Continuous-Flow Synthesis of meta-Substituted Phenol Derivatives

Article abstract of DOI:10.1021/acs.oprd.5b00077

Two complementary microreactor technologies were developed for the study of biphasic gas-liquid reactions and preparation of meta-substituted phenol derivatives. The first capillary microreactor, composed of a T-junction and simple capillary, enabled oxidative Heck/dehydrogenation on a microgram scale with a shortened reaction time; the total sequence time for oxidative Heck/dehydrogenation reactions was optimized from 2160 min in a traditional batch system to 130 min in the microchemical system. The second tube-in-tube microreactor, composed of a gas-permeable inner tube and gas-nonpermeable outer tube, successfully performed a gram-scale synthesis under the optimized safety and economic conditions which were established from the first microgram-scale study. The two microreactors have great potential for exploring reactions involving gaseous and liquid reagents.

Full text of DOI:10.1021/acs.oprd.5b00077

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Full Paper
Continuous flow synthesis of meta-substituted phenol derivatives
Jeong Hyeon Park, Chan Yi Park, Mi Jin Kim, Min Uk
Kim, Young Joon Kim, Geon-Hee Kim, and Chan Pil Park
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 04 Jun 2015
Downloaded from http://pubs.acs.org on June 6, 2015
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Continuous flow synthesis of metaꢀsubstituted
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phenol derivatives
Jeong Hyeon Park,† Chan Yi Park,† Mi Jin Kim,† Min Uk Kim,† Young Joon Kim,† Geon-Hee
Kim, †,‡ and Chan Pil Park †,‡,*
Graduate School of Analytical Science and Technology (GRAST), Chungnam National
University, Daejeon 305ꢀ764, Korea, and Korea Basic Science Institute, Daejeon 305ꢀ806, Korea
Corresponding Author
*Eꢀmail: chan@cnu.ac.kr
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ABSTRACT. Two complementary microreactor technologies for the study of biphasic gasꢀ
liquid reactions and preparation of metaꢀsubstituted phenol derivatives were developed. The first
capillary microreactor composed of a Tꢀjunction and simple capillary enabled oxidative
Heck/dehydrogenation in microgramꢀscale with shortened reaction time; the total sequence time
of oxidative Heck/dehydrogenation reactions was optimized from 2160 min in a traditional batch
system to 130 min in the microchemical system. Moreover, the second tubeꢀinꢀtube microreactor
composed of a gasꢀpermeable inner tube and gasꢀnonpermeable outer tube successfully
performed a gramꢀscale synthesis under the optimized safe and economic condition which was
established from the first microgramꢀscale study. The two microreactors have great potential for
exploring the reactions involving gaseous and liquid reagents.
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KEYWORDS. Biphasic catalysis, Gasꢀliquid reaction, Microreactors, Phenols,
Dehydrogenation
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INTRODUCTION
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Because of the enormous potential of phenol derivatives as the building blocks for the synthesis
of bioactive natural products and conducting polymers, diverse methods have been developed for
their preparation.1 Electrophilic aromatic substitution is one of the most versatile methods;
however, the strong ortho/paraꢀdirecting effect of hydroxyl group hinders the preparation of
metaꢀsubstituted phenol derivatives. In recent years, Stahl and coworkers reported the
preparation of phenol derivatives by oxidative Heck/dehydrogenation reactions;2 however, the
reactions suffer from prolonged reaction time up to several days, thus requiring further
optimization of reaction conditions including solvent, pressure, and temperature. Moreover, the
restricted contact between gaseous oxygen and liquid reagents lowers the feasibility for practical
scaleꢀup. This contact area per reaction volume significantly decreases with increasing reaction
volume, and as a result, the scaledꢀup process for their industrial applications would be
inefficient.
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Microchemical technologies have presented new concepts and several attractive possibilities as
they have been applied to various standard organic reactions and new chemistries,3 and biphasic
gas–liquid reactions are particularly challenging. A number of reactor configurations including
the segmented flow microreactor, the packedꢀbed microreactor, the falling film microreactor, and
dual channel microreactor have been reported. Increased surfaceꢀtoꢀvolume ratio in the
microchemical systems allows greater mass transfer.4 Recently, tubeꢀinꢀtube design has received
much attention as a convenient method for gasꢀliquid reactions, because Teflon AFꢀ2400 tubing
can maintain high permeability to a range of gases while remaining impermeable to liquids.
