond was the s-trans. In particular, as depicted in Figure 1, the 4E isomer showed the H3 – H5 and the H6 – H8 NOE correlations, whereas the 4Z isomer exhibited the H3 – H6 and the H5 – H8 NOE correlations. Compounds 7 are very interesting materials from synthetic point of view because these molecules are recurring structural unit in natural targets of relevant interest and in molecules showing important pharmacological activities.8 In these cases the energetic gain due to the conjugation of the styrene moiety allows the final spontaneous elimination of nitrous acid leading to trienes 7i,j. The formation of 7i,j is strongly helped by heating at reflux and is accomplished in 8 h. Anyway the dienic products 3i,j could be still obtained and charaterized by stopping the reaction as soon as they were formed.
3. Conclusions We have reported a new application of the Baylis – Hillman reaction for the diastereoselective, fast, one-pot synthesis of di- and triene derivatives. This procedure works with different conjugated nitroalkenes and affords the title compounds in good yields.
4. Experimental 4.1. General 13
C and 1H NMR spectra were recorded in CDCl3 or in C6D6 at 200 MHz on a Varian Gemini instrument; the use of C6D6 was necessary in the cases in which using CDCl3 olefinic protons signals could not be separated; J values are given in Hz. IR spectra were recorded with a Perkin – Elmer 257 spectrophotometer. Mass spectra were determined on a capillary GC/MS operating in split mode with helium carrier gas and fitted with a mass selective detector (MSD). The nitroalkenes used were commercially available or prepared according to literature procedures.10 The reactions were monitored by TLC. Microanalysis were performed using a Fisons model EA 1108. All the products were purified by flash chromatography on Merck silica gel (cyclohexane/ ethyl acetate). 4.2. General procedure for the preparation of nitrodienes 3a– h The nitroalkene 1 (1 mmol) and the bromide 2 (193 mg, 138 ml, 1 mmol) are dissolved in MeCN (15 ml) and then DBU is added (304 mg, 299 ml, 2 mmol); the obtained solution is magnetically stirred at room temperature for 30 min, then is concentrated under reduced pressure and charged into a flash chromatographic column (cyclohexane/ ethyl acetate) giving the pure compound 3.
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4.2.1. Compound 3a. Oil. IR (neat) 1720, 1630, 1543 cm21; 1H NMR (CDCl3) d 1.30 (t, 3H, J¼7.3 Hz); 1.59 (s, 3H), 1.64 (s, 3H), 1.76 (s, 3H), 3.12 (d, 2H, J¼ 1.8 Hz), 4.21 (q, 2H, J¼7.3 Hz), 5.40 (bs, 1H), 5.57 (s, 1H), 6.28 (bs, 1H); 13C NMR (CDCl3) d 167.1, 139.5, 135.1, 129.9, 125.0, 91.1, 61.4, 41.8, 27.4, 24.2, 18.8, 14.3; EI MS 195, 179, 149, 121 (100%), 79. Anal. calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81. Found: C, 59.98; H, 7.77; N, 5.65. 4.2.2. Compound 3b. Oil. IR (neat) 1719, 1629, 1542 cm21; 1H NMR (C6D6) d 0.71 (t, 3H, J¼7.5 Hz); 0.88 (t, 3H, J¼7.1 Hz), 1.41 (s, 3H), 1.60– 1.76 (m, 2H), 2.90 (d, 1H, J¼13.7 Hz), 3.00 (d, 1H, J¼13.7 Hz), 3.88 (q, 2H, J¼7.1 Hz), 5.23 (d, 1H, J¼1.1 Hz), 5.38 (dt, 1H, J¼ 15.7, 6.2 Hz), 5.68 (dt, 1H, J¼15.7, 1.5 Hz); 13C NMR (CDCl3) d 166.9, 135.8, 135.1, 130.0, 128.4, 91.4, 61.3, 40.8, 25.5, 21.3, 14.3, 13.1; EI MS 195, 149, 121 (100%), 93, 79. Anal. calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81. Found: C, 60.01; H, 8.12; N, 5.68. 4.2.3. Compound 3c. Oil. IR (neat) 1716, 1630, 1538 cm21; H NMR (CDCl3) d 0.87 (t, 3H, J¼7.3 Hz); 1.00 (t, 3H, J¼7.3 Hz), 1.29 (t, 3H, J¼7.2 Hz), 1.81 –2.20 (m, 4H), 3.02 (dd, 1H, J¼14.3, 0.7 Hz), 3.16 (dd, 1H, J¼14.3, 0.7 Hz), 4.17 (q, 2H, J¼7.2 Hz), 5.53 (bs, 1H), 5.60– 5.82 (m, 2H), 6.26 (bs, 1H); 13C NMR (CDCl3) d 167.1, 135.7, 135.4, 129.2, 125.8, 95.3, 61.3, 38.8, 29.9, 25.8, 14.3, 13.2, 8.6; EI MS 209, 163, 135 (100%), 93, 79. Anal. calcd for C13H21NO4: C, 61.16; H, 8.29; N, 5.49. Found: C, 61.34; H, 8.11; N, 5.25.
