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LETTER
Henry-Type Reaction of Aldehydes with Bromonitroalkanes
875
S.-S.; Cheng, H.-S.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125,
2958.
(3) Isaac, M. B.; Chan, T.-H. J. Chem. Soc., Chem. Commun.
1995, 1003.
(4) Augé, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron
Lett. 2002, 43, 5255.
(5) Hirashita, T.; Kinoshita, K.; Yamamura, H.; Kawai, M.;
Araki, S. J. Chem. Soc., Perkin Trans. 1 2000, 825.
(6) Araki, S.; Butsugan, Y. J. Chem. Soc., Chem. Commun.
1989, 1286.
O
O
O
O
H
O
O
O
O2N
HO
O
O
Zn (10 equiv)
In (0.12 equiv)
1g
O
O
+
THF
O
Br
NO2
O
(7) (a) Soengas, R. G.; Estévez, A. M. Eur. J. Org. Chem. 2010,
5190. (b) Soengas, R. G.; Estévez, A. M. Tetrahedron Lett.
2012, 53, 570. (c) Soengas, R. G.; Rodríguez-Solla, H.;
Alvaredo, N. in preparation.
O
O
2d
3h
Scheme 5 Indium-catalyzed Henry-type reaction of 5-bromo-2,2-
dimethyl-5-nitro-1,3-dioxane (2d) and galactose-derived aldehyde 1g
(8) (a) Aluminum, zinc, or manganese as regenerant: Araki, S.;
Jin, S.-J.; Idou, Y.; Butsugan, Y. Bull. Chem. Soc. Jpn. 1992,
65, 1736. (b) Loh, T.-P.; Li, X.-R. Angew. Chem., Int. Ed.
Engl. 1997, 36, 980. (c) Augé, J.; Lubin-Germain, N.;
Thiaw-Woaye, A. Tetrahedron Lett. 1999, 40, 9245.
(d) Augé, J.; Lubin-Germain, N.; Marque, S.; Seghrouchni,
L. J. Organomet. Chem. 2003, 679, 79. (e) Steurer, S.;
Podlech, J. Adv. Synth. Catal. 2001, 343, 251. (f) Preite, M.
D.; Jorquera-Geroldi, H. A.; Pérez-Carvajal, A. ARKIVOC
2011, (vii), 380.
The same complete anti selectivity was observed in the
stoichiometric indium-mediated reaction of 5-bromo-2,2-
dimethyl-5-nitro-1,3-dioxane (2d) and sugar aldehydes.7
The dominant effect comes from a lowering of the C–O
antibonding orbital bringing about an increased stabiliza-
tion of a Felkin–Anh antiperiplanar nucleophilic addition
of the organoindium species to the aldehyde carbonyl
group.14
(9) Sigma Aldrich on-line catalogue.
(10) Physical Data of 2-Nitro-1-phenylethanol (3a)
The aqueous workup gave 3a as a yellow oil. 1H NMR (300
MHz, CDCl3): d = 2.87 (br s, 1 H, OH), 4.53–4.61 (m, 2 H,
H-2), 5.29–5.50 (m, 1 H, H-1), 7.41–7.43 (m, 5 H, Ph) ppm.
(11) General Procedure for the Henry-Type Addition of
Bromoalkanes 2a–g to Aldehydes 1a–g
The appropriate bromonitroalkane 2a–g (1.5 mmol) was
added to a suspension of activated zinc powder (10 mmol)
and indium powder (0.12 mmol) in THF (2 mL), and the
mixture was sonicated for 20 min. The corresponding
aldehyde 1a–g (1 mmol) was then added, and sonication was
continued for a further 4 h. The reaction mixture was
quenched with sat. aq NaHCO3 (15 mL) and extracted with
Et2O (3 × 30 mL). The combined organic layers were dried
over MgSO4, filtered, and the solvent was evaporated in
vacuo to obtain the corresponding 2-nitroalkanols.
(12) As examples of the obtained nitroalkanols, we present the
physical data of compounds 3d,f–h.
