A continuous-flow resonator-type microwave reactor for high-efficiency organic synthesis and Claisen rearrangement as a model reaction
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We have developed a single-mode microwave reactor for continuous-flow synthesis with various methods of operation. This device measures the resonant frequency and modulates the oscillation frequency accordingly to maintain the maximum electric field intensity in the cavity. It can be operated either using constant applied irradiation power or using new programs which change the electric power (E-GRA) and change the flow rate (Fl-GRA), in order to rapidly screen various reaction conditions. As a model reaction, the Claisen rearrangement reaction of allyl 1-naphthyl ether 1 was rapidly optimized in this device, affording the desired product 2-allylnapthalen-1-ol 2 in high (91%) yield and up to 20 g/h productivity.
KeywordsContinuous flow Microwave Single-mode microwave reactor Flow synthesis Claisen rearrangement
Conventionally, organic reaction systems are heated by external heaters such as oil baths. However, over the last 30 years microwave (MW) heating has been utilized [1, 2] due to its advantages such as non-contact heating (which reduces the overheating of material surfaces), energy transfer instead of heat transfer (penetrative radiation) and material selectivity. Moreover, MW heating has the ability to rapidly heat or cool mixtures, where and heat transfer can benefit from the transport of heat from the interior of the reactor outward, instead of the transport of heat from the surface of reactor inward . MW heating often gives higher yields and purities of products in shorter time periods than conventional heating . Hence, the number of reports on organic synthesis using MW heating has grown in the past decades [5, 6].
The MW oscillator is either a magnetron or a solid-state device, which differ in their profile of emitted frequencies and output power. Whilst the magnetron is capable of several hundred watts of MW power, it emits numerous MW frequencies over a broad distribution and the frequency cannot be controlled. Regarding MW-assisted chemical reactions, magnetron oscillators have typically been utilized. The cavity which accepts the MW irradiation is either a multimode or single-mode cavity. Multimode cavities work by accepting the broad range of MW frequencies emitted by the magnetron at various orientations (modes) and allowing them to distribute randomly within the cavity [7, 8]. Single-mode cavities work by generating a definable MW waveform [7, 8, 9, 10, 11]. Compared to multimode cavities, single-mode cavities have higher energy efficiency and well-defined electromagnetic fields which can be matched to the reactor vessel geometry and position.
Several batch reaction-type MW reactors have been commercially available since 1997 [12, 13, 14, 15]. These reactors use a magnetron oscillator to irradiate a load within either a multimode or a single-mode cavity. Under multimode irradiation, it is difficult to control local temperature distribution due to the unknown and uneven distribution of the MW intensity. In some cases, MW energy does not propagate through the load and is instead reflected and converted into undesired forms of energy. On the other hand, single-mode irradiation harnesses a greater proportion of the energy distribution and in a well-designed reaction vessel, energy can be efficiently propagated. In either case, however, it is difficult to scale up MW-mediated syntheses from laboratory scale to production scale simply by using a larger reactor. This is because (1) the penetration depth of microwaves into the absorbing target is restricted and (2) if the reaction is carried out under high pressure, there can be a significant danger of the reaction vessel undergoing malfunction and/or rupture. Notably, a continuous-flow approach bypasses both problems.
Continuous-flow processing has shown benefits over batch processing mode in terms of environmental impact, efficiency and safety . By combining a continuous-flow system with MW heating, it is possible to scale up MW chemistry without necessarily increasing the size of the reaction vessel. The synergy of MW heating and flow chemistry was pioneered by Strauss et al. [17, 18] and Wang et al.  almost three decades ago. Initial efforts used a commercially available MW oven fitted with a reaction tube for flow. Such systems were expected to become powerful tools in organic synthesis . Indeed, there have been several reports on organic synthesis in this context such as Pd-catalyzed C-C bond formations [20, 21, 22, 23, 24], biodiesel synthesis [25, 26, 27, 28, 29] and others [30, 31, 32, 33], using a flow-type MW device. Flow-type MW heating in a microcapillary reactor has also been utilized in various reactions [34, 35, 36, 37]. Recently, several reactions were demonstrated on gram/h scale by placing a custom-made flow cell within a commercially available MW device [38, 39, 40, 41, 42, 43]. Commercially available MW flow reactors are also available [15, 44]. However, the distribution of electromagnetic field in these commercial devices is poorly characterized, so the irradiation distribution is hard to define. If the distribution of the electromagnetic field within the cavity is known, it is possible to efficiently and reproducibly irradiate a reaction vessel at the same position with the same MW power in order to realize the reproducibility of the target reaction.