Continuous flow processing in the tubeꢀinꢀtube microreactor have been applied to various
reactions such as ozonolysis, carboxylation, Heck vinylation, hydroformylation, HeckꢀHeck
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sequence, GlaserꢀHay coupling, oxidative nitroꢀMannich reaction, PaalꢀKnorr pyrrole synthesis,
iso(thio)ureas synthesis, Wacker oxidation, hydrogenation, oxazolidinone synthesis,
diazomethane generation, amitripyline synthesis, aromatic hydroxylation, biocatalytic production
of catechols, and photooxygenation.5 However, performances in the tubeꢀinꢀtube reactor often
show wasteful consumption of reagents, which would be the only drawback compared to the
previous microchemical gas–liquid approaches. The working volume in the tube in tube
microreactor is consistent due to separation between gas channel and liquid channel, while the
working volume in capillary microreactor can be regulated by changing the amounts of injected
gas and liquids.
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Figure 1. Comparative illustration of contacting modes between gas and liquid phases in two
microreactors and batch system. The detailed calcurations for contact area to volume ratio
(CA/V) and working volume are described in the supporting information.
Herein, we describe two complementary microreactors for the study of gas–liquid binary
reactions and preparation of metaꢀsubstituted phenol derivatives (Figure 1). The first capillary
microreactor (working volume: 0.098mL), composed of a Tꢀjunction and simple capillary, is
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very useful for repeated oxidative Heck/dehydrogenation reactions, which depend on several
parameters including solvent, temperature, and pressure. Multiple reaction conditions could be
easily screened in a short time with the consumption of reagents in microgramꢀscale. The second
tubeꢀinꢀtube microreactor (working volume: 7.72mL), composed of a gasꢀpermeable inner tube
and gasꢀnonpermeable outer tube, enables gramꢀscale reactions under the optimized safe and
economic reaction conditions for the first microgramꢀscale study. Both capillary and tubeꢀinꢀtube
microreactors guarantee the sufficient mass transfer of gaseous oxygen into the solution phase.
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RESULTS AND DISCUSSION
The oxidative Heck reaction in the microreactors.
Figure 2. Schematic of the oxidative Heck reaction of cyclohexꢀ2ꢀenone and 4ꢀ
methoxyphenylboronic acid in the capillary microreactor.
Palladium (Pd) catalyst has widely been used for microchemical reaction. Heterogeneous Pd
catalysts immobilized on microchannel surface or homogeneous catalysts are highly efficient in
hydrogenation, SuzukiꢀMiyaura, Sonogashira, Heck reaction, and other reactions.6 Initially for
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the oxidative Heck reaction, a segmented mode of gas bubbles and liquid slugs were utilized in
the simple capillary microreactor (Figure 2). The mode has the advantages of a simple set up and
broad choice of capillary materials for better chemical stability and mechanical strength even at
high temperatures and pressures. Importantly, the wasteful consumption of reagents and labor
could be minimized in the repeated screenings.
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Figure 3. Microgramꢀscale reactions of cyclohexꢀ2ꢀenone with 4ꢀmethoxyphenylboronic acid in
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a
the capillary microreactor. Standard reaction conditions: NMP (0.4 mL), cyclohexꢀ2ꢀenone (3
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equiv), 4ꢀmethoxyphenylboronic acid (1.0 mmol), Pd(OAc)2 (5 mol%), and dmphen (2,9ꢀ
dimethylꢀ1,10ꢀphenanthroline, 5 mol%), 1.3 atm oxygen, capillary (inner diameter = 0.6 mm,
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b
length = 5 m). Standard reaction conditions: NMP (0.4 mL), cyclohexꢀ2ꢀenone (3 equiv), 4ꢀ
methoxyphenylboronic acid (1.0 mmol), Pd(CH3CN)4(BF4)2 (5 mol%), and 6,6′ꢀdimethylꢀ2,2′ꢀ
bipyridyl (5 mol%), 1.3 atm oxygen, PTFE capillary (inner diameter = 0.6 mL, length = 5 m).
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c
d
The 1a yields in a) and b) were determined by H NMR analysis. 1.6 atm oxygen. No
significant variations over 1.6 (2.5, 3.5, and 5.0) atm oxygen.
