What is nucleophilic aromatic substitution (SNAr)?
Nucleophilic aromatic substitution, also known as SNAr, occurs when a nucleophile displaces a halide (or another suitable leaving group) on an aromatic ring. It is commonly used within the pharmaceutical and agrochemical industries to install aliphatic and aromatic amines onto an aromatic ring, which can then be further functionalised, for example through heterocycle formation or protection/deprotection sequences.
In order for this reaction to occur, the aromatic ring needs to be electron-deficient, which is usually achieved through a nitro group bonded to the ring, or through the use of aromatic heterocycles such as pyridine. Mechanistically, the transformation involves a stepwise addition–elimination sequence, with the first step being attack of the nucleophile to form the Meisenheimer complex that is followed by loss of the leaving group [1].
Scheme 1: General scheme for an SNAr reaction.
When installing nucleophiles of moderate molecular weight, for example morpholine, SNAr is relatively straightforward, with reaction conditions usually only requiring the amine, substrate, heat and solvent. However, when the nucleophile to be introduced is volatile, or a gas, the situation becomes more difficult, and this is where flow chemistry can provide significant advantage over batch processes, especially when in-line purification, or telescoping of steps, are included in the set-up.
Examples of continuous flow for SNAr
Örkényi and Greiner used a continuous flow multistep sequence to prepare drug-like anilines from nitrobenzenes in an efficient manner [2]. In this sequence, 2,4-difluoronitrobenzene was treated with morpholine in EtOH, Scheme 2. The crude mixture was subjected to hydrogenation, and the final products isolated and purified in good yield. Further optimisation included in-line purification through phase separation, giving access to high purity products (not shown).
Scheme 2: Treatment of 2,4-difluoronitrobenzene with morpholine, followed by reduction to give the aniline.
The second example includes in-line generation of dimethylamine, which circumvents the issues faced when using gaseous materials in flow [3]. For example, the small volume of the flow reactor means that the explosion risk due to excessive pressure build-up is minimised, and scale-up is facilitated by running the reaction for longer. Two methods were used: a one-step method that was suitable for less sensitive reagents, and a two-step method, where dimethylamine was generated and nucleophilic substitution were undertaken in two separate reactors, allowing independent variation of temperatures and residence times (not shown). Scale-up allowed access to 8.8 g of N4,N4,6-trimethylpyrimidine-2,4-diamine (83% yield), corresponding to a space time yield of 65 g/h/L, Scheme 3. In both cases, purification required separation and flash column chromatography and yields were comparable.
Scheme 3: Scale-up of N4,N4,6-trimethylpyrimidine-2,4-diamine preparation.
The final example showcases the use of continuous stirred-tank reactors (CSTRs), where up to 10 kg per day of 4-(2-fluoro-4-nitrophenyl)morpholine was prepared, which is a key intermediate in the synthesis of Linezolid, Scheme 4. Substitution of 3,4-difluoronitrobenzene with morpholine generated a poorly soluble product, which blocked the tubular reactors, alongside stoichiometric quantities of an insoluble fluoride salt. To circumvent issues caused by these solids, an integrated CSTR was used that enabled the handling of solids, separation of liquids and gases without requirement for a membrane separator, access to longer reaction times and active mixing.
Scheme 4: Use of CSTRs for kilo-scale preparation of 4-(2-fluoro-4-nitrophenyl)morpholine, a key intermediate in the synthesis of Linezolid.
References
[1] High-Throughput Experimentation and Continuous Flow Evaluation of Nucleophilic Aromatic Substitution Reactions (Z. Jaman, D. L. Logsdon, B. Szilágyi, T. J. P. Sobreira, D. Aremu, L. Avramova, R. G. Cooks and D. H. Thompson, ACS Comb. Sci., 2020, 22, 4, 184 – 196) https://dx.doi.org/10.1021/acscombsci.9b00212
[2] Continuous Synthesis and Purification by Coupling a Multistep Flow Reaction with Centrifugal Partition Chromatography (R. Örkényi, J. Éles, F. Faigl, P. Vincze, A. Prechl, Z. Szakács, J. Kóti and I. Greiner, Angew. Chem. Int. Ed., 2017, 56, 8742 – 8745) https://doi.org/10.1002/anie.201703852
[3] Continuous Flow Nucleophilic Aromatic Substitution with Dimethylamine Generated in Situ by Decomposition of DMF (T. P. Petersen, A. F. Larsen, A. Ritzén and T. Ulven, J. Org. Chem., 2013, 78, 8, 4190 – 4195) https://doi.org/10.1021/jo400390t
