Article pubs.acs.org/OPRD
Multikilogram Scale Organolithiation Chemistry for the Manufacture of Liquid Crystal Intermediates Yao-Hua Han,† Ting Zhou,† Yan Sui,† and Ruimao Hua*,†,‡ †
Hebei Engineering & Technology Center for FPD Materials, Chengzhi Yonghua Display Materials Co. Ltd., Shijiazhuang 050091, China ‡ Department of Chemistry, Tsinghua University, Beijing 100084, China S Supporting Information *
ABSTRACT: This paper describes the kilogram-scale regioselective synthesis of various fluorinated arylboronic acids, aryl iodides, aryl acids, aryl aldehydes, and cyclohexenyl-substituted aryls in good to high yields via in situ fluorine-directed ortholithiation of fluorinated aryls and their subsequent reactions in a one-pot manner with nucleophiles such as triisobutyl borate, iodine, carbon dioxide, N,N-dimethylformamide, and cyclohexyl ketones.
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INTRODUCTION Directed ortho-metalation (DoM) is a useful transformation for aromatic compounds bearing metalating groups (DMG) for furnishing their substituted derivatives and has been welldocumented in the synthesis of functionalized arenes (Scheme 1).1 The DMG is usually a Lewis base interacting with the
RESULTS AND DISCUSSION The directed ortho-lithiation of different fluorinated aryls (3.4− 9.5 kg scale) with 2.5 M n-BuLi/n-hexane was performed at a temperature range of −60° to −75 °C in THF under nitrogen atmosphere.4 All of the generated aryllithium reagents were used in situ for the next transformations. Formation of Arylboronic Acids. The direct formation of arylboronic acids from the reaction of 1,3-difluoro-5-(substituted-cyclohexyl)benzene with n-BuLi followed by treatment with triisobutyl borate and acid is depicted in Scheme 3.
Scheme 1. Directed ortho-lithiation of arenes
Scheme 3. Direct boronic acid formation
lithium reagent not only to promote the formation of an aryllithium, but also to maintain its stability. The aryllithium is then allowed to react with the electrophile. Fluorine is also an efficient DMG for aromatic metalation.2 A fluorinated aryl moiety is an important substructure in many liquid crystals since the introduction of fluorine atom(s) can confer unique properties such as low viscosity, large dielectric anisotropy, and good miscibility to the product.3 In this paper, we report the efficient and multikilogram scale in situ lithiation of fluorinated arenes with n-BuLi and their direct conversion into arylboronic acids, aryl iodides, aryl acids, and aryl aldehydes, as well as the formation of other carbon−carbon bond derivatives (Scheme 2), which are useful and important intermediates in the synthesis of a variety of liquid crystals.
The transformation of 1a to 2a was straightforward and efficient, and 2a was obtained in 62% yield with 92% HPLC area % purity. This was run in up to 10 kg batch scale at 70 L total volume without incident. The cyclohexyl analogue 2b was also synthesized in 80% yield with a purity of 93% in a similar manner. If the reaction was performed at a slightly higher temperature range of −55 to −60 °C, the formation of biaryl impurities occurred which we surmise might arise via a side reaction of the benzyne derivative,4 and its further reaction with a second aryllithium molecule (Scheme 4). The identity of these
Scheme 2. Ortho-lithiation of fluorination aryls and their transformation
Special Issue: Organometallic Carbanions in Practical Organic Synthesis Received: April 22, 2014
© XXXX American Chemical Society
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dx.doi.org/10.1021/op500133p | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
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reform the corresponding aryllithium reagents and underwent hydrolysis upon work up to regenerate 1c and 1d during the workup procedure. This preparation was run in up to a 5 kg batch scale at 40 L total volume without incident. Formation of Aryl Acids. The reaction of aryllithiums with carbon dioxide (CO2) is an efficient, low-cost, and facile method to produce the corresponding aryl acids.7 As shown in Scheme 7, the formation of aryl acids via the sequential
impurities were not confirmed, but the expected molecular weights were detected by GC-MS analysis. Scheme 4. Potential generation of benzyne-related impurity
Scheme 7. Direct aryl acid formation via lithiation and CO2 addition
The purities of the crude aryl boronic acids obtained following the work up were not high, but they were sufficient for the subsequent transformations to make highly pure liquid crystals, as were the products obtained for the following examples we will discuss. For example, 2b was easily converted into its corresponding phenol derivative by a catalyst-free oxidation reaction with the use of commercial 30% H2O2 at 55−60 °C in 90% yield (Scheme 5).
