F. K. MacDonald et al. / Tetrahedron Letters 52 (2011) 891–893
893
explained through steric factors because of the larger yield
obtained for 1-t-butyl-2-nitroethanol 5b. This data indicate that a
secondary carbon alpha to the carbonyl functionality lowers the
yield of the desired Henry reaction product. It should be noted that
the reaction for these two substrates was repeated and the yield of
the b-nitroalcohol was comparable.
article can be found, in the online version, at doi:10.1016/
References and notes
1. (a) Henry, L. C.R. Acad. Sci., Ser. C 1895, 1265; (b) Henry, L. Bull. Soc. Chim. Fr.
1895, 13, 999; For a recent review, see: (c) Palomo, C.; Oiarbide, M.; Laso, A. Eur.
J. Org. Chem. 2007, 2561.
2. Petrini, M.; Ballini, R.; Rosini, G. Synthesis 1987, 713.
3. Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
Aromatic aldehydes also afforded the b-nitroalcohol product,
although the reaction times were slightly longer than the aliphatic
aldehydes and a very small amount of aldehyde always remained,
as evaluated by TLC. Warming the reaction to room temperature
did not change the outcome of the reaction. The reaction of
p-methoxybenzaldehyde, o-methoxybenzaldehyde, and benzalde-
hyde with 3 afforded the trimethylsilyl protected b-nitroalcohol
along with the desired Henry reaction product 5. The overall yield
of a new carbon–carbon bond formation from the Mukaiyama
nitro-aldol reaction for these three substrates is 34%, 74% and
64% respectfully. All other examples using aromatic aldehydes
afforded only b-nitroalcohol and the yields are stated in Table 2.
To try and understand this one pot procedure, the reaction with
isovaleraldehyde was repeated, except during this attempt, TMSCl
was not added to the reaction vessel. As expected, the reaction did
not progress at all. Only isovaleraldehyde was recovered from this
reaction. Thus, the introduction of the in situ generated trimethyl-
silyl methylenenitronate was key for the Henry reaction to proceed
in equimolar amounts with the aldehyde and substoichiometric
amounts of scandium triflate.
4. (a) Angelin, M.; Rahm, M.; Fischer, A.; Brinck, T.; Ramström, O. J. Org. Chem.
2010, 75, 5882; (b) Tsuchiya, S.; Sunazuka, T.; Hirose, T.; Mori, R.; Tanaka, T.;
Iwatsuki, M.; Omura, S. Org. Lett. 2006, 8, 5577; (c) Boruwa, J.; Gogoi, N.; Saikai,
P. P.; Barua, N. C. Tetrahedron: Asymmetry 2006, 17, 3315; (d) Luzzio, F. A.
Tetrahedron 2001, 57, 915; (e) Ono, N. In The Nitro Group in Organic Synthesis;
Feuer, H., Ed.; Wiley-VCH: New York, 2001; p 30. Chapter 3.
5. Sedova, V. F.; Krivopalov, V. P.; Shkurko, O. P. Russ. J. Org. Chem. 2007, 43, 90.
6. For recent examples, see: (a) Xu, H.; Wolf, C. Chem. Commun. 2010, 46, 8026; (b)
Khann, H. H.; Prasetyanto, E. A.; Kim, Y.-K.; Ansari, M. B.; Park, S.-E. Catal. Lett.
2010, 140, 189; (c) Mayani, V. J.; Abdi, S. H. R.; Kureshy, R. I.; Khan, N. H.; Das,
A.; Bajaj, H. J. Org. Chem. 2010, 75, 6191.
7. Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44, 3881.
8. For recent examples, see: (a) Wang, Q.; Shantz, D. J. Catal. 2010, 271, 170; (b)
Cheng, L.; Dong, J.; You, J.; Gao, G.; Lan, J. Chem. Eur. J. 2010, 16, 6761; (c)
Palmieri, A.; Gabrielli, S.; Ballini, R. Chem. Commun. 2010, 46, 6165.
9. (a) Bandgar, B. P.; Zirange, M. B.; Wadgaonkar, P. P. Synlett 1996, 149; (b)
Rosini, G.; Ballini, R.; Petrini, M.; Sorrenti, P. Synthesis 1985, 515.
10. (a) Chiozza, L. Ann. 1856, 97, 350; (b) Wurtz, A. Compt. Rend. 1872, 74, 1361; (c)
Perkin, W. Chem. Ber. 1882, 15, 2802; For a recent example of this reaction, see:
(d) Kanger, T.; Kriis, K.; Laars, M.; Kailas, T.; Muurisepp, A.-M.; Pehk, T.; Lopp,
M. J. Org. Chem. 2007, 72, 5168.
11. (a) Cannizzaro, S. Ann. 1853, 88, 129; For a recent example of this reaction, see:
(b) Abaee, M. S.; Sharifi, R.; Mojtahedi, M. M. Org. Lett. 2005, 7, 5893.
