Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Aug 17;22(8):971-977.
doi: 10.1021/acs.oprd.8b00113. Epub 2018 Jul 19.

Continuous Platform to Generate Nitroalkanes On-Demand (in situ) using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor

Sergey V Tsukanov  1   2 , Martin D Johnson  1 , Scott A May  1 , Stanley P Kolis  1 , Matthew H Yates  1 , Jeffrey N Johnston  2
Affiliations

Continuous Platform to Generate Nitroalkanes On-Demand (in situ) using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor

Sergey V Tsukanov et al. Org Process Res Dev. .

Abstract

The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with the use of peracid to prepare nitroalkane substrates, and the nitroalkanes themselves. In response, a continuous and scalable chemistry platform to prepare aliphatic nitroalkanes on-demand is reported, using the oxidation of oximes with peracetic acid and direct reaction of the nitroalkane intermediate in an aza-Henry reaction. A uniquely designed pipes-in-series plug flow tube reactor addresses a range of process challenges including stability and safe handling of peroxides and nitroalkanes. The subsequent continuous extraction generates a solution of purified nitroalkane which can be directly used in the following enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors in high selectivity, thus, completely avoiding isolation of potentially unsafe low molecular weight nitroalkane intermediate. A continuous campaign (16 h) established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution.

Keywords: continuous processing; flow chemistry; nitroalkane; peroxide; pipes-in-series reactor; sustainable or green chemistry.

PubMed Disclaimer

Conflict of interest statement

Notes The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Stoessel diagram for oxime oxidation by peracetic acid
Figure 2.
Figure 2.
Major drivers for continuous platform development
Scheme 1.
Scheme 1.
Methods for nitroalkane synthesis
Scheme 2.
Scheme 2.
Technological scheme of the continuous process
Scheme 3.
Scheme 3.
aza-Henry reaction of the continuously generated nitroalkane
See this image and copyright information in PMC

References

    1. Ono N in The Nitro Group in Organic Synthesis John Wiley & Sons, Inc., New York, USA, 2001.
    2. Feuer H, Nielsen H, A. T. Eds. Nitro Compounds: Recent Advances in Synthesis and Chemistry; VCH Publishers: New York, 1990.
    1. Rezazadeh S; Devannah V; Watson DA Nickel-Catalyzed C-Alkylation of Nitroalkanes with Unactivated Alkyl Iodides, J. Am. Chem. Soc 2017, 139, 8110. - PMC - PubMed
    2. Hughes DL Patent Review of Manufacturing Routes to Recently Approved PARP Inhibitors: Olaparib, Rucaparib, and Niraparib, Org. Proc. Res. Dev 2017, 21, 1227.
    1. Noble A; Anderson JC Nitro-Mannich Reaction, Chem. Rev 2013, 113, 2887. - PubMed
    1. Moreau B; Charette AB Expedient Synthesis of Cyclopropane α-Amino Acids by the Catalytic Asymmetric Cyclopropanation of Alkenes Using Iodonium Ylides Derived from Methyl Nitroacetate, J. Am. Chem. Soc 2005, 127, 18014. - PubMed
    2. Li H; Wang Y; Tang L; Wu FH; Liu XF; Guo CY; Foxman BM; Deng L Stereocontrolled Creation of Adjacent Quaternary and Tertiary Stereocenters by a Catalytic Conjugate Addition, Angew. Chem., Int. Ed. 2004, 44, 105. - PubMed
    3. Knudsen KR; Jorgensen KA A chiral molecular recognition approach to the formation of optically active quaternary centres in aza-Henry reactions, Org. Biomol. Chem 2005, 3, 1362. - PubMed
    4. (d) Shen B; Johnston JN A Formal Enantioselective Acetate Mannich Reaction: The Nitro Functional Group as a Traceless Agent for Activation and Enantiocontrol in the Synthesis of β-Amino Acids, Org. Lett 2008, 10, 4397. - PubMed
    1. Wilt JC; Pink M; Johnston JN A diastereo- and enantioselective synthesis of α-substituted anti-α,β-diaminophosphonic acid derivatives, Chem. Commun 2008, 35, 4177. - PubMed
    2. Blaszczyk R; Gajda A; Zawadzki S; Czubacka E; Gajda T N-Carbamate α-aminoalkyl-p-tolylsulfones—convenient substrates in the nitro-Mannich synthesis of secondary N-carbamate protected syn-2-amino-1-nitroalkanephosphonates, Tetrahedron 2010, 66, 9840.

LinkOut - more resources