Synthesis of a Renewable Macrocyclic Musk: Evaluation of Batch

Flavors & Fragrances Inc. 1515 State Route 36, Union Beach, New Jersey, ... 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51...
0 downloads 0 Views 865KB Size
Subscriber access provided by Gothenburg University Library

Communication

Synthesis of a Renewable Macrocyclic Musk: Evaluation of Batch, Microwave and Continuous Flow Strategies Émilie Morin, Johann Sosoe, Michael Raymond, Benjamin Amorelli, Richard Boden, and Shawn K. Collins Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00450 • Publication Date (Web): 24 Jan 2019 Downloaded from http://pubs.acs.org on January 24, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Organic Process Research & Development

Synthesis of a Renewable Macrocyclic Musk: Evaluation of Batch, Microwave and Continuous Flow Strategies Émilie Morin, § Johann Sosoe, § Michaël Raymond, § Benjamin Amorelli,†* Richard M. Boden,† and Shawn K. Collins§* §

Department of Chemistry and Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, Québec CANADA H3C 3J7 †

Research & Development, International Flavors & Fragrances Inc. 1515 State Route 36, Union Beach, New Jersey, 07735 USA Supporting Information Placeholder ABSTRACT:

The renewable macrocyclic musk 3methylcyclohexadec-6-enone was prepared via macrocyclic olefin metathesis on gram scale using two different protocols: a room temperature batch process which afforded a 57 % yield of the desired macrocycle, but required long reaction times (5 d). In contrast, a continuous flow strategy provided a lower yield of 32% of macrocycle, although the short reaction times (150 °C, 5 min) improve throughput (1 gram/4.8 h). Batch and continuous flow protocols were also tested on other macrocyclizations involving substrates bearing tri-substituted olefins.

KEYWORDS:

Macrocycles, Metathesis, Musks.

Continuous

Flow,

Olefin

INTRODUCTION In 2017, it was estimated that the market for flavors and fragrances was worth 24.8 billion dollars.1 Macrocyclic musks support all consumer categories in the fragrance industry, and have been growing in demand 2,3,4,5 as they exhibit favorable environmental outcome, renewability options, and other sustainability attributes.6

Figure 1. Selected macrocyclic musks (ring size indicated in red).

Musk Z4, (R)-muscone, and civetone are examples 15- and 17membered macrocyclic ketones driving the transition into improved biodegradability while also retaining preferred cost and consumer benefit profiles. Consequently, synthetic chemists in both academia and industry have continued to develop new strategies to prepare macrocycles.6 Among the desired macrocycles are structures possessing a carbonyl unit and having between 13-19 carbon atoms.7 These structural

characteristics are known to produce the odor of musk, a universally appreciated odor with application in perfumes, colognes and personal care products. Small structural modifications to macrocycles such as the incorporation of olefins can produce distinctive odor profiles. In addition, the stereochemistry and position of an alkyl group substitution or double bond within the macrocycle framework can all influence the resulting musky odor. Macrocyclic ketones occupy a unique and challenging (versus polycyclic and macrocyclic lactone musks) of the chemical space of macrocyclic musks. While some of the earliest known musks are macrocyclic ketones (civetone, muscone, ring size in red),8 their challenging synthesis has often prevented use in commercial applications. In 2013, researchers from International Flavors & Fragrances disclosed the synthesis and fragrance properties of a 100% renewable macrocyclic musk, 3-methylcyclohexadec-6-enone (1) from naturally occurring 10-undecen-1-ol and citronellal.9 The ketone 1 was described as having a strong musky odor, but having highly desirable properties in the top and middle notes that were described as feminine, smooth, creamy, warm and comfortable. The patent report disclosed a macrocyclic ring-closing olefin metathesis (mRCM) strategy to prepare the macrocycle (Figures 2 and 3) from terminal mono- and tri-substituted olefins in 2. More recently, trends in olefin metathesis10 have explored controlling the geometry of the resulting olefin to selectively provide the E- or Z-olefin desired,11 and has explored for the synthesis of macrocyclic musk-like structures.12 Rutheniumbased olefin metathesis catalysts have exhibited tolerance to a wide array of functional groups and an ability to prepare new macrocycles from simple and commercial olefinic precursors.13 However, mRCM is not without drawbacks. For example, catalyst degradation within the reaction mixture can form undesired ruthenium species that can catalyze the migration of olefins in both starting materials and products.14 Consequently, the resulting mixture of products can then be challenging to purify. Herein, the investigation of various mRCM strategies for the synthesis of a renewable macrocyclic musk involving common batch synthesis, microwave-assisted techniques or using continuous flow methods, as well as the influence of concentration on each technique is described. RESULTS AND DISCUSSION The key macrocyclization involves the cyclization of the diene 2 to form 3-methylcyclohexadec-6-enone (1). Previous reports of the macrocyclization described a challenging process that employed Grubbs 2nd generation catalyst G2 (Figure 2),10 could not be reliably scaled beyond 100 mg regardless of concentration (5 to 50 mM) or solvent (at 50 °C) (Figure 3).

ACS Paragon Plus Environment

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Notably, the work-up of the reaction mixture is of critical importance. Concentration of the reaction had to be performed after a quenching/deactivation of the olefin metathesis catalyst. The use of batch/high dilution techniques ([5 mM]) for the synthesis of macrocycle 1 was explored using different Ru-based catalysts (Table 1). Indeed, when attempting to replicate the macrocyclization to form the musk 1 with G2, yields were very low (~5%) and attempts at improving the process via slow addition were not successful. Next, a more reactive catalyst, the second generation GrubbsHoveyda catalyst GH2 was investigated, and resulted in a slightly higher yield (11 %) of macrocycle 1. Increasing the catalyst loading (10 mol %) had no significant productive effect (entry 3). The catalyst GHiPr known for its stability15 was also tested using slow addition conditions and but only traces of the desired macrocycle were observed (entry 4).

Page 2 of 5

reactions, and derivatives of the diene that appear to result from olefin scrambling/cross metathesis reactions. Of note, the di-terminal olefin 2a was found to possess noteworthy perfume characteristics and was described as leather, moss, guaiac and woody (in contrast to the starting diene 2, which is described as aldehydic, powerful, fatty, floral and woody).16 The diene 2a could be independently synthesized via ethenolysis from diene 2 (Figure 4). In an attempt to further coerce cyclization, it was decided to investigate using the more reactive SG catalyst at different concentrations using rapid heating via a microwave.17 It was hoped that the rate of ring closure in macrocyclization reactions would be accelerated at higher temperatures. It was decided to evaluate the synthesis of macrocycle 1 in analogous conditions to the best surveyed conditions from the batch experiments. As such diene 2 was to be treated with SG catalyst (10 mol %) in PhMe (70 °C) for 60 min. at 5, 10 and 20 mM concentrations. Upon removal from the microwave, the reaction mixtures were quenched with ethyl vinyl ether in the same manner as the batch experiments.

Table 1: Batch Experiments to Form Macrocycle 1 from Diene 2.

Figure 2. Olefin metathesis catalysts.

Catalyst

Unreacted 2 (%)a

Yield 1 (%)a

1

G2

45