An improved, fully heterogeneous, diastereoselective synthesis of (Z)-α-bromonitroalkenes

Article abstract of DOI:10.1055/s-0032-1317695

α-Bromonitroalkenes are both key starting materials for the preparation of complex structures and possess antimicrobial activity. In this context, we disclose a simple, fully heterogeneous synthetic approach for their preparation in good overall yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317695

114▌
LETTER
lAettner Improved, Fully Heterogeneous, Diastereoselective Synthesis of
(Z)-α-Bromonitroalkenes
Synthesis of (Z)-α-Bromonitroalkenes
Alessandro Palmieri, Serena Gabrielli, Roberto Ballini*
Green Chemistry Group, School of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino 1, 62032 Camerino
(MC), Italy
Fax +39(0737)402297; E-mail: roberto.ballini@unicam.it
Received: 30.10.2012; Accepted: 02.11.2012
Some decades ago, a direct procedure7 involving the ni-
Abstract: α-Bromonitroalkenes are both key starting materials for
troaldol condensation of aldehydes with bromonitrometh-
the preparation of complex structures and possess antimicrobial ac-
ane in the presence of tri-n-butylarsine was described.
tivity. In this context, we disclose a simple, fully heterogeneous
However, the method appears to work just with aromatic
aldehydes, and requires a large excess of bromonitrometh-
ane, a dry atmosphere, and high temperatures. Moreover,
the reaction must be manipulated with attention in order to
avoid possible explosion, probably due to the use of tri-n-
butylarsine. Thus, a simpler method would be valuable. In
this context, based on our previous experience in the ni-
troaldol (Henry) reaction,8 we have developed a new, sim-
ple, mild, and fully heterogeneous approach for the
synthesis of α-bromonitroalkenes 5 starting from the Hen-
ry reaction between aldehydes 1 and bromonitromethane
6, followed by the dehydration of the obtained crude nitro
alcohols (Scheme 2).
synthetic approach for their preparation in good overall yields.
Key words: Henry reaction, dehydration, diastereoselectivity, α-bromo-
nitroalkanes, heterogeneous catalysis
Unsaturated nitro compounds are an important class of
valuable precursors to a wide variety of target molecules.1
The utility of conjugated nitroalkenes in organic synthesis
is largely due to their versatile reactivity as Michael ac-
ceptors, dipolarophiles, 1,3-dipoles, dienophiles, and het-
erodienes.2 Nitroalkenes are also distinguished by their
diverse biological activities.3 In this respect, of particular
interest are the α-bromonitroalkenes 5 since they have
shown important antimicrobial activities4 as well as being
key intermediates.5
We chose, as a model system, the reaction of 6 with
hexanal (1a) under basic and solvent-free conditions (car-
bonate on silica), in which the crude nitroalkanol 7a can
be directly dehydrated, by Amberlyst 15/Ac2O9 into the
target compound 5a avoiding any intermediate purifica-
tion step.
Due to the importance of these compounds, their easy
availability is strategically important and simpler synthet-
ic procedures for their preparation would increase the im-
portance of these bifunctionalized alkenes. The general
synthetic method for the preparation of α-bromoni-
troalkenes involves bromination–debromination of ni-
troalkenes 3 (Scheme 1). However, since nitroalkanes 3
are generated by Henry reaction followed by elimination,
it is clear that the preparation of α-bromonitroalkenes 5
starting from their ultimate precursors (nitromethane and
aldehydes) involves a complex multistep sequence.6
OH
O
a)
b)
NO2
NO2
+ BrCH2NO2
4
H
4
4
Br
Br
1a
6
7a
5a
Scheme 2 Reagents and conditions: a) SolFC, carbonate on silica,
r.t., 4.5 h; b) Amberlyst 15, EtOAc, r.t., 1.5 h.