1
4.2.4. Compound 3d. Oil. IR (neat) 1716, 1630, 1538 cm21; 1H NMR (CDCl3) d 0.88 (t, 3H, J¼7.3 Hz); 0.90 (t, 3H, J¼7.2 Hz), 1.30 (t, 3H, J¼7.2 Hz), 1.25 – 1.46 (m, 4H), 1.90– 2.22 (m, 4H), 3.04 (dd, 1H, J¼14.3, 0.7 Hz), 3.16 (dd, 1H, J¼14.3, 0.7 Hz), 4.19 (q, 2H, J¼7.2 Hz), 5.53 (bs, 1H), 5.65 (dt, 1H, J¼16.0, 6.0 Hz), 5.78 (d, 1H, J¼ 16.1 Hz), 6.24 (s, 1H); 13C NMR (CDCl3) d 167.1, 135.4, 134.5, 129.2, 126.6, 95.3, 61.3, 38.7, 32.5, 31.1, 29.9, 22.4, 14.3, 14.1, 8.6; EI MS 252, 237, 179, 123, 93, 79 (100%). Anal. calcd for C15H25NO4: C, 63.58; H, 8.89; N, 4.94. Found: C, 63.75; H, 8.74; N, 5.16. 4.2.5. Compound 3e. Oil. IR (neat) 1718, 1560, 1540 cm21; H NMR (CDCl3) d 0.91 (t, 3H, J¼7.1 Hz); 1.12 –1.46 (m, 2H), 1.29 (t, 3H, J¼7.0 Hz), 1.83– 2.15 (m, 2H), 3.04 (dd, 1H, J¼14.6, 0.7 Hz), 3.17 (dd, 1H, J¼14.6, 0.7 Hz), 4.19 (q, 2H, J¼7.0 Hz), 5.22 (d, 1H, J¼17.6 Hz), 5.35 (d, 1H, J¼ 11.3 Hz), 5.54 (d, 1H, J¼0.7 Hz), 6.19 (dd, 1H, J¼17.8, 11.2 Hz) 6.28 (d, 1H, J¼0.7 Hz); 13C NMR (CDCl3) d 166.9, 135.1, 135.0, 129.5, 117.6, 95.0, 61.3, 38.9, 38.8, 17.3, 14.3, 14.2; EI MS 195, 149, 121 (100%), 93, 79. Anal. calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81. Found: C, 59.89; H, 8.21; N, 5.65. 1
4.2.6. Compound 3f. Oil. IR (neat) 1716, 1633, 1538 cm21; H NMR (CDCl3) d 1.30 (t, 3H, J¼7.1 Hz); 1.46 –2.12 (m, 4H), 2.42 –2.55 (m, 1H), 3.00 (s, 2H), 4.21 (q, 2H, J¼ 7.0 Hz), 5.58 (bs, 1H), 5.91 (m, 1H), 6.06 (m, 1H), 6.31 (s, 1H); 13C NMR (CDCl3) d 166.8, 134.7, 134.2, 130.0, 125.5, 89.4, 61.4, 41.4, 31.4, 24.9, 19.0, 14.3; EI MS 193, 147, 119 (100%), 91, 79. Anal. calcd for C12H17NO4: C, 60.24; H, 7.16; N, 5.85. Found: C, 59.89; H, 6.97; N, 6.03.