First, we investigated reaction parameters in the synthesis of 1a through the microgramꢀscale
reactions (Figure 3). An NMP solution of 4ꢀmethoxyphenylboronic boronic acid (1 mmol) and
cyclohexꢀ2ꢀenone (3 mmol) was placed in the first inlet. An NMP solution of a Pd(II) complex
prepared from 5 mol% Pd(CH3CN)4(BF4)2 and 5 mol% 6,6′ꢀdimethylꢀ2,2′ꢀbipyridyl was placed
in the second inlet, and oxygen gas was placed in the third inlet. The injection rates of the
reagents and catalyst were varied in the range 1.0–2.0 µL/min, and the pressure of oxygen gas
was regulated in the range 1.3–5.0 atm. The reaction was terminated by dipping the reaction tube
into an ice bath at 0 °C, and the droplets collected from different positions were analyzed using
GCꢀMS/1H NMR instruments. The reactions conducted under dried air or nitrogen instead of
oxygen led to poor results (14% and 4% yields, respectively) and a significant amount of black
precipitation, as expected.7 Although the reactions in DMF showed very similar results to those
conducted in NMP, the reactions conducted in THF or ACN (acetonitrile) were very troublesome
due to the lack of solubility of the 4ꢀmethoxyphenylboronic acid and other additives. The
microchemical reactions were carried out over a range of temperatures from 40 °C to 120 °C.
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The yields in the range 40–70 °C increased with increasing reaction temperature for both
Pd(CH3CN)4(BF4)2 and Pd(OAc)2; however, the yields over 70 °C did not deviate from that of
70 °C (94.7% yield) and significant amount of black precipitation was observed in the
microchannel over 120 °C. The precipitation frequently blocked the microchannel, which was a
more serious problem in the second oxidative dehydrogenation. The oxygen pressure in the
microchemical system was one of the key parameters; it was much more important above 50 °C.
The results can be attributed to the oxygen concentration in the solution phase. The nature of the
catalyst was also important because the combination of Pd(CH3CN)4(BF4)2 and 6,6′ꢀdimethylꢀ
2,2′ꢀbipyridyl was found to be superior for both conversion and selectivity. The combination
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resulted in an excellent yield of the product (95%, 20 min) at 70 °C, while the combination of
Pd(OAc)2 and 2,9ꢀdimethylꢀ1,10ꢀphenanthroline afforded only moderate yields (67%, 20 min; 76
%, 100 min) at the same temperature. The results obtained from a batch system were compared;
the batch reaction only afforded 20% yield (20 min) at 70 °C and 90% yield (360 min) at 50 °C
due to insufficient oxygen caused by limited contact between oxygen and the reactants. Thus, the
capillary microreactor was suitable for the simple and facile variation of the parameters and
saved time and reagents significantly.
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Figure 4. Schematic of the oxidative Heck reaction of cyclohexꢀ2ꢀenone and arylboronic acids in
the tubeꢀinꢀtube microreactor. Standard reaction conditions: NMP (2.4 mL), cyclohexꢀ2ꢀenone (9
mmol, 865 mg), arylboronic acid (3 mmol), Pd(CH3CN)4(BF4)2 (5 mol%), and 6,6′ꢀdimethylꢀ
2,2′ꢀbipyridyl (5 mol%), 1.6 atm oxygen, 70 °C, inner tube (AFꢀ2400, outer diameter = 0.6 mm,
length = 2 m), outer tube (PTFE, inner diameter = 1.5 mm, length = 2 m). aIsolated yield.
Based on the optimized reaction conditions for the first capillary microreactor, we configured
the second tubeꢀinꢀtube microreactor composed of a gasꢀpermeable inner tube (AFꢀ2400,
DuPont) and gasꢀnonpermeable outer tube (Figure 4).8 The first and second inlets were
connected into the outer tube, and the third inlet was connected into the inner tube. An NMP
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solution (1.2 mL) of 4ꢀmethoxyphenylboronic acid (3 mmol) and cyclohexꢀ2ꢀenone (9 mmol)
was placed in the first inlet. An NMP solution (1.2 mL) of a Pd(II) complex prepared from 5
mol% Pd(CH3CN)4(BF4)2 and 5 mol% 6,6′ꢀdimethylꢀ2,2′ꢀbipyridyl was placed in the second
inlet, and oxygen gas at 5.0 atm was placed in the third inlet. The injection rates were varied in
the range 500–1000 ꢁL/min, and bubble formation in tubeꢀinꢀtube microreactor should be
suppressed to obtain consistent results. The oxidative Heck reaction in the tubeꢀinꢀtube
microreactor afforded the desired product 1a in an excellent isolated yield (92%), which was
almost similar to that of the capillary microreactor (95% NMR yield). To further explore the
established tubeꢀinꢀtube microreactor, we tested five reactions of cyclohexꢀ2ꢀenone with
arylboronic acids. The reactions of phenylboronic acid and 2,4ꢀdifluorophenylboronic acid
afforded the corresponding products, 1b (86% isolated yield) and 1c (88% isolated yield),
respectively. The reactions of 4ꢀtolylboronic acid, 4ꢀfluorophenylboronic acid, and 4ꢀ
(methoxycarbonyl)phenylꢀboronic acid afforded the corresponding products, 1d (91% isolated
yield), 1e (86% isolated yield), and 1f (85% isolated yield), respectively.