O
OH
LG
MeNO2
As reported in Table 1, the optimal result was obtained by
employing 0.3 equivalents of carbonate on silica, coupled
with 500 mg/mmol of Amberlyst 15 and three equivalents
of Ac2O.
NO2
NO2
R
H
R
R
1
2
LG = OAc, OMs
base
In order to assess the generality of our procedure we in-
vestigated a variety of substrates and, as reported in Table
2, satisfactory to good yields (55–85%) were achieved
with aromatic and aliphatic aldehydes, including func-
tionalized substrates.10 Only 5-bromo-2-furfural 1k (Ta-
ble 2, entry 11) afforded a low yield (31%) of alkene 5k,
probably due to the chemical frailty of the furan ring.
Br
Br2
Base
NO2
NO2
NO2
R
R
R
Br
Br
5
4
3
Scheme 1
Furthermore, all the obtained α-bromonitroalkenes were
isolated as a single Z-diastereomer. The configuration was
established by comparison with the literature data.4d,6c
SYNLETT 2013, 24, 0114–0116
Advanced online publication: 28.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317695; Art ID: ST-2012-D0929-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (Z)-α-Bromonitroalkenes
115
troalkenes that could be of interest as targets with poten-
tial biological activities.4
Table 1
Entry
Carbonate on Amberlyst 15 Ac2O
Yieldof5a
Finally, it is important to point out that our method em-
ploys a fully heterogeneous procedure and that the final
dehydration of nitroalkanol proceeds under acidic condi-
tions, contrary to the standard procedures that usually em-
ploy basic conditions.
silica (equiv) (g/mmol)
(equiv)
(%)a
1
2
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.3
0.4
0.3
0.3
0.25
0.35
0.5
1.0
0.5
0.5
0.5
0.5
0.5
–
2
2
2
2
3
4
3
3
3
3
–
20
31
3
48
Acknowledgment
4
50
The authors thank the University of Camerino and MIUR, Italy
(FIRB National Project ‘Metodologie di nuova generazione nella
formazione di legami carbonio-carbonio e carbonio-eteroatomo in
condizioni eco-sostenibili’) for financial support.
5
56
6
54
7
67
8
82
References and Notes
9
81
(1) (a) Perekalin, V. V.; Lipina, E. S.; Berestovitskaya, V. M.;
Efremov, D. A. In Nitroalkenes Conjugated Nitro
Compounds; Wiley: Chichester, 1994. (b) Ballini, R. In
Studies in Natural Products Chemistry; Atta-ur-Rahman,
Elsevier: Amsterdam, 1997, 117. (c) Ballini, R.;
Marcantoni, E.; Petrini, M. In Amino Group Chemistry;
Ricci, A., Ed.; Wiley-VCH: Weinheim, 2008, 93.
(d) Ballini, R.; Gabrielli, S.; Palmieri, A. Curr. Org. Chem.
2010, 14, 65.
10
11
no product
no product
0.5
a Yield of pure isolated product.
Table 2
(2) See, for example: (a) Berner, O. M.; Tedeschi, L.; Enders, D.
Eur. J. Org. Chem. 2002, 1877. (b) Krause, N.; Hoffmann-
Röder, A. Synthesis 2001, 171. (c) Denmark, S. E.;
Thorarensen, A. Chem. Rev. 1996, 96, 137. (d) Tietze, L. F.;
Kettschau, G. Top. Curr. Chem. 1997, 189, 1.
1) carbonate on silica (0.3 equiv)
SolFC, r.t., time
O
NO2
+ BrCH2NO2
R
R
H
2) Amberlyst 15 (3 equiv)
EtOAc, r.t., 1.5 h
Br
1
6
5
(e) Namboothiri, I. N. N.; Hassner, A. Top. Curr. Chem.
2001, 216, 1.
Entry
R
Time (h) Yield of 5 (%)a
(3) (a) Kabalka, G. W.; Varma, R. S. Org. Prep. Proced. Int.
