Characterizing Novel Methoxybenzene via Boron-ate Complex

Synthesis and Characterization of Novel (E)-1-(hexa-3,5-dien-1-yl)-4-methoxybenzene via Boron-ate Complex

• Habib Hussain[*], Syeda Rubina Gilani, Zulfiqar Ali, Imdad Hussain, Hajira Rehman 

Abstract:

Novel (E)-1-(hexa-3,5-dien-1-yl)-4-methoxybenzene was synthesized through boron-ate complex. 3-(4-methoxyphenyl)propyl diisopropylcarbamate was reacted with allylboronic acid pinacol ester in the presence of N,N,N,N-tetramethylethyllenediamine (TMEDA) to give secondary boronic ester which was further reacted with (vinylsulfonyl)benzene by using Grubbs Hoveyda II. Resulting product (E)-2-(1-(4-methoxyphenyl)-6-(phenylsulfonyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was then treated with 1-bromo-3,5-bis(trifluoromethyl)benzene in the presence of n-BuLi to get nucleophilic boron-ate complex. (E)-1-(hexa-3,5-dien-1-yl)-4-methoxybenzene was obtained in excellent yields by stirring boron-ate complex at 50^oC for 1h and refluxing for 15h.

Keywords: Lithiation Borylation, Secondary Boronic Ester, Olefin Cross Metathesis, 1-bromo-3,5-bis(trifluoromethyl)benzene , Boron-ate Complex

1. Introduction

Olefin metathesis chemistry¹ has led a number of opportunities in organic synthesis. Olefin metathesis2involves the redistribution of fragments ofalkenes by regeneration of carbon-carbondouble bonds. There are numerous applications of olefin metathesis and it is an important methodology to produce reagents.

Addition of aryl lithium reagents to secondary boronic esters results to a new class of chiral organometallic-type reagents which have broad utility in asymmetric organic synthesis. R. Larouche-Gauthier³ formed intermediate boron-ate complex by adding an aryllithium reagent to a secondary boronic ester. It behaved as a chiral nucleophile and maximum enantioselectivity was found by using electron withdrawing groups on aryllithium. Habib Hussain⁴ studied the effect of steric bulk of aryllithium on stereoselectivity of boron-ate complexes. Hoffmann⁵ obtained chiral Grignard reagents from sulfoxides Mg exchange reaction of halosulfoxides. Herbert C. Brown⁶ investigated iodination of the ate- complexes from various B-alkoxyborinane derivatives and 1-alkynyllithium. E. Vedejs⁷ synthesized ate- complexes which contained stereogenic boron by reacting trivalent boranes with nucleophiles. They noticed that stability of ate-complex depend upon the electronegativity of substituents attached to boron. Ryschkewitsch, G. E⁸ resolved chiral boron-ate complexes by classical methods. Anna Bernardi ⁹ determined the role of ate-complxes im aldol stereoselectivity.

In the recent paper, we reported the synthesis of Novel (E)-1-(hexa-3,5-dien-1-yl)-4-methoxybenzene (7). It was characterized by IR, ¹H, ¹³C and ms. Lithiation-Borylation was used to synthesize the secondary boronic ester and by using olefin cross metathesis, it gave (E)-2-(1-(4-methoxyphenyl)-6-(phenylsulfonyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane when reacted with (vinylsulfonyl)benzene. (E)-2-(1-(4-methoxyphenyl)-6-(phenylsulfonyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was converted into ate-complex when on heating produced the desired product.

2. Experimental Section

2.1. Materials:

n-butyllithium (nBuLi), sec. butyllithium solution (sBuLi) (1.6M), pinacol, N,N,N,N-tetramethylethyllenediamine (TMEDA), (vinylsulfonyl)benzene, Grubbs Hoveyda II and 1-bromo-3,5-bis(trifluoromethyl)benzene were purchased from Sigma Aldrich. All reagents were used as such as received. To avoid from moisture diethyl ether (Et₂O) and tetrahydrofuran (THF) were dried with 4 A^° molecular sieves. The experiments were performed using schlenk line under nitrogen atmosphere in the absence of air and moisture.