We previously reported a single-mode MW device for continuous-flow synthesis (MW flow reactor), with a resonator in which the electric field is well-amplified and well-characterized . The MW generator is a solid-state device which generates a uniform electromagnetic field within the cavity. Tuning of the irradiation frequency uses a technology which adjusts the frequency for detected electric power in the resonator to be maximized. Moreover, the reactor can tolerate high pressures (MPa) and allow the straightforward and safe operation of reactions at temperatures above the boiling point at normal pressure. We previously demonstrated the syntheses of carbazole derivatives  and the Diels-Alder reactions of fullerenes with indene derivatives  using this apparatus. Ley et al. have used it in the syntheses of β-lactams . Very recently, further applications of this device to other classes of reactions have been disclosed [48, 49, 50, 51, 52]. These reactions all required elevated conditions of temperature and pressure and were ideally suited to scale-up in the aforementioned MW flow reactor.
Compared to conventionally-heated stainless-steel coil flow reactors [53, 54, 55], the MW flow reactor benefits from 1) faster data acquisition toward optimization, by virtue of the ability to rapidly heat or cool mixtures under MW irradiation  and 2) negligible thermal expansion (even up to 270 °C) due to the lower coefficient of thermal expansion of reactor material (Duran) combined with engineering controls . Thermal expansion has been shown to result in up to ca. 40% larger collected reaction mixture volume than expected when operating at elevated temperatures (up to 300 °C) in a stainless-steel coil flow reactor . Moreover, reports of thermal and non-thermal MW heating effects  which benefit reaction conversion may be realized in this device.
The Claisen rearrangement is another class of reaction which generally requires high temperature and has previously benefitted from conventionally-heated flow reactors [57, 58, 59]. Herein, we report the incorporation and application of new operation programs into this MW flow reactor, which either 1) hold the flow rate constant and vary the applied MW power (E-GRA) or 2) hold the MW power constant and vary the flow rate (Fl-GRA). Thus, many reaction conditions can be rapidly screened in a short time allowing optimum reaction conditions to be quickly identified. The Claisen rearrangement of an allyl 1-naphthyl ether 1 was chosen as a model reaction for this study .
Results and discussion
This device has a built-in resonance frequency measurement system and a solid-state oscillator controlled by an algorithm that modulates the resonance frequency, so that the electromagnetic wave intensity in the cavity is maintained at the maximum. The exit temperature of the reaction solution is directly measured using a thermocouple installed at the outlet of the flow channel, set at a position which does not interact with the microwaves in the cavity. In summary, the present device can monitor and control the MW irradiation power, the reflected power, the electric field in the cavity, the pressure of the reaction solution and the exit temperature of the reaction solution at the outlet of the flow channel in real time.
Resonant frequencies and reflectances of various solvents measured by the MW flow reactor's in-built ‘Peakfinder’ functiona
Resonant frequency (GHz)
44.2 – j 11.1
36.9 – j 5.2
35.4 – j 1.8
18.6 – j 1.1
7.5 – j 7.0
7.25- j 0.2
6.2 – j 0.3
4.38 – j 0.17
2.70 – j 0.08
2.5 – j 0.1
2.14 - j 0.001
CPME is an acyclic ether solvent that can be used as a replacement for diethyl ether in a wide temperature range from −140 °C to 106 °C . It is easy to remove due to its low latent heat of evaporation, has a high ability to solubilize various organic substances and has high stability without producing peroxide. The εr’-jεr” value of CPME at 2.45 GHz was 4.38-j0.17 and the reflectance in this system was 17.5%. Hence, CPME is a low polarity solvent whose MW heating is challenging due to low MW absorption. Therefore, heating of CPME was attempted using this device.
As the applied power of the MW increased, the temperature of the CPME first increased almost proportionally, reaching about 270 °C at 60 W. At higher applied MW powers, the temperature was almost steady and is presumed to be the boiling point of CPME at 2.5 MPa . The above data show that CPME can be heated to very high temperatures (270 °C) at only 60 W using the MW flow reactor, with a flow rate of 1.0 mL/min and under back pressure of 2.5 MPa.