1987, 19, 283. (b) Barret, A. G. M. Chem. Soc. Rev. 1991,
20, 95. (c) Blades, K.; Butt, A. H.; Cockerill, G. S.;
Easterfield, H. J.; Lequeux, T. P.; Percy, J. M. J. Chem. Soc.,
Perkin Trans. 1 1999, 3609. (d) Hoashi, Y.; Yabuta, T.;
Takemoto, Y. Tetrahedron Lett. 2004, 45, 9185. (e) Dadwal,
M.; Mohan, R.; Panda, D.; Mobin, S. M.; Namboothiri, I. N.
N. Chem. Commun. 2006, 338. (f) Rastogi, N.; Mohan, R.;
Panda, D.; Mobin, S. M.; Namboothiru, I. N. N. Org.
Biomol. Chem. 2006, 4, 3211. (g) Mohan, R.; Rastogi, N.;
Namboothiri, I. N. N.; Mobin, S. M.; Panda, D. Bioorg. Med.
Chem. 2006, 14, 8073. (h) Parry, R.; Nishino, S.; Spain, J.
Nat. Prod. Rep. 2011, 28, 152.
(4) See, for example: (a) Cancio, C.; Ramon, N.; Placeres, G.;
Exiquio, T. WO 0153283, 2001. (b) McCoy, W. F.;
Thornburgh, S. WO 8911793, 1989. (c) González-Diaz, H.;
Tenorio, E.; Castañedo, N.; Santana, L.; Uriarte, E. Bioorg.
Med. Chem. 2005, 13, 1523. (d) Estrada, E.; Gόmez, M.;
Castañedo, N.; Pérez, C. J. Mol. Struct. (Theochem) 1999,
468, 193.
1
2
1a Me(CH2)4
1b Me(CH2)6
1c cyclohexyl
1d Ph(CH2)2
4.5
5
5a 82
5b 82
5c 84
5d 85
5e 61
5f 72
5g 73
5h 55
5i 72
5j 56
5k 31
3
5
4
4
5
1e EtOOC
5
6
1f 4-t-BuC6H4
1g 3-MeOC6H4
1h 4-MeOC6H4
1i 2-BrC6H4
6
7
5
8
5
9
5
10
11
1j 3,4,5-(MeO)3C6H2
1k 5-Br-2-furyl
6
5
a Yield of pure isolated product.
(5) (a) Ganesh, M.; Namboothiri, I. N. N. Tetrahedron 2007, 63,
11973. (b) McCooey, S. H.; McCabe, T.; Connon, S. J. J.
Org. Chem. 2006, 71, 7494. (c) Romashov, L. V.;
Khomutova, Y. A.; Danilenko, V. M.; Ioffe, S. L.; Lesiv, A.
V. Synthesis 2010, 407.
(6) See, for example: (a) Sarkisyan, Z. M.; Sadikov, K. D.;
Smirnov, A. S.; Kuzhaeva, A. A.; Makarenko, S. V.;
Anisimova, N. A.; Deiko, L. I.; Berestovitskaya, V. M.;
Russian, V. M. J. Org. Chem. 2004, 40, 908. (b) Tuan, D. T.;
Tung, D. T.; Langer, P. Synlett 2006, 2812. (c) Ganesh, M.;
Namboothiri, I. N. N. Tetrahedron 2007, 63, 11973.
(7) Shen, Y.; Yang, B. Synth. Commun. 1993, 23, 1.
In conclusion, our procedure offers important advantages
with respect to the previous reported approaches since it
gives access to the target compounds, without the need for
excess bromonitromethane, under mild reaction condi-
tions (room temperature) and short reaction times, with
evident economical and environmental benefits. More-
over, a variety of other important functionalities can be
tolerated giving access to polyfunctionalized α-bromoni-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 114–116

116
A. Palmieri et al.
LETTER
(8) (a) Ballini, R.; Castagnani, R.; Petrini, M. J. Org. Chem.