2.2. Synthesis and Characterization of 2-(1-(4-methoxyphenyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3):

To a solution of 3-(4-methoxyphenyl)propyl diisopropylcarbamate (1.0g, 3.41mmol, 1.0eq) (1) and N,N,N,N-tetramethylethyllenediamine (TMEDA) (0.61mL, 4.09mmol, 1.2eq) (2a) in Et₂O (17mL) at -78^oC, Sec. BuLi (1.6M in 92:8 cyclohexane/hexane, 2.9mL, 3.75mmol, 1.1eq) was dropwise added and stirred for 5h at -78^oC. Then allylboronic acid pinacol ester (0.77mL, 4.09mmol, 1.2eq) (2) was dropwise added to the reaction mixture and further stirred at -78^oC for 1h and allowed to warm to room temperature. At this stage, a solution of MgBr₂.OEt₂ in Et₂O, made as follows, was added to the reaction mixture. [At room temperature, 1,2-dibromoethane (0.60mL, 6.88mmol, 1.0eq) was added into a suspension of magnesium (0.17g, 6.88mmol, 1.0eq) in Et₂O (8.6mL). The reaction flask was further stirred for 2h after placing into a water bath in order to control the moderate exotherm]. Biphasic mixture having two layers thus obtained was added to the former reaction mixture via syringe and then refluxed for 16h.

After cooling the reaction mixture to room temperature it was quenched with water. Et₂O was added, the layers were separated and the aqueous phase was extracted with Et₂O. The combined organic layers were washed with 1N HCl, 1N NaOH, water and brine, dried (MgSO₄), concentrated and purified by column chromatography (SiO₂) and pure (R)-2-(1-(4-methoxyphenyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3) (0.84g, 77.60%) was obtained as colorless oil. The reaction is given in Figure 1.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.09 (2H, d, J=8.80 Hz, 2 ï‚´ ArH) 6.81 (2H, d, J=8.80 Hz, 2 ï‚´ ArH) 5.86 – 5.75 (1H, m, CH=CH₂) 5.04 (1H, d, J=2.20 Hz, CH=CHH) 4.94 (1H, d, J=10.27 Hz, CH=CHH) 3.78 (3H, s, OCH₃) 2.63 – 2.48 (2H, m, ArCH₂CH₂CHBCH₂) 2.27 – 2.11 (2H, m, ArCH₂CH₂CHBCH₂) 1.78 – 1.58 (2H, m, ArCH₂CH₂CHBCH₂) 1.25 (12H, s, 4 ï‚´ CH₃) 1.08 – 1.18 (1H, m, ArCH₂CH₂CHBCH₂)

¹³C NMR (100 MHz, CDCl₃) δ ppm 157.6 (1C, -OCH₃), 138.4 (2C, 2 ï‚´ ArCH), 135.0 (2C, 2 ï‚´ ArCH), 129.2 (1C, ArC-O), 114.9 (1C, -CH₂CH=CH₂), 113.6 (1C, -CHb=CH₂), 83.0 (2C, 2 ï‚´ C(CH₃)₂), 55.2 (1C, ArCCH₂), 35.3 (1C, –CH₂CH₂CHB), 34.5 (1C, -CH₂CHB), 33.1 (1C, -CHBCH₂CH), 24.9 (1C, -CH₂CH₂CHB), 24.8 (4C, 2 ï‚´ (CH₃)₂C).

¹¹B NMR (96.23 MHz, None) δ ppm 33.24

IR (film): ν (cm^–1) 3026 (sp²C-H Stretch), 2977, 2924, 2852 (sp³ C-H Stretch), 1511, 1456(sp² C=C Stretch), 1243, 1175, 1142 (sp³C-O Stretch), 846, 822, 670 (sp² C-H oop bending).