With an applied power of 60 W, the temperature of the solution reached 264 °C and the conversion of 1 was 98.7%, indicating that the reaction proceeded almost quantitatively at the corresponding residence time (RT = 1 min). Traces of unreacted 1 (1.3%), in addition to the o-Claisen rearrangement product 2-allyl-1-naphthol (2) (86.3%) and a small amount of p-Claisen rearrangement product 4-allyl-1-naphthol (3) (3.3%) were observed in the reaction mixture. In Claisen rearrangements of allyl aryl ethers, the o-Claisen rearrangement product often undergoes enolization to give an o-allyl phenol derivative [65, 66]. Moreover, it is known that the p-Claisen rearrangement product occurs for allyl aryl ethers with substitution at the o-position via Cope rearrangement of the enol intermediate . A previous study showed that the reaction of 1 produces both 2 and 3 .
As the flow rate decreased, both the residence time of the solution and the temperature increased. Therefore, the conversion of 1 and the yield of 2 increased as the solution temperature rose (Table SI-5). On the other hand, the yield of 3 at its maximum at the flow rate of 1.0 mL/min (225 °C) and decreased at flow rates slower than 1.0 mL/min (and higher temperatures than 225 °C). This is the same trend as the E-GRA method, which gave the maximum yield of 3 at the same specific temperature (ca. 226 °C). When the residence time was longer, the reaction selectivity favoured 2. At the lowest flow rate of 0.6 mL/min, the temperature became ca. 232 °C and 1 reacted completely. We found that the reaction was accelerated by the temperature rises as a result of (and possibly in addition to) the longer residence times employed.
Relationship between concentration of 1, complex permittivity ε and tan δ
Concentration of 1
εr’ @ 2.45 GHza
εr” @ 2.45 GHza
tan δ @ 2.45 GHz
Based on the above findings, the operation time for the Claisen rearrangement of 1 was extended under the appropriate conditions (2.0 M, 50 W, flow rate 1.0 mL/min, back pressure 2.5 MPa). A solution containing 11.1 g of 1 was processed over 30 min at 259.9 °C. The crude yields of 2 and 3 were 91.3% and 2.6%, translating to productivities of 20.26 g/h and 0.29 g/h, respectively. The isolated yields of 2 and 3 after purification were 9.17 g (82.6%) and 0.29 g (2.6%), respectively. Thus, scalability of the Claisen rearrangement of 1 was demonstrated in the MW flow applicator as well as the ability to safely execute the process at a temperature > 100 °C higher than the b.p. of the solvent (CPME) over an extended operation time. Regarding scalability, the g/h productivity and employed flow rate of the MW flow Claisen rearrangement herein are similar to (or superior to) previously reported Claisen rearrangements in conventionally-heated flow reactors [57, 58, 59].
A continuous-flow MW device (MW flow reactor) was developed with adjustable applied MW power and flow rate, which was applied to the Claisen rearrangement reaction of allyl 1-naphthyl ether as a model reaction. The effects of MW power, flow rate and reactant concentration on the yield and productivity were examined. By virtue of the ability to rapidly change reaction temperature by MW heating, combined with the ability of continuous-flow to quickly screen different reaction conditions, the optimal reaction temperature was swiftly identified by screening 14 different temperatures in just 3.5 h. Prolonged continuous operation was performed under the determined optimum reaction conditions, to demonstrate scalability and viability toward production. Finally, whilst it is generally thought that solvents with poor MW absorption (low εr’) are unsuitable for MW reactions, our system successfully heated CPME solvent up to 260 °C in a safe manner in continuous-flow. Application of this device to other organic reactions, as well as the influence of substrate-selective heating detected herein on the reaction conversion are topics currently under investigation.
All reagents and solvent are commercially available and were used without further purification. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AVANCE III 400 MHz using tetramethylsilane (TMS) as internal standard in chloroform-d (CDCl3). The purification of reaction mixture was performed by recycling gel permeation (GPC) chromatography (chloroform as eluent, Japan Analytical Industry Co., Ltd.).