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The oxidative dehydrogenation in the microreactors
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Figure 5. Schematic of the microchemical oxidative dehydrogenation. Standard reaction
conditions: The reaction solution (0.8 mL) collected from the oxidative Heck reaction in the
tubeꢀinꢀtube microreactor; 5% TFA in DMSO, 2 mL. The overall yield after the first oxidative
Heck reaction in the tubeꢀinꢀtube microreactor and the second oxidative dehydrogenation in the
capillary microreactor was determined by 1H NMR analysis.
We attempted the oxidative dehydrogenation in the capillary microreactor (Figure 5). The
solution collected from the tubeꢀinꢀtube reaction of 4ꢀmethoxyphenylboronic acid and cyclohexꢀ
2ꢀenone was placed in the first inlet. 5% TFA (trifluoroacetic acid) in DMSO was placed in the
second inlet, and oxygen gas was placed in the third inlet. The synthesis of 4′ꢀmethoxybiphenylꢀ
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3ꢀol 2a progressed very slowly at 60 °C; however, the rate of the reaction increased with an
elevated reaction temperature. We also regulated the pressure, which was not investigated in the
previous study.2 The reaction at 5.0 atm and 120 °C completed after 120 min (85% yield). The
low oxygen concentration in the solution phase may have caused the long reaction time in the
lowꢀpressure and batch reactions, which was closely related to the precipitation of Pd(0).
Consequently, higher pressure was much more important in the reaction conducted at elevated
temperatures. Additionally, the microchemical reactions under different pressures were easily
conducted, the highꢀpressure reaction in traditional batch system requires a special reactor that
suffers from somewhat difficult handling and high reagent consumption (>100 times). The
reactions conducted over 120 °C were suffered from heavy precipitation of palladium black.
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Figure 6. Continuous flow synthesis of metaꢀsubstituted phenol derivatives in the tubeꢀinꢀtube
microreactor. Standard reaction conditions: NMP (1.6 mL) of cyclohexꢀ2ꢀenone (15 mmol, 1.43
g) and arylboronic acid (5 mmol), NMP (1.6 mL) of Pd(CH3CN)4(BF4)2 (5 mol%) and 6,6′ꢀ
dimethylꢀ2,2′ꢀbipyridyl (5 mol%), 5 atm oxygen, 5% TFA (trifluoroacetic acid) in DMSO (8
mL), 120 °C, residence time of 130 min, inner tube (AFꢀ2400, outer diameter = 0.6 mm, length =
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b
2 m), outer tube (PTFE, inner diameter = 1.5 mm, length = 2 m). Isolated yield. Residence
time of 180 min and cyclohexꢀ2ꢀenone of 25 mmol.
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With optimized reaction conditions, we attempted the gramꢀscale oxidative
Heck/dehydrogenation sequences in the tubeꢀinꢀtube microreactor (Figure 6). To our delight, the
system functioned well at the same pressure and temperature for the oxidative
Heck/dehydrogenation. The oxidative Heck reaction at 5.0 atm and 120 °C showed a similar
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result for the reaction under the optimized conditions, 1.6 atm and 70 °C. The sequences were
completed within 130 min, and the isolated yield of 4′ꢀmethylbiphenylꢀ3ꢀol 2d increased to 87%.
The products, 4′ꢀmethoxybiphenylꢀ3ꢀol 2a (837 mg, 84% isolated yield) and biphenylꢀ3ꢀol 2b
(705 mg, 83% isolated yield), could be synthesized. Three more phenol derivatives were
synthesized in good isolated yields (2′,4′ꢀdifluorobiphenylꢀ3ꢀol 2c: 85%, 4′ꢀfluorobiphenylꢀ3ꢀol
2e: 84%, and methyl 3′ꢀhydroxybiphenylꢀ4ꢀcarboxylate 2f: 80%). However, there was a
limitation in the synthesis of 4'ꢀ(trifluoromethyl)biphenylꢀ3ꢀol 2g (32 % isolated yield, 65 %
conversion), 2'ꢀmethylbiphenylꢀ3ꢀol 2h (54 % isolated yield, 75 % conversion), and 3'ꢀ
methoxybiphenylꢀ3ꢀol 2i (59 % isolated yield, 81 % conversion). Even though we increased the
residence time (180 min) and the amount of cyclohexꢀ2ꢀenone (5 equiv.), the conversions were
significantly lowered due to the low reactivity of the boronic acids in the first oxidative Heck
reaction. We tried to increase the conversions with the longer residence time (over 180 min) and
o
the harsher reaction temperature (over 120 C), but a black precipitation frequently blocked the
microchannel under such reaction conditions.
