Synthesis of Nitroolefins via the Direct Nitration of Alkenes

Key words

nitrooelfin - Michael acceptor - synthetic methodology - nitration - alkenes

(from left to right) Mohamed Hassan was born in Aswan (Egypt) in 1988. He graduated with BSc and MSc degrees in chemistry from Aswan­ University (Egypt). In 2019 he joined the group of Georg Manolikakes­ at the TU Kaiserslautern for his PhD with a joint supervision scholarship with Aswan University. His current field of research focuses on the chemistry and biochemistry of nitrated fatty acids.
Cedric Ndefo Nde studied chemistry at the University of Yaounde 1 (Cameroon), where he received his BSc and MSc degrees. In 2019 he joined the group of Georg Manolikakes for his PhD (funded by a DAAD doctoral fellowship). He is currently working on the synthesis of nitro fatty acid analogues.
Georg Manolikakes studied chemistry at the Ludwig-Maximilians University (LMU) Munich (Germany). At the LMU he joined the group of Prof. Paul Knochel and received his PhD in 2009 in the field of organometallic chemistry. After a postdoctoral stay with Prof. Phil S. Baran at the Scripps Research Institute (La Jolla, USA), he started his independent career at the Goethe-University Frankfurt (Germany) in 2010. In 2017, he was appointed as associate professor at the Technical University Kaiserslautern (Germany). His research interests cover multicomponent and one-pot reactions, the synthesis of sulfonyl-containing molecules, asymmetric synthesis, and medicinal chemistry with a particular focus on nitro fatty acids.

Nitroolefins are highly versatile building blocks for organic synthesis.[1] Their strongly electron-withdrawing nitro group renders the alkene highly electron deficient. Indeed, nitroalkenes are powerful electrophiles and undergo addition reactions with various different nucleophiles. Furthermore, the nitro group can be readily converted into various other functionalities such as amines, ketones, carboxylic acids, nitrile oxides, oximes, or hydroxylamines.[2] In addition, the nitroolefin moiety forms the key functionality in nitro fatty acids (NFAs), a class of potent endogenous lipid signaling mediators, which mainly act by posttranslational protein modification via nucleophilic addition of thiol residues to the electrophilic nitroalkene.[3] Consequently, the synthesis of nitroolefins has received considerable attention.[4] A two-step Henry reaction–condensation sequence is arguably the most common approach for the preparation of nitroolefins.[5] However, the direct nitration of alkenes provides a powerful and straightforward synthetic approach to the nitroolefin scaffold. Indeed, naturally occurring nitro fatty acids are formed by the reaction of reactive nitrogen species, such as nitric oxide, with the corresponding unsaturated acids.[6] Also the direct chemical nitration of alkenes has been reported already 60 years ago.[7] Since then, various new procedures for the direct nitration of alkenes have been reported.[4]

Herein, we want to highlight some of the most recent advances in the synthesis of nitroolefins via a direct nitration of their parent alkenes (Table [1]). Despite all recent advances, one should be aware that the stereo- and regioselective nitration of di- or trisubstituted olefins stills remains a considerable challenge. Whereas the direct nitration of terminal alkenes usually proceeds with almost excellent regio- and stereoselectivities, reactions starting from unsymmetrical internal alkenes usually afford an almost equimolar mixture of both possible regioisomers. Therefore, many studies solely focus on examples with terminal alkenes or symmetrical cycloalkenes.

Table 1 Synthesis of Nitroolefins via Direct Nitration

(A) Maiti (2013); Begari (2014) TEMPO-mediated nitration using AgNO2, Fe(NO3)3, or clay-supported Cu(NO3)2 (claycop) affords nitroolefins with exclusive E-selectivity. Particularly well suited for the nitration of terminal alkenes, also with complex scaffolds.
(B) Maiti (2013); Guo (2015) TEMPO-mediated nitration using NaNO2, or tBuONO affords nitroolefin with high E-selectivities.
(C) Kuhakarn (2014); Singh (2019) Room-temperature nitration with NaNO2, mediated by Oxone/KI or K2S2O8/TFA. Studies are almost exclusively limited to terminal alkenes.
(D) Corey (2021) Nitration with in situ generated triflyl nitrate. Amendable to the nitration of complex structures. Formation of allylic nitroolefins or rearrangement can occur­.
(E) Nacci (2020) Catalyst- and additive-free nitration with NaNO2, limited to styrenes.
(F) Katayev (2019) Photoredox-catalyzed nitration using a novel nitrating agent. Photochemically induced switching of the nitroolefin configuration for β-nitrostyrenes (R1 = Ar).