2.3. Synthesis and Characterization of (E)-2-(1-(4-methoxyphenyl)-6-(phenylsulfonyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5):

Grubbs-Hoveyda II (4a) (3.9mg, 0.0063mmol, 0.05eq) was added to a solution of 2-(1-(4-methoxyphenyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3) (40mg, 0.126 mmol, 1.0eq) and (vinylsulfonyl)benzene (4) (0.0635g, 0.378mmol, 3.0eq) in CH₂Cl₂ (2mL). After fitting a condenser to the flask, reaction mixture was refluxed for 15h under nitrogen. The reaction mixture was then reduced in volume to 0.5mL and purified directly on a silica gel column eluting with 9:1 Pet. Ether/ EtOAc to provide the desired product (E)-2-(1-(4-methoxyphenyl)-6-(phenylsulfonyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5) as dark brown solid (0.0438g, 77.25%)¹⁰.

m.p. 82.0^oC

¹H NMR (400 MHz, CDCl₃) δ ppm 7.88-7.84 (2H, m, 2 ï‚´ ArH) 7.62-7.56 (1H, m, , 1 ï‚´ ArH) 7.54-7.48 (2H, m, 2 ï‚´ ArH) 7.05-6.99 (2H, m, 2 ï‚´ ArH) 6.96 (1H, t, J=6.97 Hz, CH₂-CH=CH) 6.84-6.77 (2H, m, 2 ï‚´ ArH) 6.31 (1H, dt, J=15.16, 1.47 Hz, CH₂-CH=CH) 3.78 (3H, s, -CH₃) 2.59-2.45 (2H, m, CH₂-CH₂-CHB) 2.43-2.26 (2H, m, CH₂-CHB-CH₂) 1.77-1.66 (1H, m, CH₂-CHB-CHH) 1.63-1.53 (1H, m, CH₂-CHB-CHH) 1.27-1.21 (1H, m, CH₂-CHB-CH₂) 1.18 (12 H, s, 4 ï‚´ CH₃)

¹³C NMR (100 MHz, CDCl₃) δ ppm 157.7 (1C, ArC-O) 146.9 (1C, ArC-S) 140.8 (1C, CH=CH-S) 134.2 (1C, CH=CH-S) 133.1 (1C, ArC-CH₂) 130.6 (1C, ArCH) 129.2 (2C, 2 ï‚´ ArCH) 129.1 (2C, 2 ï‚´ ArCH) 127.5 (2C, 2 ï‚´ ArCH) 113.7 (2C, 2 ï‚´ ArCH) 83.4 (2C, 2 ï‚´ C(CH₃)₂) 55.2 (1C, OCH₃) 34.1 (1C, CH₂CHBCH₂) 33.1 (1C, CH₂CH₂CHB) 32.8 (4C, 2 ï‚´ (CH₃)₂C) 24.8 (1C, -CHBCH₂CH) 24.7 (1C, CH₂CH₂CHB)

¹¹B NMR (96.23 MHz, None) δ ppm 33.24

IR (film): ν (cm^–1) 2977, 2924 (sp³ C-H Stretch), 1511, 1446(sp² C=C Stretch), 1244, 1176, 1141 (sp³C-O Stretch), 822, 730, 687 (sp² C-H oop bending).

2.4. Synthesis and Characterization of (E)-1-(hexa-3,5-dien-1-yl)-4-methoxybenzene (7):

To a solution of 3,5-(CF₃)₂C₆H₃Br (24.6mg, 0.084mmol, 1.2eq) in THF (1.9mL) at -78^oC was added n-BuLi (1.6M in hexanes, 0.053mL, 0.084mmol, 1.2eq) dropwise. The mixture was stirred for 1 hr at -78^oC before a solution of boronic ester (32mg, 0.070mmol, 1.0eq) in THF (1.5mL) was added dropwise. The reaction mixture was stirred for 30min at -78^oC and 30min at room temperature to form boron-ate complex which was further heated at 50^oC for 1 hr and refluxed for 15hr.

Reaction was quenched with water, EtOAc was added and layers were separated. The aqueous phase was extracted with EtOAc. Then layers were combined, washed with brine, dried (MgSO₄), concentrated. The crude mixture was finally purified by column chromatography (SiO₂, 2:1 Pet.Ether/EtOAc) to get desired product as colorless oil (19.87mg, 62.10%).