reactions of 1,3-difluorobenzene derivatives with n-BuLi followed by CO2 in a one-pot operation was efficient, and the corresponding aryl acids 2e and 2f were isolated in high yields with a purity of more than 98%. These are important intermediates for the synthesis of a variety of functionalized liquid crystals via further transformation of the carboxylic acid.8 In these reactions, in order to efficiently suppress the sidereaction of biaryl impurity formation as described in the synthesis of 2a, the bubbling rate of CO2 required careful control to maintain the reaction temperature below −65 °C. The lithio intermediates have good stability in this temperature range, allowing the longer times required for CO2 addition on larger scale. This was run in up to a 5 kg batch scale at 50 L total volume without incident. While the purity of the products was not particularly high, the product mixture was acceptable for further processing to highly pure liquid crystals. Formation of Aryl Aldehydes. Ortho-fluorinated aryl aldehydes are important precursors in the synthesis of the terminal cyanoaryl moiety which play an important role to improve the dielectric anisotropy of the linear rigid liquid crystals.9 The reaction of fluorinated aryllithiums with DMF is a widely employed reaction for synthesizing such aryl aldehydes.10 When the pyrimidine 1g was reacted with n-BuLi at ca. −70 °C (Scheme 8), the reaction produced a complicated mixture
Scheme 5. Conversion of boronic acid intermediate 2b to the corresponding phenol by oxidation
Formation of Aryl Iodides. Ortho-fluoroaryl iodides have been applied in the industrial-scale synthesis of rigid linear liquid crystals via cross-coupling reactions with terminal alkynes or aryl boronic acids5 and thus represent an important target for our work (Scheme 6). Scheme 6. Direct aryl iodide formation
Scheme 8. Direct aryl aldehyde formation
The iodination reactions of 1c and 1d with 1.1 equiv of I2 after metalation with n-BuLi occurred, efficiently producing 2c and 2d in excellent yields when the reaction temperature was less than −75 °C. As anticipated, 1c underwent lithiation with high regioselectivity.6 In order to obtain 2c and 2d in high yields, only a slight excess of n-BuLi (1.1 equiv) was required. When 1.5 equiv of nBuLi was employed, a considerable amount of starting materials 1c or 1d were recovered, since the iodines in the desired products 2c and 2d further reacted with the excess n-BuLi to
with low selectivity towards formation of 2g. In order to obtain a satisfactory yield of 2g, the impact of other organometallic bases were screened. After optimization, we discovered that the use of freshly prepared iPr2NLi greatly increased the efficiency of the formation of 2g. Therefore, the preparation of iPr2NLi in situ was conducted at −40 to −50 °C by the reaction of iPr2NH with n-BuLi. This was subsequently used in the Li−H exchange in 1g and reacted with DMF to afford 2g in 51% yield. This was B
dx.doi.org/10.1021/op500133p | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Scheme 9. Nucleophilic addition to cyclohexyl ketone
All of the reactions were performed in stainless steel reactors with mechanical stirring. The inner wall of the reactor was lined with stainless steel pipes for cooling to the reported temperature. n-BuLi in n-hexane was added dropwise, operated by positive nitrogen pressure. 2a−d, 2f, and 2g are known compounds, which were characterized by their 1H NMR, 13C NMR, and 19F-NMR spectra; 2e, 2h-1, and 2h-2 are new compounds, and their structures were confirmed by 1H NMR, 13C NMR, and 19FNMR, as well as HRMS (ESI). (4-((1S,4R)-4-Butylcyclohexyl)-2,6-difluorophenyl)boronic Acid (2a). A solution of 1,3-difluoro-5-(trans-npropylcyclohexyl)benzene (1a) (9.54 kg, 40.0 mol) in THF (50 L) in a 200 L reaction vessel was cooled to −60 to −70 °C with stirring under nitrogen atmosphere, and n-BuLi in n-hexane (17.6 L, 2.5 M, 44.0 mol) was added over 1 h at a rate to maintain the reaction temperature below −70 °C. The reaction mixture was further stirred at −70 to −75 °C for 0.5 h, and then isobutyl borate (13.8 kg, 60.0 mol) in THF (10.0 L) was added over 1 h at the same temperature. The resulting mixture was warmed up to −20 °C over 1.5 h. At this temperature, the reaction mixture was worked up by addition of dilute HCl (a mixture of 20.0 L of water and 5.0 L of conc. HCl) and stirred for 0.5 h. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (20.0 L × 2), and the combined organic layers were washed with saturated brine (30 L × 2). After the solvent was concentrated under reduced pressure, the obtained oil was dissolved into petroleum ether (50.0 L, bp 90−120 °C) under reflux for 0.5 h. The obtained mixture was cooled to room temperature and kept at −10 °C overnight. The crude 2a was obtained in 62% (6.9 kg, 24.0 mol) as white solid after filtration and dried under vacuum at 80 °C. HPLC area % = 91.6%. Mp 181.9 °C; 1H NMR (300 MHz, DMSO-d6) 8.56 (s, 2H), 6.81 (d, 2H, J = 8.4 Hz), 2.48− 2.45 (m, 1H), 1.79−1.72 (m, 4H), 1.41−1.23 (m, 4H), 1.20− 1.11 (m, 2H), 1.04−0.95 (m, 2H), 0.84 (t, 3H, J = 6.9 Hz); 13C NMR (75 MHz, DMSO-d6) 164.6 (dd, J = 242.0 Hz, J = 16.1 Hz), 152.4 (t, J = 8.6 Hz), 110.4 (t, J = 33.4 Hz), 109.4 (d, J = 26.3 Hz), 44.1, 40.2, 36.8, 33.9, 33.3, 20.1, 14.7; 19F-NMR (564 MHz, DMSO-d6) −104.3 (d, J = 10.1 Hz). 2b was also synthesized in a similar manner in 80% yield, HPLC area % = 98.0%. mp 203.7 °C; 1H NMR (300 MHz, DMSO-d6) 8.55 (s, 2H), 6.80 (d, 2H, J = 8.2 Hz), 1.74−1.66 (m, 8H), 1.42−1.22 (m, 4H), 1.11−0.93 (m, 9H), 0.89−0.79 (m, 6H); 13C NMR (75 MHz, DMSO-d6) 164.7 (dd, J = 242.2 Hz, J = 16.1 Hz), 152.3 (t, J = 8.9 Hz), 109.3 (d, J = 27.0 Hz), 44.1, 43.5, 42.8, 39.9, 37.7, 34.2, 33.7, 30.3, 30.2, 20.0, 14.6; 19FNMR (564 MHz, DMSO-d6) −104.2 (d, J = 8.5 Hz).
run in up to 5 kg batch scale at 90 L total volume without incident. Nucleophilic Addition to Cyclohexyl Ketones. The nucleophilic addition of organolithium reagents to carbonyl compounds is a useful reaction for forming carbon−carbon bonds.11 The structural moiety of cyclohexane ring(s) in liquid crystals plays an important role to decrease the viscosity of molecules,12 and depress the smectic phase.13 These can be introduced by the nucleophilic addition of aryllithium reagents to cyclohexyl ketones, followed by dehydration to produce the aryl cyclohexene derivative, followed by a final hydrogenation of the cyclohexane double bond (Scheme 9). The difluoro starting material 1h was directly lithiated at −70 to −75 °C, and the aryllithium intermediate was used as a nucleophile for the addition to cyclohexyl ketones. The resulting alcohols underwent a dehydration reaction catalyzed by p-toluenesulfonic acid to produce the corresponding cyclohexenyl-substituted aryls 2h-1 and 2h-2 in good yields. Since ketones can lead to side reactions, in order to suppress enolate formation the reaction temperature had to be maintained below −70 °C and the size/rate of the n-BuLi charge (1.1 equiv) controlled. The low temperature range also repressed biaryl formation. This was run in up to a 3 kg batch scale at 50 L total volume without incident.
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CONCLUSIONS The present work reports the formation of fluorinated aryllithium reagents generated in situ via the reaction of fluorinated aryls with n-BuLi and their application in the synthesis of functionalized aromatic compounds, which are useful and important intermediates for the synthesis of liquid crystals. The obtained results prove that the directed ortholithiation DOM reaction of certain fluorinated arenes with nBuLi is efficient and selective, and the transformation of the generated aryllithium reagents in situ is a general and useful method for the preparation of functionalized fluorinated aryls on a multikilogram scale.
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EXPERIMENTAL SECTION 1a, 1b, and 1g were synthesized in our company, and other starting materials and solvents were purchased from commercial suppliers and used without further purification. The content of water in commercial THF used in the lithiation reaction was