1
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4.2.7. Compound 3g. Oil. IR (neat) 1717, 1628, 1539 cm21; 1H NMR (C6D6) d 0.72 (t, 3H, J¼7.2 Hz); 0.92 (t, 3H, J¼7.2 Hz), 1.50 (s, 3H), 1.64 –1.80 (m, 2H), 2.02– 2.16 (m, 2H), 2.22 –2.36 (m, 2H), 2.96 (d, 2H, J¼ 2.2 Hz), 3.88 (q, 2H, J¼7.2 Hz), 5.22 (bs, 1H), 5.35 (dt, 1H, J¼16.1, 6.0 Hz), 5.60 (dd, 1H, J¼16.1, 6.6 Hz), 6.12 (s, 1H); 13C NMR (CDCl3) d 206.8, 166.9, 136.2, 134.8, 130.0, 125.6, 94.3, 61.4, 39.6, 38.4, 30.2, 29.5, 25.8, 14.3, 13.1; EI MS 251, 193, 121, 91, 43 (100%). Anal. calcd for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C, 60.77; H, 8.02; N, 4.51. 4.2.8. Compound 3h. Oil. IR (neat) 1716, 1628, 1538 cm21; 1H NMR (CDCl3) d 1.00 (t, 3H, J¼7.5 Hz); 1.12– 1.46 (m, 2H), 1.29 (t, 3H, J¼7.1 Hz), 1.53 –1.70 (m, 2H), 1.86 –2.37 (m, 4H), 2.30 (t, 2H, J¼7.5 Hz), 3.02 (d, 1H, J¼14.4 Hz), 3.15 (d, 1H, J¼14.4 Hz), 3.67 (s, 3H), 4.18 (q, 2H, J¼7.1 Hz), 5.53 (bs, 1H), 5.59 – 5.72 (m, 1H), 5.76 (d, 1H, J¼16.2 Hz), 6.26 (bs, 1H); 13C NMR (CDCl3) d 173.9, 167.0, 135.7, 135.2, 129.4, 125.0, 94.7, 61.3, 51.7, 39.1, 36.3, 33.8, 25.8, 25.0, 23.6, 14.3, 13.2; EI MS 310, 294, 237 (100%), 177, 91. Anal. calcd for C17H27NO6: C, 59.81; H, 7.97; N, 4.10. Found: C, 60.03; H, 8.14; N, 3.98. 4.2.9. Compound 3i. Oil. IR (neat) 1718, 1629, 1542 cm21; H NMR (C6D6) d 0.86 (t, 3H, J¼7.3 Hz); 1.35 (s, 3H); 2.90 (d, 2H, J¼3.3 Hz); 2.99 (d, 2H, J¼6.2 Hz); 3.87 (q, 2H, J¼7.3 Hz); 5.2 (d, 1H, J¼1.1 Hz); 5.51 (dt, 1H, J¼15.7, 6.6 Hz); 5.73 (dt, 1H, J¼15.7, 1.5 Hz); 6.11 (d, 1H, J¼ 1.1 Hz); 6.91 –7.15 (m, 5H); 13C NMR (CDCl3) d 166.9, 139.1, 135.0, 133.0, 130.7, 130.2, 128.9, 128.8, 126.7, 91.3, 61.4, 40.8, 38.9, 21.4, 14.4; EI MS 256, 181, 167, 115, 91. Anal. calcd for C17H21NO4: C, 67.29; H, 6.98; N, 4.62. Found: C, 67.11; H, 7.17; N, 4.47.
J¼7.2 Hz), 4.23 (q, 0.3H, J¼7.2 Hz), 5.53– 5.90 (m, 1H), 6.07 (d, 0.83H, J¼10.6 Hz), 6.19 (d, 0.17H, J¼10.6 Hz), 6.25 (d, 1H, J¼1.1 Hz), 6.49 (d, 1H, J¼15.4 Hz), 6.99 (dd, 0.17H, J¼15.4, 10.6 Hz), 7.01 (dd, 0.83H, J¼15.7, 10.6 Hz), 7.16 – 7.43 (m, 5H); 13C NMR (CDCl3) d 167.3, 138.8, 138.0, 136.6, 131.1, 128.8, 127.6, 127.3, 126.4, 126.2, 125.5, 61.0, 41.9, 17.1, 14.4. Anal. calcd for C17H20O2: C, 79.65; H, 7.86. Found: C, 79.90; H, 7.99. 4.3.2. Compound 7j. Diastereomeric mixture 4E,6E and 4Z,6E (2:1): Oil. IR (neat) 2966, 1716, 1628, 1142 cm21; 1H NMR (CDCl3) d 1.07 (t, 2H, J¼7.3 Hz), 1.08 (t, 1H, J¼ 7.3 Hz), 1.30 (t, 1H, J¼7.3 Hz), 1.31 (t, 2H, J¼7.3 Hz), 2.13 (q, 1.33H, J¼7.3 Hz), 2.29 (q, 0.67H, J¼7.3 Hz), 3.14 (s, 0.67H), 3.30 (s, 1.33H), 4.24 (m, 2H), 5.52 (bs, 0.67H), 5.57 (bs, 0.33H), 5.99 (d, 0.33H), 6.20 (d, 0.67H, J¼10.7 Hz), 6.23 (bs, 0.67H), 6.27 (bs, 0.33H), 6.49 (d, 0.33H, J¼ 15.3 Hz), 6.53 (d, 0.67H, J¼15.6 Hz), 6.97 (dd, 0.67H, J¼15.6, 10.7 Hz), 7.02 (dd, 0.33H, J¼15.6, 11.0 Hz), 7.16 – 7.43 (m, 5H); 13C NMR (CDCl3) d 167.5, 167.4, 142.8, 141.7, 138.3, 138.1, 131.5, 131.3, 128.8 (4C), 127.8, 127.4 (2C), 126.7, 126.5 (2C), 126.4, 125.7, 125.6, 125.2, 61.1, 61.0, 39.0, 33.0, 30.3, 24.3, 14.5 (2C), 13.7, 12.9. Anal. calcd for C18H22O2: C, 79.96; H, 8.20. Found: C, 80.21; H, 8.01.