To demonstrate the utility of the gramꢀscale synthesis in the tubeꢀinꢀtube microreactor,
biphenylꢀ3ꢀol 2b (705 mg) was reacted with cyclohexyl isocyanate (778 mg, 1.5 equiv) to afford
cyclohexylcarbamic acid biphenylꢀ3ꢀyl ester 3b (URB524, 92% isolated yield, 1.12g), which
inhibited the fatty acid amide hydrolase (FAAH) activity in rat brain membranes (Scheme 1).9
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Scheme 1. Gramꢀscale synthesis of URB524.
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CONCLUSION
The total sequence time of oxidative Heck/dehydrogenation was optimized from 36 h in a
traditional batch system to 130 min in the microchemical systems. The working volume in
capillary microreactor can be regulated by changing the amounts of injected gas and liquids, and
it enabled the microgramꢀscale study without the wasteful reagent consumption. The tubeꢀinꢀtube
microreactor successfully performed the gramꢀscale synthesis under the optimized conditions. In
addition, the operations with capillary microreactor were very easy, but bubble formation in
tubeꢀinꢀtube microreactor should be suppressed to obtain consistent results.
EXPERIMENTAL SECTION
General information
Thinꢀlayer chromatography (TLC) was performed using 60 mesh silica gel plates visualized
with shortꢀwavelength UV light (254 nm). Silica gel 60 (230~400 mesh) was used for column
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chromatography. H NMR and C NMR spectra were recorded on Bruker Advance 300 and
Bruker Advance 600. Proton chemical shifts are reported in ppm (δ) relative to TMS with the
solvent resonance employed as the internal standard (CDCl3, δ = 7.26 ppm). Data are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet
and doublet dt = doublet and triplet, m = multiplet), coupling constants (Hz) and integration.
Carbon chemical shifts are reported in ppm from TMS with the solvent resonance as the internal
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standard (CDCl3 δ = 77.0 ppm). PTFE tubing and static mixing tees were purchased from
UPCHURCH, USA.
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General description of the microreactor mediated oxidative Heck reaction
NMP(Nꢀmethylꢀ2ꢀpyrollidine) solution(0.4 mL) of aryl boronic acid (1.0 mmol) and cyclohexꢀ
2ꢀenone (3.0 mmol) was placed in the first inlet. NMP solution(0.4 mL) of a Pd(II) complex
prepared with 0.05 mmol Pd(CH3CN)4(BF4)2 and 0.05 mmol 6,6’ꢀdimethylꢀ2,2’ꢀbipyridyl was
placed in the second inlet, oxygen gas was placed in the third inlet. The reaction streams were
introduced to the threeꢀinlets of the microreactor, the injection rates of reagent and catalyst
varied from 1.0 to 2.0 ꢁL/min, and pressure of oxygen gas was varied from 1.3 to 1.6 atm. The
reaction result was collected through a backpressure regulator, reaction yield was measured
through the 1H NMR analysis using an external capillary standard.
General description of the microreactor mediated oxidative dehydrogenation reaction
0.8 mL NMP solution of the oxidative Heck reaction was placed in a syringe, and 2.0 mL of a
DMSO solution containing 5% CF3CO2H was placed in another syringe. Oxygen gas was placed
in the third inlet. The reaction streams were introduced to the three inlets of the microreactor, the
injection speeds were varied from 0.5 to 2.0 µL/min, and the pressure of the oxygen gas was
varied from 1.6 to 2.0 atm. The product was collected through a backpressure regulator, and
reaction yield was measured through the 1H NMR analysis using an external capillary standard.
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Characterization of the compounds
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3-(4-methoxyphenyl)cyclohex-2-enone (1a). The compound was isolated after column
chromatography (EtOAc : Hexane = 1 : 4) in 92% yield (559 mg, yellow solid (m.p.: 81ꢀ83oC)).
Experimental data were in accordance with those reported in the previous literature.1 1H NMR
(300 MHz, CDCl3) δ 7.54(d, J = 8.82 Hz, 2H), 6.95 (d, J = 8.89 Hz, 2H), 6.41 (s, 1H), 3.86 (s,
3H), 2.76 (t, J = 5.46 Hz, 2H), 2.48 (t, J = 6.97 Hz, 2H), 2.20ꢀ2.11 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 199.78, 161.26, 159.05, 130.86, 127.61, 123.74, 114.17, 55.37, 37.19, 27.89, 22.78.
