SYNLETT0936-52141437-2096 Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart 2020, 31, A–F cluster A Integrated Synthesis Using Continuous- Synlett O. M. Griffiths et al. Cluster Photochemical Flow Oximation of Alkanes Oliver M. Griffithsa,b Michele Ruggeria Ian R. Baxendale*a a Department of Chemistry, University of Durham, South Road, Durham, Durham, DH1 3LE, UK [email protected] b Department of Chemistry, Cambridge University, South Road, Cambridge, Cambridgeshire, CB2 1EW, UK Published as part of the Cluster Integrated Synthesis Using Continuous-Flow Technologies Corresponding Author IanDepartmenteMail R. Baxendalea [email protected] of Chemistry, University of Durham, South Road, Durham, Durham, DH1 3LE, UK Received: 24.07.2020 In 2019 Lebl et al.8 reported a continuous version of the Accepted after revision: 19.08.2020 Toray process claiming 57% overall yield for the photochem- Published online: 21.09.2020 DOI: 10.1055/s-0040-1707281; Art ID: st-2020-u0416-c ical step and showing how the transformation could benefit from flow processing in terms of scaling-up, sustainability, Abstract The nitrosation of several alkanes using tert-butyl nitrite has reaction time, and safety. Despite the power of this strategy been performed in flow showing a remarkable reduction in the reaction it has several drawbacks, primarily amongst these is the time compared with batch processing. Due to the necessity for large ex- cesses of the alkane component a continuous recycling process was de- need to generate the unstable nitrosyl chloride (2) and the vised for the preparation of larger quantities of material. highly corrosive character of its reaction byproduct hydro- chloric acid. Consequently, several other nitrosylating Key words nitrosation, oximes, flow chemistry, Toray process, photo- agents have been studied, with alkyl nitrites9 showing good chemistry synthetic utility and being readily available especially tert- butyl nitrite. The corresponding oxamination reaction Oximes are an important class of molecules that have (Scheme 2), like the Toray process, also involves the photo- found numerous applications in many different fields such promoted dissociation of the nitrosylating agent 4, the as coordination chemistry,1 material science,2 and medici- alkoxy radical formed then abstracts a hydrogen atom from nal chemistry.3 The further importance of these molecules the hydrocarbon generating a second radical which can re- is also highlighted by the large number of important biolog- act with the remaining nitroso radical leading to the de- ically active compounds possessing this chemical moiety.4 sired product 3 after tautomerization. However, it has been However, the greatest application of oximes is often as in- shown that the main product of the reaction is actually the termediates in cascades, such as the named Beckmann rear- trans-configured dimer 510 whilst the desired oxime 3 is Downloaded by: University of Cambridge. Copyrighted material. rangement or the related fragmentation, and in their reac- obtained as only a minor product; however, the reaction tions leading to nitriles.5 shows good yields (>80% varying ratios 3/5).11 As a result Cyclohexanone oxime is a compound that exemplifies several batch methods have been devised to convert 5 into the aforementioned rearrangement chemistry being a pre- the synthetically more valuable oxime 3.12 cursor of caprolactam, itself a starting material for nylon-6 HO synthesis. Because of the immense industrial demand for O N N hν nylon there has been significant research into the prepara- O O N + N tion of all the intermediates along the chemical pipeline. 1 O Since the discovery of the Toray photonitrosation of cyclo- 4 5 3 hexane (PNC) process (Scheme 1),6 which enables oxime formation directly from cyclohexane in a single step with- Scheme 2 Nitrosation of cyclohexane with tert-butyl nitrile out going through the related ketone, interest in photo-oxi- mation7 has grown considerably. Interested in the synthetic potential of being able to ac- tivate normally inert alkanes and the inherent benefits of- HO 13 high-pressure N fered by conducting photochemical reactions in flow we mercury lamp + NOCl + HCl embarked upon a more in-depth study of this chemistry in HCl, 15 °C 2 flow. 1 86% 3 For our study we utilized a commercial Vapourtec E-se- ries flow reactor in combination with a UV 150 photochem- Scheme 1 The Toray process towards nylon-6 synthesis © 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany B Synlett O. M. Griffiths et al. Cluster ical add-on allowing constant monitoring of temperature Table 1 Selected Data for the Evaluation of the Molar Ratio 1/t-BuOH/4a and application of external cooling if required.14 The photo- reactor was equipped with