Nitro-Mannich reaction
The nitro-Mannich reaction (or aza-Henry reaction) is the
Although extensive research has been conducted into the aforementioned reactions, the nitro-Mannich reaction has been studied to a far lesser extent even though it has been known for well over 100 years.
History
Early Examples of the Nitro-Mannich Reaction
The first nitro-Mannich reaction was reported by Henry in 1896.
After Henry’s seminal report, Mousset
The next contributions appeared in 1946, when Senkus and Johnson independently reported their studies into the nitro-Mannich reaction. Senkus and co-workers
Up until this point, all of the nitro-Mannich methodologies reported had used imines that were formed in situ from an aldehyde and an amine. In 1950, Hurd and Strong reported[12] the first nitro-Mannich reaction using a preformed imine. Exposing an imine to a nitroalkane afforded a substituted beta-nitroamines in moderate yields. The moderate yields obtained when using the preformed imine could possibly be attributed to a competing decomposition pathway of the imine or the product.
These early nitro-Mannich methodologies have been used by a number of groups for the synthesis of a variety of heterocyclic products, conjugated nitroalkenes (via elimination of the amino group)[13][14] and dinitroamines.[15]
Non-Enantioselective Nitro-Mannich Reactions
Although the nitro-Mannich reaction enables access to synthetically useful beta-nitroamine motifs, the lack of selectivity in their synthesis remained a significant problem. Interest in the field started to increase considerably after Anderson and co-workers reported the first
The authors then converted the beta-nitroamines into unprotected 1,2-diamines via a two step procedure. Firstly, the nitro group was reduced to amines using samarium iodide, followed by PMB removal in the presence of ceric ammonium nitrate (CAN). The same group later reported improvements to this methodology and expanded these preliminary results in further publications.[16][17]
In 2000, Anderson and co-workers reported the
Following Anderson’s report, Qian and co-workers described the Ytterbium(III) trifluoromethanesulfonate [Yb(OiPr)3] catalysed nitro-Mannich reaction of N-sulfonyl imines and nitromethane.
Direct Metal Catalysed Enantioselective Nitro-Mannich Reactions
The first enantioselective metal catalysed nitro-Mannich reaction was reported by Shibasaki and co-workers in 1999.[20] The authors used a binaphthol ligated Yb/K heterobimetallic complex to induce enantiocontrol in the reaction, furnishing β-nitroamines in moderate to good yields with good enantioselectivities. However, nitromethane was the only nitroalkane that could be used with the heterobimetallic complex and the reactions were very slow (2.5–7 days) even when using a relatively high catalyst loading of 20 mol%.
Building on the work of Shibasaki, Jørgensen and co-workers reported the asymmetric nitro-Mannich reaction of nitroalkanes and a N-PMP-α-iminoesters.[21] Catalysed by Cu(II)-BOX 52 and triethylamine (Et3N), the reaction afforded β-nitro-α-aminoesters in good yields with excellent enantiocontrol (up to 99% ee). The reaction tolerates a selection of nitroalkanes but is limited exclusively to N-PMP-α-iminoesters. The authors propose that the reaction proceeds via the chair-like transition structure, where both the N-PMP-α-iminoester and the nitronate anion bind to the Cu(II)-BOX complex.
In 2007, Feng and co-workers reported that CuOTf used in conjunction with the shown chiral N-oxide ligand and
Around the same time as the report of Feng, Shibasaki and co-workers reported one of the most successful enantioselective nitro-Mannich reactions, catalysed by the shown Cu/Sm heterobimetallic complex.[23] Combining N-Boc protected imines and nitroalkanes resulted in moderate to excellent yields and good to excellent enantioselectivities of the products. Interestingly, the nitro-Mannich reaction catalysed by complex affords syn-β-nitroamines, whereas most other enantioselective methodologies favour anti-β-nitroamines. The authors later reported an improved version of the protocol and proposed a mechanistic rational to account for the observed syn diastereoselectivity.[24]
Organocatalysed Enantioselective Nitro-Mannich Reactions
Since the inception of organocatalysis, numerous accounts of organocatalysed enantioselective nitro-Mannich reactions have been reported.[1] These include examples using Brønsted base catalysts, Brønsted acid catalysts, bifunctional Brønsted base/H-bond donor catalysts and phase-transfer catalysts.
Bifunctional Brønsted Base/H-Bond Donor Organocatalysis
Small chiral molecule H-bond donors can be used as a powerful tool for enantioselective synthesis.
Building on the work of Jacobsen, it was recognised that H-bond donor motifs can be linked via a chiral scaffold to
Based on this concept, Takemoto and co-workers reported the first bifunctional Brønsted base/H-bond donor thiourea organocatalyst 62 (see below) in 2003.
Also the bifunctional thioureas 64 and 65, again derived from the cinchona alkaloids, are very effective catalysts in Michael addition reactions.
References
This article incorporates text by David Michael Barber available under the CC BY 2.5 license.
- ^ PMID 23461586.
- ^ R. Mahrwald, Modern Aldol Reactions; Wiley-VCH, Weinheim, 2004.
- .
- PMID 21405021.
- ^ a b L. Henry, Bull. Acad. Roy. Belg. 1896, 32, 33.
- ^ ISSN 0022-3263.
- ^ T. Mousset, Bull. Acad. Roy. Belg. 1901, 37, 622.
- ^ P. Duden, K. Bock, H. J. Reid, Chem. Ber. 1905, 33, 2036.
- ^ (a) H. Cerf de Mauny, Bull. Soc. Chim. 1931, 4, 1451; (b) H. Cerf de Mauny, Bull. Soc. Chim. 1931, 4, 1460.
- ISSN 0002-7863.
- ^ (a) H. G. Johnson, J. Am. Chem. Soc. 1946, 68, 12; (b) H. G. Johnson, J. Am. Chem. Soc. 1946, 68, 14.
- ISSN 0002-7863.
- ISSN 0002-7863.
- ISSN 0368-1769.
- ISSN 0022-3263.
- PMID 15651800.
- ISSN 0039-7881.
- .
- .
- PMID 10602222.
- PMID 12203626.
- PMID 18044933.
- PMID 17394322.
- PMID 20218689.
- ^ PMID 18072808.
- ISSN 0002-7863.
- ^ (a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672; (b) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am. Chem. Soc. 2005, 127, 119.
- PMID 15303849.
- PMID 16136258.
- ISSN 0936-5214.
- PMID 16136619.
- PMID 15876031.
- PMID 16429453.