3-phenylcyclohex-2-enone (1b). The compound was isolated after column chromatography
(EtOAc : Hexane = 1 : 3) in 86% yield (445 mg, colorless crystals solid (m.p.: 58ꢀ60oC)).
Experimental data were in accordance with those reported in the previous literature.1 1H NMR
(300 MHz, CDCl3) δ 7.55ꢀ7.52 (dd, J = 5.44 Hz, 2.28 Hz, 2H), 7.41ꢀ7.42(m, 3H), 6.43(s, 1H),
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2.78 (t, J = 5.7 Hz, 2H), 2.49 (t, J = 6.75 Hz, 2H), 2.20ꢀ2.09 (m, 2H); C NMR (75 MHz,
CDCl3) δ 199.82, 159.79, 138.80, 129.97, 128.75, 126.07, 125.43, 37.26, 28.11, 22.82.
3-(2,4-difluorophenyl)cyclohex-2-enone (1c). The yellowish liquid was isolated after column
chromatography (EtOAc : Hexane = 1 : 3) in 88% yield (549 mg, yellow oil). Experimental data
were in accordance with those reported in the previous literature.1 1H NMR (300 MHz, CDCl3) δ
7.39ꢀ7.22 (m, 1H ), 6.96ꢀ6.80 (m, 2H), 6.27 (s, 1H), 2.75 (t, J = 5.85 Hz, 2H), 2.52 (t, J = 6.98
Hz, 2H), 2.20ꢀ2.12 (m, J = 6.4, 2H); 13C NMR (75 MHz, CDCl3). δ 199.38, 163.43 (JCF = 251.34
Hz), 160.17 (JCF = 253.21 Hz), 156.00, 129.94, 129.88, 124.06 (JCF = 13.56 Hz), 111.83 (JCF
=
20.8 Hz), 104.82 (JCF = 25.42 Hz), 37.33, 29.59, 23.08; HRMS (ESI) m/z: [M + Na]+ Calcd for
C12H10F2ONa 231.0597; Found 231.0582.
3-p-tolylcyclohex-2-enone (1d). The compound was isolated after column chromatography
(EtOAc : Hexane = 1 : 3) in 91% yield (509 mg, yellow oil). Experimental data were in
accordance with those reported in the previous literature.1 1H NMR (300 MHz, CDCl3) δ 7.46 (d,
J = 8.2 Hz, 2H), 7.23 (d, J = 7.99 Hz, 2H), 6.43 (s, 1H), 2.77 (t, J = 5.41 Hz, 2H), 2.49 (t, J = 7.1
Hz, 2H), 2.39 (s, 3H), 2.20ꢀ2.11 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 200.02, 159.75, 140.42,
135.85, 129.52, 126.08, 124.71, 37.32, 28.04, 22.85, 21.35.
3-(4-fluorophenyl)cyclohex-2-enone (1e). The compound was isolated after column
chromatography (EtOAc : Hexane = 1 : 3) in 86% yield (491 mg, colorless oil). Experimental
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data were in accordance with those reported in the previous literature.2 1H NMR (300 MHz,
CDCl3) δ 7.57ꢀ7.47 (dd, J = 5.18 Hz, 2H), 7.12 (t, J = 8.87 Hz, 2H), 6.39 (s, 1H), 2.77 (t, J = 5.54
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Hz, 2H), 2.50 (t, J = 7.70 Hz, 2H), 2.17 (q, J = 6.12 Hz, 2H); C NMR (150 MHz, CDCl3) δ
199.68, 163.8 (JCF = 250.77 Hz), 158.43, 134.88, 128,05, 128.00, 125.31, 115.91, 115.77, 37.16,
28.15, 22.76.
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3-(4-tert-butylphenyl)cyclohex-2-enone (1f). The compound was isolated after column
chromatography (EtOAc : Hexane = 1 : 3) in 85% yield (582 mg, offꢀwhite crystalline solid
(m.p.: 47.5ꢀ49.5 oC)). Experimental data were in accordance with those reported in the previous
literature.2 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 8.70 Hz, 2H), 7.47 (d, J = 8.70 Hz, 2H),
6.46 (s, 1H), 2.80 (t, J = 5.60 Hz, 2H), 2.51 (t, J = 7.13 Hz, 2H), 2.17 (q, J = 6.37 Hz, 2H), 1.36
(s, 9H); 13C NMR (150 MHz, CDCl3) δ 200.02, 159.60, 153.57, 136.74, 125.92, 125.76, 124.75,
37.31, 34.82, 31.19, 27.97, 22.84.