1992, 57, 2160. (b) Ballini, R.; Bosica, G.; Forconi, P.
Tetrahedron 1996, 52, 1677. (c) Ballini, R.; Bosica, G. J.
Org. Chem. 1997, 62, 425. (d) Ballini, R.; Bosica, G.;
Parrini, M. Chem. Lett. 1999, 1105. (e) Ballini, R.; Bigi, F.;
Giorgi, E.; Maggi, R.; Sartori, G. J. Catal. 2000, 191, 348.
(f) Ballini, R.; Bosica, G.; Livi, D.; Palmieri, A.; Maggi, R.;
Sartori, G. Tetrahedron Lett. 2003, 44, 2271. (g) Ballini, R.;
Fiorini, D.; Gil, M. V.; Palmieri, A. Tetrahedron 2004, 60,
2799. (h) Ballini, R.; Barboni, L.; Palmieri, A. Synlett 2007,
3019. (i) Ballini, R.; Bosica, G.; Palmieri, A.; Pizzo, F.;
Vaccaro, L. Green Chem. 2008, 10, 541. (j) Ballini, R.; Noé,
M.; Perosa, A.; Selva, M. J. Org. Chem. 2008, 73, 8520.
(9) Usually, the dehydration of bromonitroalkanols is
performed under basic conditions, see ref. 6.
(10) Typical Procedure for the Synthesis of Compounds 5
The catalyst (0.56 g, 0.3 mmol) was slowly added at r.t. to a
mechanically stirred mixture of the bromonitromethane (6, 1
mmol, 0.155 g, pure 90%) and the requisite aldehyde 1 (1
mmol), and the reaction was stirred for the appropriate time
(see Table). The mixture was then treated with EtOAc (5
mL), and the catalyst was filtered off and washed with
additional EtOAc (10 mL). The solution was concentrated
under reduced pressure to a volume of 3 mL and then treated
with Ac2O (306 mg, 3 mmol) and Amberlyst 15 (0.5 g) and
stirred, at r.t., for an additional 1.5 h. Finally, the Amberlyst
15 was removed by filtration, washing with EtOAc (7 mL),
and the solution was concentrated under vacuum giving the
crude product 5 which was purified by flash chromatography
(hexane–EtOAc = 9:1).
(Z)-Ethyl 3-Bromo-3-nitroacrylate (5e)
Light yellow oil. IR (neat): ν = 1733, 1622, 1552, 1323 cm–
1. 1H NMR (400 MHz, CDCl3): δ = 1.35 (t, 3 H, J = 7.3 Hz),
4.34 (q, 2 H, J = 7.3 Hz), 7.74 (s, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 14.2, 62.8, 125.8, 139.3, 162.2. MS (EI, 70 eV):
m/z (%) = 180, 178, 166, 164, 151, 149, 133, 131, 106, 104,
69, 53, 29 (100). Anal. Calcd for C5H6BrNO4 (224.01): C,
26.81; H, 2.70; N, 6.25. Found: C, 26.86; H, 2.72; N, 6.22.
(Z)-1-(2-Bromo-2-nitrovinyl)-4-tert-butylbenzene (5f)
Yellow solid, mp 50–52 °C. IR (neat): ν = 3030, 1599, 1530,
1325, 953, 834, 762 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.35 (s, 9 H), 7.51 (d, 2 H, J = 8.5 Hz), 7.86 (d, 2 H, J = 8.5
Hz), 8.64 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 31.3,
35.4, 126.3, 127.3, 127.5, 131.3, 136.7, 156.3. MS (EI, 70
eV): m/z (%) = 285, 283, 270, 268, 222, 220, 143 (100), 128,
115, 57. Anal. Calcd for C12H14BrNO2 (284.15): C, 50.72; H,
4.97; N, 4.93. Found: C, 50.76; H, 5.00; N, 4.90.