¹H NMR (400 MHz, CDCl₃) δ ppm 7.14-7.07 (2H, m, 2 ï‚´ ArH) 6.85 – 6.80 (2H, m, 2 ï‚´ ArH) 6.30 (1H, dt, J=17.00, 10.21 Hz, CH=CH-CH=CH₂) 6.12-5.97 (1H, m, CH=CH-CH=CH₂) 5.78-5.69 (1H, m, CH=CH-CH=CH₂) 5.21-5.06 (1H, m, CH=CHH) 4.99-4.95 (1H, m, CH=CHH) 3.79 (3H, s, -CH₃) 2.70-2.60 (2H, m, CH₂CH₂CH) 2.52-2.33 (2H, m, CH₂CH₂CH)

¹³C NMR (100 MHz, CDCl₃) δ ppm 157.7 (1C, ArC-O) 137.0 (1C, CH=CH₂) 133.7 (1C, CH=CH-CH=CH₂) 132.0 (1C, ArC-CH₂) 129.5 (1C, CH=CH-CH=CH₂) 129.1 (2C, 2 ï‚´ ArCH) 114.9 (1C, CH=CH₂) 113.6 (2C, 2 ï‚´ ArCH) 55.1 (1C, –CH₃) 34.6 (1C, CH₂CH₂CH) 34.5 (1C, CH₂CH₂CH)

IR (film): ν (cm^–1) 2955, 2921, 2852 (sp³ C-H Stretch), 1737, 1461(sp² C=C Stretch), 1277, 1184, 1137 (sp³C-O Stretch), 967, 805 (sp² C-H oop bending).

HRMS (ESI) calcd. for C₁₃H₁₇O [M+H]⁺ 189.1279, found 189.1287.

2.5. Equipments

¹H and ¹³C spectral measurements were done by using Varian NMR (400 MHz) spectrometer (model DMX 400). For protons, the chemical shifts were measured relative to tetramethylsilane (TMS) at d = 0 ppm.

3. Results and Discussion

Starting material 2-(1-(4-methoxyphenyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3) has been synthesized as colorless oil in excellent yields (77.6%) (table 1, entry 1) by using Lithiation-Borylation methodology; Carbamate (1) was reacted with pinacol (2) by using TMEDA (2a) at suitable conditions (fig.1). Spectral studies proved the structure as mentioned in literature¹¹. By using application of olefin cross metathesis, boronic ester (3) was then reacted with (vinylsulfonyl)benzene (4) to give (E)-2-(1-(4-methoxyphenyl)-6-(phenylsulfonyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5) as dark brown solid. Yield was again excellent (table 1, entry 2) for this reaction.

Table 1: Physical states and yields

Boron-ate complex (6) which acted as nucleophile was synthesized by reacting (E)-2-(1-(4-methoxyphenyl)-6-(phenylsulfonyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5) with aryllithium (5a). Boron-ate complex (6) showed best nucleophilic character by using 3,5-(CF₃)₂C₆H₃Br (5a) as aryllithium¹¹ and it was then stirred at 50^oC for 1hr and then refluxed for 15hrs and desired product (E)-1-(hexa-3,5-dien-1-yl)-4-methoxybenzene (7) was collected.

4. Conclusions:

Novel (E)-1-(hexa-3,5-dien-1-yl)-4-methoxybenzene has been synthesized through a novel route and characterized by spectral techniques like IR, ¹H, ¹³C and ms. Boron-ate complex was successfully converted into aromatic dienes. This novel synthetic route resulted in excellent yields.

Acknowledgment:

Authors gratefully acknowledge financial support to the work by Higher Education Commission of Pakistan and moreover authors acknowledge the Department of Chemistry, University of Engineering and Technology, Lahore-Pakistan and Superior University Lahore-Pakistan for guidance, research and laboratory facilities.

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[*]Corresponding Author: Habib Hussain