In summary, we have demonstrated that zinc can be used
in the addition of bromonitroalkanes to aldehydes in the
presence of a catalytic amount of indium to afford the cor-
responding nitroalkanols. This economical protocol can
be easily scaled up to preparative amounts and overcomes
the major drawback of the indium-mediated Henry reac-
tion, which performs better than the classical base-cata-
lyzed reaction in terms of yields and substrate scope but
has been of limited interest in synthesis due to the high
cost of having to use stoichiometric amounts of expensive
indium powder.
Acknowledgment
Thanks are due to the University of Aveiro, Fundação para a Ciên-
cia e a Tecnologia (FCT) and FEDER for funding the Organic Che-
mistry Research Unit (project PEst-C/QUI/UI0062/2011) and the
Portuguese National NMR Network (RNRMN). R.S. thanks the
FCT for a ‘Investigador Auxiliar’ position.
1-(4-Methoxyphenyl)-2-methyl-2-nitropropan-1-ol (3d)
The aqueous workup afforded 3d as a yellow oil. 1H NMR
(300 MHz, CDCl3): d = 1.41 and 1.55 (2 s, 2 × 3 H, 2 CH3),
3.79 (s, 3 H, OCH3), 5.23 (br s, 1 H, OH), 5.28 (s, 1 H, H-1),
6.88 (d, 2 H, H-3,5 of Ar), 7.28 (d, 2 H, H-2,6 of Ar) ppm.
2,5-Dimethyl-2-nitrohexan-3-ol (3f)
After the aqueous workup 3f was obtained as a yellow oil.
1H NMR (300 MHz, CDCl3): d = 0.89–1.01 (m, 2 × 3 H, 2
CH3), 1.29–1.34 (m, 2 H, CH2), 1.42 and 1.53 (2 s, 2 × 3 H,
2 CH3), 1.79–1.83 (m, 1 H), 3.66–3.72 (m, 1 H) ppm.
1-Cyclohexyl-2-nitropropan-1-ol (3g)
The aqueous workup gave 3g as a 40:60 mixture of syn/anti
isomers. 1H NMR (400 MHz, CDCl3): 1.18–1.25 (m, 6 × 2
H, 6 CH2, syn + anti), 1.52–1.56 (m, 2 × 3 H, 2 CH3, syn +
anti), 1.66–1.78 (m, 4 × 2 H, 2 × 1 H, 4 CH2, 2 CH, syn +
anti), 3.67 (dd, J = 4.4, 7.3 Hz, 1 H, H-2, syn), 3.94 (dd,
J = 3.3, 8.2 Hz, 1 H, H-2, anti), 4.60–4.76 (m, 2 H, H-1, syn
+ anti) ppm.
References and Notes
(1) For reviews on indium chemistry, see: (a) Cintas, P. Synlett
1995, 1089. (b) Li, C. J. Tetrahedron 1996, 52, 5643.
(c) Marshall, J. A. Chemtracts: Org. Chem. 1997, 10, 481.
(d) Li, C. J. In Green Chemistry: Frontiers in Benign
Chemical Syntheses and Processes; Anastas, P.;
Williamson, T. C., Eds.; Oxford University Press: New
York, 1998, Chap. 14. (e) Paquette, L. A. Green Chemistry:
Frontiers in Benign Chemical Syntheses and Processes;
Anastas, P.; Williamson, T. C., Eds.; Oxford University
Press: New York, 1998, Chap. 15. (f) Li, C.-J.; Chan, T.-H.
Tetrahedron 1999, 55, 11149. (g) Ranu, B. C. Eur. J. Org.
Chem. 2000, 2347. (h) Podlech, J.; Maier, T. C. Synthesis
2003, 633.
(13) Physical Data of 1,2:3,4-Di-O-isopropylidene-6-(R)-(2,2-
dimethyl-5-nitro-1,3-dioxan-5-yl)-b-D-galacto-
heptopyranose (3h)
After aqueous workup and column chromatography
(EtOAc–hexane = 1:2) 3h was obtained as a colorless oil
(70%). 1H NMR (300 MHz, CDCl3): d = 1.33, 1.35, 1.36,
(2) (a) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53,
1831. (b) Araki, S.; Kamei, T.; Hirashita, T.; Yamamura, H.;
Kawai, M. Org. Lett. 2000, 2, 847. (c) Tan, K.-T.; Chang,
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Synlett 2012, 23, 873–876