(Z)-1-(2-Bromo-2-nitrovinyl)-3-methoxybenzene (5g)
Yellow solid, mp 68–70 °C. IR (neat): ν = 3070, 3029, 1607,
1553, 1331, 1176, 897, 743 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 3.86 (s, 3 H), 7.07 (d, 1 H, J = 7.7 Hz), 7.38–
7.46 (m, 3 H), 8.61 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ
= 55.6, 115.8, 118.0, 124.0, 128.5, 130.2, 131.5, 136.6,
159.9. MS (EI, 70 eV): m/z (%) = 259, 257, 212, 210, 150,
148, 132 (100), 102, 89, 77, 63. Anal. Calcd for C9H8BrNO3
(258.07): C, 41.89; H, 3.12; N, 5.43. Found: C, 41.93; H,
3.10; N, 5.40.
(Z)-1-(2-Bromo-2-nitrovinyl)-4-methoxybenzene (5h)
Yellow solid, mp 59–61 °C. IR (neat): ν = 3041, 1520, 1310,
1261, 1181, 957, 825 cm–1. 1H NMR (400 MHz, CDCl3): δ
= 3.88 (s, 3 H), 7.00 (d, 2 H, J = 8.5 Hz), 7.92 (d, 2 H, J = 8.5
Hz), 8.63 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 55.8,
114.8, 122.6, 125.6, 133.7, 136.6, 163.0. MS (EI, 70 eV):
m/z (%) = 259, 257, 212, 210, 132 (100), 117, 89, 63. Anal.
Calcd for C9H8BrNO3 (258.07): C, 41.89; H, 3.12; N, 5.43.
Found: C, 41.93; H, 3.09; N, 5.45.
(Z)-1-Bromo-2-(2-bromo-2-nitrovinyl)benzene (5i)
Yellow waxy solid. IR (neat): ν = 3078, 3035, 1606, 1582,
1532, 1300, 898, 764, 733, 703 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.35 (t, 1 H, J = 7.7 Hz), 7.44 (t, 1 H, J = 7.7
Hz), 7.69 (d, 1 H, J = 7.7 Hz), 7.86 (d, 1 H, J = 7.7 Hz), 8.77
(s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 125.7, 127.7,
130.6, 131.3, 131.6, 132.5, 133.5, 136.2. MS (EI, 70 eV):
m/z (%) = 309, 307, 305, 262, 260, 258, 228, 226, 198, 196,
182, 180 (100), 147, 101, 75, 50. Anal. Calcd for
(Z)-1-Bromo-1-nitrohept-1-ene (5a)
Light yellow oil. IR (neat): ν = 3045, 1551, 1325, 1261, 942,
722 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.91 (t, 3 H, J =
6.8 Hz), 1.30–1.40 (m, 4 H), 1.51–1.61 (m, 2 H), 2.37 (q, 2
H, J = 7.3 Hz), 7.67 (t, 1 H, J = 7.3 Hz). 13C NMR (100MHz,
CDCl3): δ = 14.1, 22.5, 27.3, 31.3, 31.6, 131.2, 141.6. MS
(EI, 70 eV): m/z (%) = 165, 142, 119, 95, 69, 55, 41 (100),
39, 30. Anal. Calcd for C7H12BrNO2 (222.08): C, 37.86; H,
5.45; N, 6.31. Found: C, 37.91; H, 5.49; N, 6.28.
(Z)-1-Bromo-1-nitronon-1-ene (5b)
Light yellow oil. IR (neat): ν = 3040, 1542, 1321, 1254, 960,
768 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.89 (t, 3 H, J =
6.8 Hz), 1.23–1.41 (m, 8 H), 1.50–1.61 (m, 2 H), 2.37 (q, 2
H, J = 7.3 Hz), 7.66 (t, 1 H, J = 7.3 Hz). 13C NMR (100 MHz,
CDCl3): δ = 14.3, 22.8, 27.6, 29.1, 29.4, 31.3, 31.9, 131.2,
141.6. MS (EI, 70 eV): m/z (%) = 234, 121, 93, 81, 67, 55,
43 (100), 41, 39, 29. Anal. Calcd for C9H16BrNO2 (250.13):
C, 43.22; H, 6.45; N, 5.60. Found: C, 43.27; H, 6.49; N, 5.58.