The group of Maiti disclosed two closely related methods for an efficient and predictable nitration of alkenes using either AgNO₂ or Fe(NO₃)₃ in combination with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as catalyst (entry A).[8] Both methods give access to various nitroolefins in high yields with a good tolerance towards functional groups with excellent E-selectivity. Although some examples with internal alkenes are reported, both reactions seem to be particularly well suited for terminal alkenes. The utility of these methods was demonstrated in the nitration of natural product derived alkenes. Later, Begari and co-workers reported a similar method using clay-supported Cu(NO₃)₂ (claycop) as mild nitrating agent.[9] Recently, Maiti and Guo described analogous, TEMPO-mediated nitrations of alkenes using either tert-butyl nitrite (tBuONO) or NaNO₂ (entry B).[10] Although both methods do not utilize (transition) metals, additional oxidants (air or K₂S₂O₈) and (sub)stoichiometric amounts of TEMPO are necessary. Two attractive alternatives for the direct nitration of alkenes using NaNO₂ were described by Kuhakarn and Singh (entry C).[11] Both reactions proceed readily at ambient temperature, mediated either by a combination of Oxone and KI or K₂S₂O₈ and trifluoroacetic acid (TFA). Unfortunately, the scope of these methods seems limited and both processes proceed efficiently only with styrenes or monosubstituted alkenes. A closely related reaction with tBuONO and K₂S₂O₈ by the group of Patel gives access to different product types, depending on the starting material structure, and is therefore of limited use for a general preparation of nitroolefins.[12] A recently reported process from Corey based on in situ generated triflyl nitrate provides a useful process for the direct conversion of olefins into nitroolefins (entry D).[13] This procedure was successfully employed for the nitration of more complex substrates. However, in several cases, the reaction conditions led to the formation of the allylic nitroolefins or a rearrangement product instead. Nacci and co-workers reported a straightforward ionic liquid controlled nitration of alkenes with NaNO₂ (entry E).[14] Employing the imidazolium-based ionic liquid [Bmim]Cl (1-butyl-3-methylimidazolium chloride) styrenes were efficiently converted into the corresponding nitroolefins in the absence of any additional catalyst or mediator. Unfortunately, this process seems solely limited to monosubstituted styrenes. The group of Katayev introduced N-nitrosuccinimide as a versatile and inexpensive nitrating agent (entry F).[15] This reagent was successfully employed for a visible-light-mediated, photoredox-catalyzed nitration of alkenes, affording E-nitroolefins in good yields and high stereoselectivities. As before, the reported substrate scope mostly includes terminal alkenes, but also some more complex, druglike scaffolds. Interestingly, the authors could induce a photoisomerization of the E- to the Z-nitroolefin upon prolonged irradiation. Thereby, this method offers a so far very rare access to the thermodynamically unfavored nitro­alkene, albeit limited to β-nitrostyrenes.

In conclusion, the direct nitration of alkenes has become a versatile synthetic tool for the construction of the nitro­olefin scaffold from simple alkenes. Current methods are particularly well suited for the regio- and stereoselective nitration of terminal alkenes. On the other hand, the regio­selective nitration of unsymmetrical internal alkenes remains a challenge yet to be solved.

Conflict of Interest

The authors declare no conflict of interest.

• References

• 1 Barrett AG. M, Graboski GG. Chem. Rev. 1986; 86: 751
• 2 Ono N. The Nitro Group in Organic Synthesis . Wiley-VCH; New York: 2001
• 3 Piesche M, Roos J, Kühn B, Fettel J, Hellmuth N, Brat C, Maucher IV, Awad O, Matrone C, Comerma SteffensenS. G, Manolikakes G, Heinicke U, Zacharowski KD, Steinhilber D, Maier T. J. Front. Pharmacol. 2020; 11: 1297
• 4 Yan G, Borah AJ, Wang L. Org. Biomol. Chem. 2014; 12: 6094

For two recent examples, see:
• 5a Hassan M, Krieg S.-C, Ndefo Nde C, Roos J, Maier TJ, El Rady EA, Raslan MA, Sadek KU, Manolikakes G. Eur. J. Org. Chem. 2021; 2239
• 5b Ishitani H, Saito Y, Tsubogo T, Kobayashi S. Org. Lett. 2016; 18: 1346
• 6 Freeman BA, Baker PR. S, Schopfer FJ, Woodcock SR, Napolitano A, d’Ischia M. J. Chem. Biol. 2008; 283: 15515
• 7 Tinsley SW. J. Org. Chem. 1961; 26: 4723
• 8a Maity S, Manna S, Rana S, Naveen T, Mallick A, Maiti D. J. Am. Chem. Soc. 2013; 135: 3355
• 8b Naveen T, Maity S, Sharma U, Maiti D. J. Org. Chem. 2013; 78: 59545
• 9 Begari E, Singh C, Nookaraju U, Kumar P. Synlett 2014; 25: 1997
• 10a Maity S, Naveen T, Sharma U, Maiti D. Org. Lett. 2013; 15: 3384
• 10b Zhao A, Jiang Q, Jia J, Xu B, Liu Y, Zhang M, Liu Q, Luo W, Guo C. Tetrahedron Lett. 2016; 57: 80
• 11a Hlekhlai S, Samakkanad N, Sawangphon T, Pohmakotr M, Reutrakul V, Soorukram D, Jaipetch T, Kuhakarn C. Eur. J. Org. Chem. 2014; 7433
• 11b Ambala S, Singh R, Singh M, Cham PS, Gupta R, Munagala G, Yempalla KR, Vishwakarma RA, Singh PP. RSC Adv. 2019; 9: 30428
• 12 Mir BA, Singh SJ, Kumar R, Patel BK. Adv. Synth. Catal. 2018; 360: 3801
• 13 Reddy GS, Corey EJ. Org. Lett. 2021; 23: 3399
• 14 Casiello M, Caputo D, Fusco C, Cotugno P, Rizzi V, Dell’Anna MM, D’Accolti L, Nacci A. Eur. J. Org. Chem. 2020; 6012
• 15 Zhang K, Jelier B, Passera A, Jeschke G, Katayev D. Chem. Eur. J. 2019; 25: 12929

Publication History

Received: 07 July 2021

Accepted after revision: 29 July 2021

Accepted Manuscript online:
03 August 2021

Article published online:
13 August 2021