4'-methoxybiphenyl-3-ol (2a). The compound was isolated after column chromatography
(EtOAc : Hexane = 1 : 6) in 84% yield (837 mg, white powder (m.p.: 117oC)). Experimental data
were in accordance with those reported in the previous literature.1 1H NMR (300 MHz, CDCl3) δ
7.53 (d, J = 8.66 Hz, 2H), 7.30 (t, J = 7.76 Hz, 1H), 7.15 (d, J = 7.53 Hz, 1H), 7.05 (s, 1H), 6.99
(d, J = 8.67 Hz, 2H), 6.80 (dd, J = 7.71 Hz, 1.94 Hz, 1H), 4.94 (bs, OH), 3.87 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ 159.32, 155.87, 142.64, 133.32, 129.91, 128.11, 119.36, 114.22, 113.68,
113.60, 55.36.
biphenyl-3-ol (2b). The compound was isolated after column chromatography (EtOAc : Hexane
= 1 : 6) in 83% yield (705 mg, white solid (m.p.: 73ꢀ74oC)). Experimental data were in
accordance with those reported in the previous literature.1 1H NMR (300 MHz, CDCl3) δ 7.60
(dd, J = 6.98 Hz, 1.52 Hz, 2H), 7.46 (t, J = 6.98 Hz, 2H), 7.31ꢀ7.39 (m, 2H), 7.20 (d, J = 7.71
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Hz, 1H), 7.09 (s, 1H), 6.84 (dd, J = 8.18Hz, 1.79 Hz, 1H), 4.75 (bs, OH); C NMR (150 MHz,
CDCl3): δ 155.86, 143.04, 140.76, 130.01, 128.77, 127.52, 127.15, 119.83, 114.18, 114.12.
2',4'-difluorobiphenyl-3-ol (2c). The compound was isolated after column chromatography
(EtOAc : Hexane = 1 : 7) in 85% yield (876 mg, yellow oil). Experimental data were in
accordance with those reported in the previous literature.3 1H NMR (600 MHz, CDCl3) δ 7.43 (q,
1H), 7.35 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.02 (s, 1H), 6.99ꢀ6.92 (m, 2H), 6.89 (dd,
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J = 7.9 Hz, 1.83 Hz), 4.78(bs, OH); C NMR (150 MHz, CDCl3): δ 162.37(JCF = 249.43 Hz),
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159.72(JCF = 250.61 Hz), 155.52, 136.57, 131.39, 129.78, 124.86 (JCF = 13.48 Hz), 121.53,
115.94, 114.75, 111.56 (JCF = 20.28 Hz), 104.40 (JCF = 24.75 Hz).
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4'-methylbiphenyl-3-ol (2d). The compound was isolated after column chromatography (EtOAc :
Hexane = 1 : 4) in 87% yield (801 mg, white solid (m.p.: 75.2ꢀ75.3oC)). Experimental data were
in accordance with those reported in the previous literature.1 1H NMR (300 MHz, CDCl3) δ 7.53
(d, J = 8.09 Hz, 2H), 7.37 (t, J = 8.05 Hz, 1H), 7.29 (d, J = 7.77 Hz, 2H), 7.23 (d, J = 7.89, 1H),
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7.10 (s, 1H), 6.83 (dd, J = 7.89, 1.7 Hz, 1H), 5.28 (bs, OH), 2.44 (s, 3H); C NMR(75 MHz,
CDCl3) δ 155.82, 143.00, 137.88, 137.32, 129.98, 129.50, 126.97, 119.66, 113.99, 113.97, 21.10.
4'-fluorobiphenyl-3-ol (2e). The compound was isolated after column chromatography (EtOAc :
Hexane = 1 : 6) in 84% yield (792 mg, amorphous solid (m.p.: 78ꢀ79oC)). Experimental data
were in accordance with those reported in the previous literature.3 1H NMR (300 MHz, CDCl3) δ
7.57ꢀ7.52 (dd, J = 5.66 Hz, 8.48Hz, 2H), 7.33 (t, J = 7.91 Hz, 1H), 7.17ꢀ7.11 (m, 3H), 7.04 (s,
1H), 6.86 (dd, J = 7.79, 2.03 Hz, 1H), 4.89 (bs, OH); 13C NMR(150 MHz, CDCl3) δ 162.57 (JCF
= 246.06 Hz), 155.95, 142.04, 136.88, 130.07, 128.70, 128.65, 119.61, 115.69, 115.56, 114.21,
114.02.