(Z)-(2-Bromo-2-nitrovinyl)cyclohexane (5c)
C8H5Br2NO2 (306.94): C, 31.30; H, 1.64; N, 4.56. Found: C,
31.33; H, 1.65; N, 4.54.
(Z)-5-(2-Bromo-2-nitrovinyl)-1,2,3-trimethoxybenzene
(5j)
Light yellow oil. IR (neat): ν = 3030, 1539, 1320, 971, 960,
761 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.18–1.44 (m, 6
H), 1.65–1.84 (m, 4 H), 2.39–2.53 (m, 1 H), 7.48 (d, 1 H, J
= 9.8 Hz). 13C NMR (100 MHz, CDCl3): δ = 25.3, 25.7, 30.8,
40.8, 129.7, 145.3. MS (EI, 70 eV): m/z (%) = 218, 216, 137,
119, 97, 91, 81, 79, 71, 69, 55 (100), 41, 39. Anal. Calcd for
C8H12BrNO2 (234.09): C, 41.05; H, 5.17; N, 5.98. Found: C,
41.09; H, 5.21; N, 5.96.
Orange solid, mp 113–115 °C. IR (neat): ν = 3075, 3035,
1603, 1577, 1522, 1333, 1246, 1125, 824, 618 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 3.91 (s, 6 H), 3.93 (s, 3 H),
7.19 (s, 2 H), 8.59 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ
= 56.4, 56.5, 61.3, 105.9, 108.9, 125.2, 127.1, 131.9, 136.7,
141.8, 153.4. MS (EI, 70 eV): m/z (%) = 319, 317, 272, 270,
257, 255, 192, 177 (100), 149, 134, 119, 63. Anal. Calcd for
C11H12BrNO5 (318.12): C, 41.53; H, 3.80; N, 4.40. Found:
C, 41.57; H, 3.82; N, 4.38.
(Z)-(4-Bromo-4-nitrobut-3-enyl)benzene (5d)
Light yellow oil. IR (neat): ν = 3035, 1618, 1525, 1331, 937,
750, 724, 698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.71
(q, 2 H, J = 7.7 Hz), 2.88 (t, 2 H, J = 7.7 Hz), 7.17–7.36 (m,
5 H), 7.67 (t, 1 H, J = 7.7 Hz). 13C NMR (100 MHz, CDCl3):
δ = 33.0, 33.6, 127.0, 128.5, 129.0, 131.8, 139.7, 140.2. MS
(EI, 70 eV): m/z (%) = 240, 238, 129, 91 (100), 65. Anal.
Calcd for C10H10BrNO2 (256.10): C, 46.90; H, 3.94; N, 5.47.
Found: C, 46.88; H, 3.97; N, 5.44.
(Z)-2-Bromo-5-(2-bromo-2-nitrovinyl)furan (5k)
Yellow solid, mp 87–89 °C. IR (neat): ν = 3134, 3036, 1618,
1537, 1505, 1348, 1292, 1025, 948, 818, 786, 645 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 6.61 (d, 1 H, J = 3.4 Hz), 7.37
(d, 1 H, J = 3.4 Hz), 8.50 (s, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 115.8, 122.3, 124.0, 125.1, 129.6, 148.6. MS
(EI, 70 eV): m/z (%) = 299, 297, 295, 225, 223, 221, 135,
133, 79, 63 (100). Anal. Calcd for C6H3Br2NO3 (296.90): C,
24.27; H, 1.02; N, 4.72. Found: C, 24.30; H, 1.03; N, 4.69.
Synlett 2013, 24, 114–116
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