Asymmetric Synthesis of Î³-Hydroxy Pinacolboronates through Copper

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Asymmetric Synthesis of #-Hydroxy Pinacolboronates through CopperCatalyzed Enantioselective Hydroboration of #,#-Unsaturated Aldehydes Won Jun Jang, Seung Min Song, Yeji Park, and Jaesook Yun J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03045 • Publication Date (Web): 14 Mar 2019 Downloaded from http://pubs.acs.org on March 17, 2019

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The Journal of Organic Chemistry

Asymmetric Synthesis of γ-Hydroxy Pinacolboronates through Copper-Catalyzed Enantioselective Hydroboration of α,βUnsaturated Aldehydes

Won Jun Jang,† Seung Min Song,† Yeji Park, and Jaesook Yun*

Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea

E-mail: [email protected]

Abstract:

We report a copper-catalyzed enantioselective hydroboration of α,β-unsaturated aldehydes with pinacolborane. pinacolboronate

α,β-Unsaturated alcohols

in

aldehydes

good

yields

were and

converted

to

enantioselectivities

the

corresponding

through

γ-

consecutive

hydroboration of the C=O and C=C bonds. This process provides simple access to the hydroborated product of allylic alcohols and the resulting γ-pinacolboronate alcohols could be utilized in various transformations.

The hydroboration of alkenes is one of the fundamental methods to produce organoboron compounds, which are recognized as versatile synthetic intermediates in organic synthesis.1 In recent decades, there have been significant advances in the transition-metal catalyzed

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hydroboration field, allowing highly regio- and enantioselective syntheses of chiral alkylboron compounds.2 Moreover, a range of stereospecific transformations of carbon–boron bonds to other functionalities have increased the synthetic utility of organoboranes, which has further encouraged investigations on the efficient synthesis of chiral organoboron compounds.3

Controlling regioselectivity and enantioselectivity in the asymmetric hydroboration of terminal olefins has been an important issue, as most transition-metal catalytic systems produce antiMarkovnikov addition products, linear products with no chiral center, or a mixture of products.4 While regioselective hydroboration of internal alkenes is more challenging than that of terminal alkenes, our group previously disclosed that copper(I)-bisphosphine catalysts could hydroborate vinyl arenes and disubstituted internal alkenes with high regio- and enantioselectivities with pinacolborane as the hydroborating reagent.5 In particular, copper(I) chloride and DTBM-Segphos (L*) as the chiral ligand was the most effective catalytic combination for the asymmetric hydroboration of both terminal and internal alkenes, producing secondary alkylboronates with high enantioselectivity.5b, 5c

Studies on the asymmetric hydroboration of internal allylic alcohols are rare, and only a few examples of hydroborations of protected terminal allylic alcohols have been reported in Rhcatalyzed directed-hydroborations6 and hydroboration of an allylic ester with a copper catalyst5b (Scheme 1, A). Based on our copper-catalyzed enantioselective hydroboration with chiral copper(I)-bisphosphine complexes, we decided to investigate this catalytic system in the


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asymmetric hydroboration of internal allylic alcohols. With the copper-(R)-DTBM-Segphos catalyst, however, hydroboration reaction of cinnamyl alcohol failed to give the desired product with no conversion (Scheme 1, B). We thought this problem could be circumvented by using α,βunsaturated aldehydes, hoping that 1,2-hydroboration of the aldehyde carbonyl would occur faster

than

1,4-hydroboration.

Herein,

we

describe

a

copper-catalyzed

enantioselective

hydroboration of α,β-unsaturated aldehydes with pinacolborane to produce γ-pinacolboronate alcohols.

