Published: August 18, 2011 r2011 American Chemical Society 1428 dx.doi.org/10.1021/op200162c | Org. Process Res. Dev. 2011, 15, 1428–1432 ARTICLE pubs.acs.org/OPRD Safe, Convenient ortho-Claisen Thermal Rearrangement Using a Flow Reactor Juan A. Rinc on,* ,† Mario Barberis, † María Gonz  alez-Esguevillas, †,§ Martin D. Johnson, ‡ Jeffry K. Niemeier, ‡ and Wei-Ming Sun ‡ † Centro de Investigaci on Lilly S.A., Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain ‡ Eli Lilly & Company LTC-South, Indianapolis, Indiana 46285-4813, United States b S Supporting Information ABSTRACT: The [3,3] Claisen rearrangement is a well-known reaction that has been very useful for the synthesis of o-allyl phenols. The thermally induced rearrangement could present safety and operational issues at large batch scale. Herein, we report a process that utilized a tube reactor to make 80 g of an early phase intermediate in a short time while mitigating the potential chemistry hazards. Thus, both project material demands and flow chemistry proof of concept were achieved. ’ INTRODUCTION During the development of one of our research projects, phenol 1 was identified as a key piece for one of the most advanced platforms. The 3-step sequence involved a [3,3] sigmatropic shift of the allyl aryl ether (2) leading to the o-allyl phenol (3), which was easily hydrogenated to the desired product (Scheme 1). Although the original procedure 1 described this rearrange- ment using neat 4-(allyloxy)acetophenone (2) at 230 °C, our medicinal chemists found that the use of diphenyl ether as solvent facilitated the handling and the isolation of the product at 1520 g scale. However, the operational issues associated with the high temperature of the process and the range of concentration used (>25% w/w) made us look for an alternative reactor technology (ART) that would provide a large amount of this material in a safe and timely fashion. ’ RESULTS AND DISCUSSION Batch Chemistry. The commercially available 1-(4-hydroxy- phenyl)ethanone was transformed in high yield to the allyl ether (2) in a similar manner as previously described in the literature. 2 Then, a mixture of the resulting oil crude and biphenyl ether was heated to 250 °C for the thermal rearrangement, and the o-allyl phenol (3) had to be isolated at a higher temperature than the melting point of the solvent (2527 °C). After some experi- mentation, we also observed that the optimal temperature for the reaction was 220 °C (with a ratio of 2 g Ph 2 O/g substrate). At lower temperatures, the reaction times were too long (>48 h), and many tar byproducts began to form. At higher temperatures decomposition of the product was observed. Under desired conditions, the product precipitated in high yield during the cooling process and the biphenyl ether could be removed by washing with hexane. Subsequent catalytic hydrogenation led to the desired product in 60% of overall yield. An accelerating rate calorimeter (ARC) test on neat 2 showed an exotherm onset of 172 °C, a maximum self-heat rate of 2.3 °C/min, and a heat of reaction of 366 J/g (Φ = 2.0) The main reaction went directly into an exothermic gassy secondary reaction at 265 °C as shown in Figure 1. The secondary reaction was not identified but is believed to be due to decomposition of product. With a reaction temperature of 220 °C a moderate exotherm could cause the temperature to rise to the boiling point of diphenyl ether (259 °C) and cause vaporization. If venting were not sufficient the reactor could increase in temperature and pressure and the secondary reaction could initiate. The heat of reaction of 366 J/g for the desired reaction would be sufficient to cause an adiabatic temperature rise of about 180 °C if the reaction were run neat. These factors indicate a potentially hazardous or at least di fficult to control process in the case of a large-scale batch campaign, so we considered these data signi ficant enough to change the process conditions. Since the discovery of the Claisen rearrangement almost one century ago, 3 it has been focus of attention by many research groups. 4 Many synthetic methods involving Al(III) or bismuth(III) derivatives, 5 lanthanides triflates, 6 clays or zeolites, 7 or more recently, gold 8 as catalysts for the sigmatropic rearrangements of allyl aryl ethers have been reported. We tried some of these additives to see if we could run the reaction at lower temperatures. Unfortunately, none of the con- ditions tested led to the selective formation of desired product, and in many cases, degradation to byproduct were observed (Table 1). These results made us reconsider the process in thermal (noncatalytic) conditions but in a safer way. Continuous Chemistry. Although the batch conditions for the rearrangement reaction seemed to work well, we were concerned about how well it would work on a larger scale. The concerns were the following: • Standard large-scale reactors are not equipped to run at temperatures above 200 °C due to limitations in heat transfer systems. Special Issue: Safety of Chemical Processes 11 Received: June 20, 2011