Synthesis of 1
Compound 1 was prepared according to a literature procedure . To a mixture of 1-naphthol (M.W. = 144.17, 15.0 g, 104.0 mmol) and allyl bromide (M.W. = 120.98, 15.0 g, 124.0 mmol) in acetone (200 mL), 7.0 g of KOH (M.W. = 56.11, 124.8 mmol) was added under nitrogen. The mixture was stirred at 60 °C for 2 h and then filtered. The filtrate was concentrated in vacuo and the residue was purified by using GPC to afford 1 in chloroform as a colorless oil (20.1 g, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.33–8.30 (m, 1 H), 7.81–7.78 (m, 1 H), 7.50–7.44 (m, 2 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 6.80 (d, J = 7.5, 1H), 6.22–6.12 (m, 1 H), 5.52 (d, J = 22.7 Hz), 5.33 (d, J = 12.4 Hz), 4.71 (dt, J1 = 5.1 Hz, J2 = 1.5 Hz, 2 H); 13C NMR (400 MHz, CDCl3) δ 154.2, 134.5, 133.3, 127.4, 126.3, 125.7, 125.7, 125.1, 122.1, 120.3, 117.2, 105.0, 68.8 ppm. 1H and 13C NMR data are consistent with the literature.
Configuration of a flow type microwave reactor
The output power of this system is 10 to 100 W where microwaves can be irradiated continuously. The flow system is equipped with a back pressure regulator after the reactor and a cooling coil, so that the pressure of the flowing solution can be set between 1.0–3.0 MPa. When the pressure was below 1.0 MPa, MW irradiation was stopped in order to prevent bumping of the solution. The upper and lower-limits of the settable flow rate were 0.1 to 9.99 mL/min.
Measurement of resonance frequency and reflectance
The resonance frequency and reflectance of each solvent at room temperature were measured as follows. The helical tubular reactor was filled with solvent, plugged in the upper and lower entrances and set at the center of the cavity. In order to adjust the resonance frequency, a cylindrical borosilicate (Duran) tube (outer diameter: 20 mm, inner diameter: 17.6 mm, length: 140 mm) was placed around the helical reactor. Then, the resonance frequency and reflectance were measured using the ‘Peakfinder’ function of the flow-type MW reactor.
Microwave irradiation of CPME using ISO method
The applied power, flow rate and back pressure were set to 45 W, 1.0 mL/min and 2.5 MPa, respectively. After filling the flow path with CPME, the flow was started and the back pressure was increased to 2.5 MPa. Then, MW irradiation was carried out for 30 min.
Microwave irradiation of CPME using E-GRA method
After filling the flow path with CPME, CPME was flowed at a rate of 1.0 mL/min and a back pressure of 2.5 MPa. The MW was applied with the initial power setting (20 W). The E-GRA test was started upon reaching stable temperature. Under this method, the power of the MW irradiation was increased stepwise by 5 W every 15 min from 20 to 80 W.
Microwave irradiation of CPME using Fl-GRA method
After filling the flow path with CPME, CPME was flowed at an initial flow rate of 2.4 mL/min under an output electric power of 50 W and a back pressure of 2.5 MPa. After the MW application was started and the temperature stabilized, the Fl-GRA method was carried out. In this method, the flow rate was decreased from 2.4 to 0.6 mL/min in steps of 0.2 mL/min every 10 min.
Microwave irradiated reaction of 1 in CPME solution using E-GRA method
The reactant 1 (M.W. = 184.23, 2.763 g, 15.0 mmol) was dissolved in CPME (300 mL) to prepare a 50 mM solution of 1. After the flow path was filled with CPME only, CPME was flowed at a rate of 1.0 mL/min and a back pressure of 2.5 MPa. The MW was applied with the initial power setting (20 W). After the temperature stabilized, the flow path was switched to CPME solution of 1 (50 mM) and was discarded for the same volume as the entire flow path (ca. 8 mL) before the E-GRA mode was started. The power of MW irradiation was increased stepwise by 5 W every 15 min from 34 to 60 W. After each change in the applied power and reaching stable temperature, the initial 9 mL reaction solution was discarded and then 5 mL of subsequent solution was collected and used for yield determination. To these 5 mL aliquots collected at different temperatures were added 0.5 mL aliquots of 1,3,5-trimethoxybenzene solution in acetonitrile (500 mM) as an internal standard to match the initial material (1 eq.) and then the solvent was removed in vacuo. The recovery ratio of 1 and the yields of 2 and 3 were calculated by the 1H NMR spectrum of the crude reaction mixture.