Scheme 1. Asymmetric Hydroboration Reactions of Allylic Alcohol Derivatives

(A) Previous work R

(1)

Me O

(2)

Ar

N

HBpin [Rh]

Me

Me Me Bpin O R N Me Bpin

HBpin [Cu]

OAc

Ar

OAc

(B) Current work O Ar

H

Bpin

HBpin L*CuH

Ar

HBpin OH

L*CuH

Ar

No Rxn t-Bu OCH3

O O

P

t-Bu

O

P

t-Bu

O

2

OCH3 t-Bu

Me Me

O

Me Me

O

BH

HBpin 2

L* = (R)-DTBM-Segphos


OH


We started our investigation by examining the hydroboration of cinnamaldehyde 1a with copper catalyst (Scheme 2). The reaction proceeded smoothly to afford target product 2a in good yield and good enantioselectivity in toluene at 60 ℃.7 Then, we investigated the substrate scope of cinnamaldehyde derivatives. Most of the desired products were obtained in good yields and good enantioselectivities. A naphthyl moiety (2b) was accommodated with no problem. Substrates with an electron-donating or electron–withdrawing substituent at the para position afforded the desired products (2c and 2d) in good yields and enantioselectivities. The hydroboration reaction was amenable to enal substrates with a methyl or halogen substituent at the ortho- or metaposition of the aryl group (1e–1h). Heteroaryl compounds (1i and 1j) such as 2-benzofuranyl and 2-thienyl reacted with good conversion to the desired products, but with slightly decreased enantioselectivities. However, γ-hydroxy pinacolboronate products with ortho-substitution (2g and 2h) or heteroaryl substituent (2i and 2j) were not very stable on SiO2 and thus, the corresponding diols were obtained after oxidation. This protocol was not suitable for α,β-unsaturated aldehydes with β-alkyl substituents either, as the reaction produced fully reduced, non-borylated alcohol products.8

Scheme 2. Copper-Catalyzed Enantioselective Hydroborationa


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O H +

Ar 1a1j

HBpin

5 mol % CuCl 5.5 mol % L* 10 mol % NaOt-Bu

(2.5 equiv) toluene, 60 °C, 24 h

Bpin Ar

OH OH

2a2j

NaBO3

Bpin

Bpin

Ar

THF/H2O

OH 3a3j

Bpin

OH

OH

OH MeO

2a 84% yield,b 90% eec

2c 83% yield, 91% ee

2b 78% yield, 90% ee

Bpin

Bpin OH

Me

Bpin OH

F

OH

F3C 2d 82% yield, 91% ee

Cl

2e 80% yield, 91% ee

Me

OH

OH

OH OH

OH

3g 74% yield, 87% ee

2f 81% yield, 88% ee

3h 79% yield, 90% ee

OH O 3i 82% yield, 87% ee

OH OH S 3j 85% yield, 88% ee

aGeneral

reaction conditions: 1 (0.5 mmol), pinacolborane (1.25 mmol), CuCl (0.025 mmol), ligand

L* ((R)-DTBM-Segphos) (0.0275 mmol), NaOt-Bu (0.05 mmol) in toluene (1 mL); see the Experimental Section for details.

bIsolated

yield. cDetermined by chiral HPLC analysis of the

corresponding diol 3.

The hydroboration protocol was suitable for large scale synthesis (Scheme 3a). A 1.0 mol % loading of copper catalyst was sufficient to perform the hydroboration reaction on a 3.0 mmol



scale of 1a. Despite the reduced amounts of catalyst and ligand, 2a was produced in 82% yield and 90% ee. Next, the chiral boronates (2a) were stereospecifically converted to compounds containing a new C–C bond (Scheme 3b). Suzuki-coupling9 of 2a with 4-bromotoluene stereospecifically produced the arylated product 410 in the presence of a palladium catalyst. Both reactions occurred in high yields and with complete conservation of the enantiomeric excess of the original hydroborated products.

Scheme 3. Gram-Scale Synthesis and Transformation of Chiral Boron Products

a) Gram-scale synthesis O H +

HBpin (2.5 equiv)

1a 3.0 mmol

1 mol % CuCl 1.1 mol % L* 2 mol % NaOt-Bu toluene, 60 oC, 24 h

Bpin OH 2a 82% yield, 90% ee

b) Transf ormation of chiral boron products Me

Bpin OH 2a

1.5 equiv 4-bromotoluene 1 mol % Pd2(dba)3 2 mol % RuPhos 3 equiv KOH THF/toluene/H2O, 70 oC, 24 h

OH 4 80% yield, 90% ee

To investigate the mechanism of the hydroboration, an NMR study was carried out with 1.1 equivalents of pinacolborane to detect a reaction intermediate (Scheme 4). The 1,2-hydroboration of the aldehyde carbonyl occurred faster than conjugate addition, resulting in the formation of II, which was chemically compatible to yield 2a by reaction with HBpin.