4'-tert-butylbiphenyl-3-ol (2f). The compound was isolated after column chromatography
(EtOAc : Hexane = 1 : 6) in 80% yield (906 mg, yellow solid (m.p.:89.5oC)). Experimental data
were in accordance with those reported in the previous literature.3 1H NMR (300 MHz, CDCl3) δ
7.53 (d, J = 8.29 Hz, 2H), 7.47 (d, J = 8.11 Hz, 2H), 7.32 (t, J = 7.92 Hz, 1H), 7.20 (d, J = 7.91
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Hz 1H), 7.08 (s, 1H), 6.84 (d, J = 7.90, 1H), 4.79 (bs, OH), 1.38 (s, 9H); C NMR(150 MHz,
CDCl3) δ 155.79, 150.56, 142.88, 137.80, 129.93, 126.75, 125.72, 119.68, 113.92, 113.91, 34.56,
31.37.
4'-(trifluoromethyl)biphenyl-3-ol (2g). The compound was isolated after column chromatography
(EtOAc : Hexane = 1 : 6) in 32% yield (381 mg, colorless needles (m.p.: 73ꢀ75oC)).
Experimental data were in accordance with those reported in the previous literature.4 1H NMR
(300 MHz, CDCl3) δ 7.70 (s, 4H), 7.37 (t, J = 7.79Hz, 1H), 7.20 (d, J = 7.79Hz, 1H), 7.09(s, 1H),
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6.90 (dd, 7.79Hz, 1.95Hz, 1H), 4.86 (bs, OH); C NMR (75 MHz, CDCl3): δ 156.00, 144.26,
141.54, 130.24, 127.40, 125.70 (JCF = 3.42 Hz), 119.90, 115.11, 114.24.
2'-methylbiphenyl-3-ol (2h). The compound was isolated after column chromatography (EtOAc :
Hexane = 1 : 4) in 54% yield (497 mg, colourless oil). Experimental data were in accordance
with those reported in the previous literature.5 1H NMR (300 MHz, CDCl3) δ 7.33ꢀ7.25 (m, 5H),
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6.92 (d, J = 7.15Hz, 1H), 6.85ꢀ6.82 (m, 2H), 4.80 (bs, OH), 2.30 (s, 3H); C NMR (75 MHz,
CDCl3): δ 155.19, 143.72, 141.48, 135.29, 130.29, 129.58, 129.28, 127.35, 125.71, 121.91,
116.20, 113.70, 20.38.
3'-methoxybiphenyl-3-ol (2i). The compound was isolated after column chromatography (EtOAc
: Hexane = 1 : 4) in 59% yield (590 mg, brown oil). Experimental data were in accordance with
those reported in the previous literature.6 1H NMR (300 MHz, CDCl3) δ 7.40ꢀ7.30 (m, 2H), 7.20ꢀ
7.08 (m, 4H), 6.93 (dd, J = 8.41 Hz, 2.4 Hz, 1H), 6.85 (dd, J = 8 Hz, 2 Hz, 1H), 3.89 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ 159.93, 155.82, 142.91, 142.29, 129.95, 129.74, 119.83, 119.65,
114.34, 114.16, 113.00, 112.85, 55.32.
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biphenyl-3-yl cyclohexylcarbamate (3b). The compound was isolated after column
chromatography (EtOAc : hexane = 1 : 3) in 92% yield (1.12 g, white crystals (m.p.: 141ꢀ143
oC)) Experimental data were in accordance with those reported in the previous literature.7 1H
NMR (300 MHz, CDCl3) δ 7.51ꢀ7.04 (m, 9H), 4.86 (m, 1H), 3.52 (m, 1H), 1.97ꢀ1.13(m, 10H);
13C NMR(150 MHz, CDCl3) δ 153.65, 151.48, 142.63, 140.42, 129.52, 128.75, 127.51, 127.22,
123.94, 120.41, 50.18, 33.31, 25.48, 24.78.
ASSOCIATED CONTENT
Supporting Information. Copies of 1H NMR and 13C NMR spectra for isolated products. This
material is available free of charge via the internet at http://pubs.acs.org.
AUTHOR INFORMATION
Notes
The authors declare no competing financial interest
.
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ACKNOWLEDGMENT
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We acknowledge generous financial support from the National Research Foundation of Korea
Grant Funded by the Korean Government (NRFꢀ2012R1A1A1012596) and the project named
Development of optical instruments for the creative industries (D34500) by Korea Basic Science
Institute.
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