Microwave irradiated reaction of 1 in CPME solution using Fl-GRA method
The reactant 1 (2.763 g) was dissolved in 500 mL of CPME (50 mM). The flow rate was decreased from 2.2 to 0.6 mL/min stepwise by 0.2 mL/min every 10 min using the Fl-GRA method. The flow path was filled with pure CPME, then CPME flow was started at the set initial flow rate of 2.4 mL/min and back pressure of 2.5 MPa. MW irradiation was started at an applied power of 50 W. After the temperature stabilized, the liquid was switched to CPME solution of 1 (50 mM). After each change in the applied power, the initial 9.5 mL of the reaction solution was discarded and then 5 mL of solution was collected and used for yield determination. To these 5 mL aliquots collected at different temperatures were added 0.5 mL aliquots of 1,3,5-trimethoxybenzene solution in acetonitrile (500 mM) as an internal standard to match the initial material (1 eq.) and the solvent was removed in vacuo. The recovery ratio of the starting material 1 and the yields of 2 and 3 were calculated by the 1H NMR spectrum of the crude reaction mixture.
Microwave irradiation of CPME solutions of 1 at various concentrations using ISO method
The reactant solutions (1 in CPME at 50 mM, 100 mM, 200 mM, 500 mM, 1.0 M and 2.0 M) were prepared with a volume of 50 mL each. The reaction conditions all used MW power of 50 W, ISO mode, a flow rate of 1.0 mL/min and a back pressure of 2.5 MPa. CPME was flowed and irradiated until constant temperature was achieved. Then, the flow of CPME solution of 1 was started and was discarded for the same volume as the entire flow path (ca. 8 mL) and then 5 mL of subsequent solution was collected. To these 5 mL aliquots collected at different temperatures were added 0.5 mL of 1,3,5-trimethoxybenzene solution in acetonitrile (500 mM) as an internal standard to match the initial material (1 eq.) and the solvent was removed in vacuo. The recovery ratio of the starting material 1 and the yields of 2 and 3 were calculated by the 1H NMR spectrum of the crude reaction mixture.
Microwave irradiation of CPME solution of 1 for 30 min using ISO method
The solution of 1 in CPME was prepared (2.0 M, 80 mL). The reaction conditions used MW power of 50 W, ISO mode, a flow rate of 1.0 mL/min and a back pressure of 2.5 MPa. CPME was flowed and the 50 W MW irradiation was used to achieve constant temperature. Then, the flow of a CPME solution of 1 was started and was discarded for the same volume as the entire flow path (ca. 8 ml). Then, 30 mL of the reaction solution was collected over 30 min. To this 30 mL aliquot was added 1,3,5-trimethoxybenzene solution in acetonitrile (500 mM) as an internal standard so as to match the initial material (1 eq.) and then the solvent was removed in vacuo. The recovery ratio of the starting material 1 and the yields of 2 and 3 were calculated by the 1H NMR spectrum of the crude reaction mixture. The crude reaction mixture was then purified by GPC to determine the isolated yields of compounds 1–3.
Measurement of permittivity
A network analyzer (Rohde & Schwarz ZVB14, 10–14 GHz) was used to determine the permittivity of samples. The complex relative permittivity (εr*) was determined by the coaxial probe method using the εr and tan δ measurement system (Keycom Corp.). The real and imaginary parts of εr* are equivalent to εr’ and εr”, respectively. The dielectric and the dielectric loss (tan δ) is estimated by εr”/ εr’.
We are grateful for financial support from the Subsidy Program for Innovative Business Promotion of Shizuoka Prefecture. J.B. is a JSPS International Research Fellow and is grateful for financial support from JSPS.