Scheme 4. NMR Study of Chemoselective Hydroboration of Cinnamaldehyde


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O H +

5 mol % CuCl 5.5 mol % L* 10 mol % NaOt-Bu

HBpin (1.1 equiv) benzene-d, rt, 3 h 99%

1a

OBpin

II

Bpin 1.4 equiv HBpin

OH

benzene-d, 60 °C, 24 h 3a 76% yield, 90% ee

A proposed catalytic cycle for the hydroboration of enals is shown in Scheme 5. The active catalyst L*Cu–H reacts with the aldehyde to form the copper alkoxide I, which subsequently reacts with HBpin to generate II and the active L*Cu-H catalyst. Further hydroboration of intermediate II with the catalyst forms alkylcopper intermediate III, which reacts with HBpin to form the final borylated product.

Scheme 5. Proposed Catalytic Cycle



Bpin Ar

O

L*Cu H

OBpin

Ar Chemoselective 1,2-addition

Catalyst Regeneration

HBpin

H

CuL* Ar

OBpin

Ar

OCuL* I

III

HBpin L*Cu H

Regio- and Enantioselective Hydrocupration

Ar

OBpin II

In summary, we have developed a copper-catalyzed enantioselective hydroboration of α , β unsaturated aldehydes with pinacolborane. The DTBM-Segphos‒copper catalyst was effective in this transformation, furnishing useful chiral hydroxyboronates with high enantioselectivities via consecutive hydroboration of C=O and C=C bonds. Moreover, the protocol could be easily scaled up to gram-scale, and stereospecific transformations of the resulting hydroxyboronates to various compounds demonstrate their synthetic utility.

Experimental Section

General methods: All reactions were carried out under a nitrogen atmosphere using oven-dried glassware. CuCl, NaOt-Bu, pinacolborane, and other commercial reagents were purchased from Aldrich and were used as received. (R)-DTBM-Segphos was purchased from TCI. Unsaturated aldehydes 1b–1j were prepared following literature procedures.11 All liquid aldehydes were distilled from calcium hydride and solid aldehydes were purified by recrystallization. Deactivated


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silica gel was prepared by stirring a slurry of the silica gel in a 5 mol% NaOAc aqueous solution for 30 minutes. Toluene was purified using the PureSolv solvent purification system, from Innovative Technology, Inc. All 1H NMR spectra were obtained on Bruker at 500 systems and reported in parts per million (ppm) downfield from tetramethylsilane. reported in ppm referenced to deuteriochloroform (77.16 ppm).

11B

13C

NMR spectra were

NMR spetra were obtained on

Bruker at 400 systems at Kyonggi University (Suwon, Korea). High performance liquid chromatography (HPLC) was performed using Younglin Acme 9100 series. Infrared spectra (IR) were obtained on Nicolet 205 FT-IR and were recorded in cm-1. High resolution mass spectra (HRMS) were obtained by electrospray ionization (ESI) method using ion trap mass analyzer at Sogang Center for Research Facilities of Sogang University (Seoul, Korea) and reported in the form of m/z (intensity relative to peak = 100).

General procedure for the copper-catalyzed enantioselective hydroboration of α , β unsaturated aldehydes

A mixture of CuCl (5 mol %, 0.025 mmol), (R)-DTBM-Segphos (5.5 mol %, 0.0275 mmol) and NaOt-Bu (10 mol %, 0.05 mmol) in toluene (0.5 mL) was stirred for 5 min in a Schlenk tube under an atmosphere of nitrogen. Pinacolborane (2.5 equiv, 1.25 mmol) was added to the reaction mixture and stirring was continued for another 15 min at room temperature. Substrate 1 (1 equiv, 0.5 mmol) dissolved in toluene (0.5 mL) was added to the reaction mixture. The reaction mixture was stirred at 60 ℃ and monitored by TLC. Upon completion of the reaction, the reaction mixture



was diluted with ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, and concentrated in

vacuo. The product was purified by deactivated silica gel chromatography. Rapid silica gel chromatography (5 min) is imperative for reproducible results because the γ-pinacolboronate alcohol decompose readily on silica gel.