a set of 365 nm LEDs (9 W) pro- Entry Molar ratio Temp (°C) tR (min) Total NMR Ratio of 1/tBuOH/4 conv. (%) 5/3 viding irradiation to a 10 mL FEP coiled tube flow reactor (1 mm ID). The choice of the light source was influenced by 1 100:0:1 50 10 66 5.4:1 the absorption spectra of the species involved in the trans- 2 100:0:1 28 10 55 6.4:1 formation. The absorption band responsible for the homo- 3 100:0:1 18 10 42 9.5:1 lytic breaking of t-BuONO lies between 320–430 nm, but is 4 100:0:1 18 20 41 4.3:1 partially overlapped, with the absorption band of the oxime product 3 and the dimer 5 which have a maximum at 300 5 100:15:1 28 10 58 6.3:1 nm but extends to around 360 nm. Wysocki et al.15 has 6 100:15:1 28 2.5 53 12.3:1 shown that efficient activation of t-BuONO can be achieved 7 100:15:1 28 1.25 37 6.4:1 using an emission between 365 and 405 nm and therefore a 8 100:15:1 50 5 60 6.2:1 set of 365 nm LEDs were used. However, this does introduce 9 200:30:1 50 5 62 10.5:1 some limitation regarding photon flux and can therefore 10 30:0:1 18 10 32 8.9:1 lead to the requirement for longer reaction times to ensure high conversions. 11 30:15:1 18 10 46 7.9:1 To establish the flow process, we used cyclohexane and 12 30:15:1 28 10 57 5.9:1 screened several molar ratios of reagents, temperature, and 13 30:15:1 50 10 68 4.6:1 flow rates in order to find optimum conditions for the 14 45:15:1 50 10 68 8.8:1 transformation. In their study, Wysocki et al.15 had deter- 15 60:15:1 50 10 67 10.1:1 mined that the addition of t-BuOH as an additive was highly beneficial to the reaction progress in batch. We therefore 16 45:0:1 50 10 69 6.2:1 additionally wished to validate this finding with respect to 17 15:30:1 50 10 55 4.5:1 the flow process (Table 1). 18 30:60:1 50 10 55 4.5:1 Several general observations can be made. Firstly, the a 10 mL flow coil; conversion vs an internal standard. reaction produces mainly the dimer 5 in accordance with previous-literature-reported batch results.16 Furthermore and in validation of Wysocki’s study15 the addition of t- tent with studies of Mackor et al. when high nitric oxide BuOH does have an impact on conversion (Table 1; cf. en- concentrations were employed.12 The impact of tempera- tries 3 and 5, 10 and 11) and also changes the ratio between ture is less clear but to discount a purely thermal fragmen- 5 and 3 in favor of the desired monomer 3; again in accor- tation process the reaction was also conducted (repeat of dance with their report (albeit not as significantly). Howev- Table 1, entry 9) without irradiation which resulted in re- er, the influence of the t-BuOH seems limited (cf. entries 13 covery of only unreacted starting materials. As higher tem- and 14, 17 and 18) and seemingly dilution (cf. entries 3 and peratures yield higher compositions of the monomer 3 it Downloaded by: University of Cambridge. Copyrighted material. 10) and more significantly temperature (cf. entries 1–3, 11– may be the monomer is more stable than the dimer 5 to de- 13) has a more pronounced effect on the reaction outcome composition and hence this accounts for the improved con- with regards to overall conversion and product composi- versions. tion. The fact that equitable results were obtained at higher We have previously found value in screening a range of reactor temperature (higher temperatures failed to give alkyl nitrites in other projects,17 therefore additional alkyl better results) without the addition of the t-BuOH suggests nitrite sources were evaluated (e.g. isoamyl nitrite, butyl ni- that under these conditions it does not play an important trite) but all gave inferior results (conversion/purity) com- role behaving only as a diluent (entries 1, 8, 9, 14, and 16). pared to tert-butyl nitrite. This is consistent with other lit- Finally, residence time indicates an optimal reaction win- erature studies12,15,18 explaining that non-tertiary alkyl ni- dow of between 5–10 min based upon this initial scoping. trites undergo undesirable side reactions, such as the Several of these observations can be rationalized. A high Barton reaction, when irradiated. dilution of the tert-butyl nitrite reduces competing termi- With good initial results from the direct reaction of tert- nation and side reactions which are competitive when us- butyl nitrite (4) and cyclohexane (1, Table 1, entry 16, 48% ing non-activated reactants such as cyclohexane.6–8 For ex- isolated yield of 5 by recrystallization from cyclohexane) ample, it was noted that nitrocyclohexane was formed in we decided to target these conditions for further optimiza- small amounts (2–9%) as a byproduct increasing propor- tion focusing on concentration and residence time (Table 2, tionally with higher concentration of tert-butyl nitrite Figure 1).