- 1.Gedye R, Smith F, Westaway K, Ali H, Baldisera L, Laberge L, Rousell J (1986) The use of microwave ovens for rapid organic synthesis. Tetrahedron Lett. (3):279–282Google Scholar
- 2.Giguere RJ, Bray TL, Duncan SM, Majetich G (1986) Application of commercial microwave ovens to organic synthesis. Tetrahedron Lett. (41):4945–4948Google Scholar
- 8.Kappe CO, Stadler A, Dallinger D (2013) Microwaves in organic and medicinal chemistry, chapter 3.3–3.5. Wiley-VCH. WeinheimGoogle Scholar
- 10.Metaxas AC, Meredith RJ (1983) Industrial microwave heating. Peter Peregrinus Ltd., London, pp 146–185Google Scholar
- 11.Leonelli C (2017) in Microwave Chemistry. (Eds.: G. Cravotto, D. Carnaroglio). Walter de Gruyter GmbH & Co. KG, pp. 39–45Google Scholar
- 12.Biotage Co. Ltd., Initiator, http://www.biotage.com. (Last accessed: April 8, 2018)
- 13.CEM CO. Ltd., Discover, http://cem.com/en/. (Last accessed: April 8, 2018)
- 14.J-Science Lab Co., Ltd., Green Motif, http://www.j-sl.com. (Last accessed: April 8, 2018)
- 15.Sairem Co. Ltd., LABOTORON, https://www.sairem.com/microwave-radio-frequency-rf-products/microwave-chemistry/ (Last accessed: April 8, 2018)
- 17.Strauss CR (1990) A continuous microwave reactor for laboratory-scale synthesis. Chem. Aust. 186Google Scholar
- 19.Chen S-T, Chiou S-H, Wang K-T (1990) Preparative scale organic synthesis using a kitchen microwave oven. J. Chem. Soc. Chem. Commun.:807–809Google Scholar
- 29.Muley P, Boldor D (2013) Scale-up of a continuous microwave-assisted transesterification process of soybean oil for biodiesel production. Trans. ASABE 56:1847–1818Google Scholar
- 36.Shore G, Morin S, Organ MG (2006) Catalysis in capillaries by Pd thin films using microwave-assisted continuous-flow organic synthesis (MACOS). Angew. Chem. Int. Ed. 45:2761‑2766lGoogle Scholar
- 44.Sairem Co., Ltd., MiniFlow, https://www.sairem.com/microwave-radio-frequency-rf-products/microwave-chemistry/microwave-assisted-synthesis-laboratory/ (Last accessed: April 8, 2018)
- 45.Yokozawa S, Ohneda N, Muramatsu K, Okamoto T, Odajima H, Ikawa T, Sugiyama J, Fujita M, Sawairi T, Egami H, Hamashima Y, Egi M, Akai S (2015) Development of a highly efficient single-mode microwave applicator with a resonant cavity and its application to continuous flow syntheses. RSC Adv. 5:10204–10210CrossRefGoogle Scholar
- 48.Ichikawa T, Mizuno M, Ueda S, Ohneda N, Odajima H, Sawama Y, Monguchi Y, Sajiki H (2018) A practical method for heterogeneously-catalyzed Mizoroki–Heck reaction: flow system with adjustment of microwave resonance as an energy source. Tetrahedron Lett. 74:1801–1816Google Scholar
- 49.Egami H, Sawairi T, Tamaoki S, Ohneda N, Okamoto T, Odajima H, Hamashima Y (2018) (E)-3-[4-(Pent-4-en-1-yloxy)phenyl]acrylic acid. Molbank:M996Google Scholar
- 50.Vámosi P, Matsuo K, Masuda T, Sato K, Narumi T, Takeda K, Mase N (2018) Rapid optimization of reaction conditions based on comprehensive reaction analysis using a continuous flow microwave reactor. Chem. Rec. https://doi.org/10.1002/tcr.201800048
- 56.Martin RE, Morawitz F, Kuratli C, Alker AM, Alanine AI (2012) Synthesis of annulated pyridines by intramolecular inverse-electron-demand hetero-Diels–Alder reaction under superheated continuous flow conditions. Eur. J. Org. Chem.:47–52Google Scholar
- 59.Razzaq T, Glasnov TN, Kappe CO (2009) Continuous-flow microreactor chemistry under high-temperature/pressure conditions. Eur. J. Org. Chem.:1321–1325Google Scholar
- 62.Science of Petroleum II (1938) 1281Google Scholar
- 64.Schünemann K, Furkert DP, Connelly S, Fraser JD, Sperry J, Brimble MA (2014) Synthesis and biological evaluation of 7-deoxy analogues of the human rhinovirus 3C protease inhibitor thysanone. Eur J Org Chem. https://doi.org/10.1002/ejoc.201301515
- 66.Rhoads SJ, Raulines NR (1975) The Claisen and cope rearrangements. Org React 22:1–252Google Scholar
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