For determination of enantiomeric excess (ee), the γ-pinacolboronate alcohol was transformed to the corresponding diol by the following procedure: To a solution of γ-pinacolboronate alcohol (1 equiv) in THF:H2O (2 mL, 1:1(v/v)) sodium perborate (3 equiv) was added. The reaction mixture was stirred for 6 h at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The product was purified by silica gel chromatography.

General procedure for the gram scale synthesis of γ-Hydroxy Pinacolboronates

A mixture of CuCl (1 mol %, 0.03 mmol), (R)-DTBM-Segphos (1.1 mol %, 0.033 mmol) and NaOtBu (2 mol %, 0.06 mmol) in toluene (0.5 mL) was stirred for 5 min in a Schlenk tube under an atmosphere of nitrogen. Pinacolborane (2.5 equiv, 7.5 mmol) was added to the reaction mixture and stirring was continued for another 15 min at room temperature. Substrate 1 (1 equiv, 3 mmol) dissolved in toluene (0.5 mL) was added to the reaction mixture. The reaction mixture was stirred at 60 ℃ and monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, and concentrated in vacuo. The


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product was purified by deactivated silica gel chromatography. Rapid silica gel chromatography (5 min) is imperative for reproducible results because the γ-pinacolboronate alcohol decompose readily on silica gel.

(S)-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-1-ol (2a): Following the general procedure, 2a was obtained in 84% yield (110.3 mg, 0.42 mmol, colorless oil). Rƒ = 0.4 (EtOAc/hexane = 1/1). 1H NMR (500 MHz, CDCl3) δ 7.28–7.21 (m, 4H), 7.16–7.13 (m, 1H), 3.71–3.64 (m, 1H), 3.63–3.55 (m, 1H), 2.44 (t, J = 7.5 Hz, 1H), 2.16–2.09 (m, 1H), 1.95–1.89 (m, 1H), 1.51 (brs, 1H), 1.21 (s, 6H), 1.19 (s, 6H);

13C{1H}

NMR (125 MHz, CDCl3) δ 142.7, 128.41, 128.40, 125.4, 83.5,

62.5, 35.6, 24.61, 24.58. The carbon bonded to boron was not detected due to quadrupolar relaxation;

11B{1H}

NMR (128 MHz, CDCl3) : δ 33.9; IR (neat) 3437, 2977, 1458, 1382, 1324, 1144

cm-1; HRMS (ESI-Ion Trap) m/z [M + H]+ calcd for C15H24BO3 263.1819, found 263.1820.; 90% ee was measured by chiral HPLC on an AD-H column with the corresponding diol obtained after oxidation (i-PrOH:hexanes = 5:95, 0.5 mL/min); tR = 29.70 min (major), tR = 27.97 min (minor).

(S)-3-(naphthalen-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-1-ol (2b): Following the general procedure, 2b was obtained in 78% yield (121.6 mg, 0.39 mmol, colorless oil). Rƒ = 0.4 (EtOAc/hexane = 1/1). 1H NMR (500 MHz, CDCl3) δ 7.79–7.74 (m, 3H), 7.66 (s, 1H), 7.45–7.38 (m, 3H), 3.74–3.69 (m, 1H), 3.66–3.60 (m, 1H), 2.63 (t, J = 7.5 Hz, 1H), 2.28–2.19 (m, 1H), 2.05–1.99 (m, 1H), 1.56 (brs, 1H), 1.21 (s, 6H), 1.19 (s, 6H);

13C{1H}

NMR (125 MHz, CDCl3) δ 140.3, 133.8, 131.8,

127.9, 127.6, 127.5, 127.4, 126.3, 125.8, 125.0, 83.6, 62.5, 35.4, 24.62, 24.60. The carbon bonded to



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boron was not detected due to quadrupolar relaxation; IR (neat) 3474, 3052, 2970, 1457, 1390, 1314, 1147 cm-1; HRMS (ESI-Ion Trap) m/z [M + H]+ calcd for C19H26BO3 313.1975, found 313.1977.; 90% ee was measured by chiral HPLC on an AS-H column with the corresponding diol obtained after oxidation (i-PrOH:hexanes = 10:90, 0.5 mL/min); tR = 24.60 min (major), tR = 27.20 min (minor).