1
4.2.10. Compound 3j. Oil. IR (neat) 1718, 1629, 1542 cm21; 1H NMR (C6D6) d 0.63 (t, 3H, J¼7.3 Hz); 0.88 (t, 3H, J¼7.0 Hz); 1.55 –1.95 (m, 2H); 2.89 (d, 1H, J¼14.6 Hz); 3.00 (d, 1H, J¼14.6 Hz); 3.05 (d, 2H, J¼ 6.6 Hz); 3.88 (q, 2H, J¼7.0 Hz); 5.21 (s, 1H); 5.46 (dt, 1H, J¼16.0, 6.6 Hz); 5.74 (dt, 1H, J¼16.0, 1.5 Hz); 6.09 (s, 1H); 6.96– 7.18 (m, 5H); 13C NMR (CDCl3) d 167.0, 139.3, 135.2, 132.8, 129.5, 128.9, 128.8, 128.1, 126.6, 95.2, 61.4, 39.2, 38.8, 30.0, 14.4, 8.7; EI MS 270, 167, 123, 91, 79. Anal. calcd for C18H23NO4: C, 68.10; H, 7.31; N, 4.42. Found: C, 67.93; H, 7.42; N, 4.57. 4.3. General procedure for the preparation of trienes 7i,j The nitroalkene 1i,j (1 mmol) and the bromide 2 (193 mg, 138 ml, 1 mmol) are dissolved in MeCN (15 ml) and then DBU is added (304 mg, 299 ml, 2 mmol); the obtained solution is magnetically stirred at room temperature until the products 3i,j are formed (30 min., TLC); after that the mixture is refluxed for 8 h to yield the products 7i,j each as diastereomeric mixture of 4E,6E and 4Z,6E. The mixture is finally concentrated and submitted to flash chromatographic column (ciclohexane/ethyl acetate). 4.3.1. Compound 7i. Diastereomeric mixture 4E,6E and 4Z,6E (5:1): Oil. IR (neat) 2964, 1715, 1628, 1140 cm21; 1H NMR (CDCl3) d 1.31 (t, 3H, J¼7.2 Hz), 1.83 (s, 0.5H), 1.86 (s, 2.5H), 3.12 (s, 1.7H), 3.28 (s, 0.3H), 4.22 (q, 1.7H,
Acknowledgements The work was carried out in the framework of the National Project ‘Il Mezzo Acquoso nelle Applicazioni Sintetiche dei Nitrocomposti Alifatici’ supported by the Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica, Rome-Italy.
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6. Basavaiah, D.; Sharada, D. S.; Kumaragurubaran, N.; Reddy, M. R. J. Org. Chem. 2002, 67, 7135. 7. The efficiency of DBU in the generation of carbon– carbon bond is well documented: (a) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311. (b) Ballini, R.; Bosica, G.; Fiorini, D.; Giarlo, G. Synthesis 2003, 2001. (c) Ballini, R.; Bosica, G.; Fiorini, D.; Gil, M. V.; Petrini, M. Org. Lett. 2001, 3, 1265. (d) Ballini, R.; Bosica, G.; Mase`, A.; Petrini, M. Eur. J. Org. Chem. 2000, 2927. (e) Ballini, R.; Bosica, G.; Fiorini, D.; Gil, M. V.; Palmieri, A. Tetrahedron Lett. 2003, 44, 9033. (f) Ballini, R.; Barboni, L.; Bosica, G.; Fiorini, D.; Gil, M. V. Synlett 2002, 1706.
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