12. (a) Tishtschenko, W. J. Russ. Phys. Chem. 1906, 38, 355; For a recent example of
this reaction, see: (b) Mojtahedi, M. M.; Akbarzadeh, E.; Sharifi, R.; Abaee, M. S.
Org. Lett. 2007, 9, 2791.
3. Typical experimental conditions
13. (a) Colvin, E. W.; Seebach, D. J. Chem. Soc., Chem. Commun 1978, 689; (b) Colvin,
E. W.; Beck, A. K.; Seebach, D. Helv. Chim. Acta 1981, 64, 2264.
14. (a) Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442; (b)
Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054; (c) Knudsen, K.
R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgenson, K. A. J. Am. Chem. Soc.
2001, 123, 5843.
Nitromethane (0.14 mL, 2.60 mmol) in anhydrous THF (10 mL)
was cooled to À78 °C and 1.6 M BuLi in hexanes (1.63 mL,
2.60 mmol) was added. The reaction mixture was stirred for fifteen
minutes. TMSCl (0.33 mL, 2.60 mmol) was then introduced and the
reaction mixture was stirred for an additional 15 min. Scan-
dium(III) triflate (0.10 mmol) dissolved in THF (5 mL) was added
to the mixture and immediately followed by the appropriate alde-
hyde (2 mmol). The reaction mixture was stirred at À78 °C for 18–
120 h as indicated in Table 2 and the solvent was then removed
under reduced pressure. Products were purified by flash chroma-
tography (silica gel, 20% ethyl acetate/hexanes or 30% ethyl ace-
tate/hexanes as eluent) to afford the b-nitroalcohol product. Each
product was characterized by spectroscopic methods and the ac-
quire data agreed with reported literature values (5a,23 5b,23
5c,23 5d,24 5e,25 5f,26 5g,27 5h,28 5i,28 5j,28 5k,28 5l,29 5m,28).
In conclusion, the first Mukaiyama nitro-aldol reaction with
nitromethane as the starting nitroalkane is presented. Unlike pre-
vious examples, the reaction conditions are acidic and do not use
an anhydrous fluoride source to promote the reaction, which is
similar to the original conditions stated by Mukaiyama.17 This
reaction has been performed with equimolar amounts of nitronate
and aldehyde, which could enable more elaborate nitronate mole-
cules to be used in the Henry reactions. The diastereoselectivity of
this reaction is presently being investigated.
15. Risgaard, T.; Gothelf, K. V.; Jørgenson, K. A. Org. Biomol. Chem. 2003, 1, 153.
16. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo,
C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi,
R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, Revision B.05; Gaussian: Pittsburgh, PA, 2003.
17. (a) Torssell, K. B. G.; Zeuthen, O. Acta Chem. Scand. 1978, B32, 118; (b) Colvin, E.
W.; Beck, A. K.; Bastani, B.; Seebach, D.; Kai, Y.; Dunitz, J. D. Helv. Chim. Acta
1980, 63, 697.
18. (a) Wang, C.-L. J.; Calabrese, J. C. J. Org. Chem. 1991, 56, 4341; (b) Das, N. B.;
Torssell, K. B. G. Tetrahedron 1983, 39, 2247.
19. Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.
20. For recent examples, see: (a) Landa, A.; Minkkilä, A.; Blay, G.; Jørgenson, K. A.
Chem. Eur. J. 2006, 12, 3472; (b) Remy, P.; Langner, M.; Bolm, C. Org. Lett. 2006,
8, 1209.
21. For recent examples, see: (a) Crimmins, M. T.; Smith, A. C. Org. Lett. 2006, 8,
1003; (b) Delas, C.; Blacque, O.; Moise, C. Tetrahedron Lett. 2000, 41, 8269.
22. Denmark, S. E.; Lee, W. J. Org. Chem. 1994, 59, 707.
Acknowledgments
23. Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2003, 125, 12692.
The authors would like to acknowledge funding from the Na-
tional Science and Engineering Council of Canada, Canadian Foun-
dation of Innovation and Mount Saint Vincent University’s
Committee of Research and Publication that supported this work.
24. Taylor, E. C.; Liu, B. J. Org. Chem. 2003, 68, 9938.
25. Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1993, 58, 3850.
26. Concellón, J. M.; Roderiguez-Solla, H.; Concellón, C. J. Org. Chem. 2006, 71, 7919.
27. McNulty, J.; Dyck, J.; Larichev, V.; Capretta, A.; Robertson, A. J. Lett. Org. Chem.
2004, 1, 137.
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29. Bray, C. V.-L.; Jiang, F.; Wu, X.-F.; Sortais, J.-B.; Darcel, C. Tetrahedron Lett. 2010,
51, 4555.
Supplementary data
Supplementary data (detailed experimental as well as the spec-
troscopic data for all compounds generated) associated with this