(S)-3-(4-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-1-ol (2c): Following the general procedure, 2c was obtained in 83% yield (121.0 mg, 0.41 mmol, colorless oil). Rƒ = 0.4 (EtOAc/hexane = 1/1). 1H NMR (500 MHz, CDCl3) δ 7.14–7.12 (m, 2H), 6.82–6.80 (m, 2H), 3.78 (s, 3H), 3.69–3.63 (m, 1H), 3.61–3.55 (m, 1H), 2.38 (t, J = 7.5 Hz, 1H), 2.11–2.04 (m, 1H), 1.91–1.85 (m, 1H), 1.50 (brs, 1H), 1.21 (s, 6H), 1.19 (s, 6H);

13C{1H}

NMR (125 MHz, CDCl3) δ 157.5, 134.6, 129.3,

113.9, 83.5, 62.4, 55.2, 35.9, 24.63, 24.59. The carbon bonded to boron was not detected due to quadrupolar relaxation; IR (neat) 3401, 2978, 1608, 1511, 1447, 1380, 1324, 1216, 1141 cm-1; HRMS (ESI-Ion Trap) m/z [M + H]+ calcd for C16H26BO4 293.1924, found 293.1926.; 91% ee was measured by chiral HPLC on an AD-H column with the corresponding diol obtained after oxidation (i-PrOH:hexanes = 5:95, 0.5 mL/min); tR = 43.42 min (major), tR = 41.52 min (minor).

(S)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-ol

(2d):

Following the general procedure, 2d was obtained in 82% yield (140.3 mg, 0.43 mmol, colorless oil). Rƒ = 0.4 (EtOAc/hexane = 1/1). 1H NMR (500 MHz, CDCl3) δ 7.52–7.50 (m, 2H), 7.34–7.32 (m, 2H), 3.70–3.65 (m, 1H), 3.60–3.55 (m, 1H), 2.53 (t, J = 7.5 Hz, 1H), 2.19–2.11 (m, 1H), 1.94–1.88 (m,


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1H), 1.54 (brs, 1H), 1.20 (s, 6H), 1.19 (s, 6H);

13C{1H}

NMR (125 MHz, CDCl3) δ 147.2, 128.6, 127.7 (q,

J = 30 Hz), 125.3 (q, J = 3.8 Hz), 124.5 (q, J = 270 Hz), 83.8, 62.1, 35.3, 24.60, 24.57. The carbon bonded to boron was not detected due to quadrupolar relaxation; IR (neat) 3444, 2958, 1445, 1381, 1325, 1124, 1015 cm-1; HRMS (ESI-Ion Trap) m/z [M + H]+ calcd for C16H23BF3O3 331.1692, found 331.1690.; 91% ee was measured by chiral HPLC on an OD-H column with the corresponding diol obtained after oxidation (i-PrOH:hexanes = 10:90, 0.5 mL/min); tR = 13.85 min (major), tR = 6.45 min (minor).

(S)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(m-tolyl)propan-1-ol

(2e):

Following

the

general procedure, 2e was obtained in 80% yield (110.7 mg, 0.40 mmol, colorless oil). Rƒ = 0.4 (EtOAc/hexane = 1/1). 1H NMR (500 MHz, CDCl3) δ 7.16–7.14 (m, 1H), 7.03–7.01 (m, 2H), 6.97–6.95 (m, 1H), 3.71–3.65 (m, 1H), 3.60–3.54 (m, 1H), 2.40 (t, J = 7.5 Hz, 1H), 2.31 (s, 3H), 2.15–2.07 (m, 1H), 1.94–1.88 (m, 1H), 1.54 (brs, 1H), 1.21 (s, 6H), 1.20 (s, 6H);

13C{1H}

NMR (125 MHz, CDCl3) δ

142.6, 137.9, 129.3, 128.3, 126.2, 125.4, 83.5, 62.5, 35.7, 24.6, 21.5. The carbon bonded to boron was not detected due to quadrupolar relaxation; IR (neat) 3347, 2968, 1467, 1371, 1311, 1134, 1008 cm-1; HRMS (ESI-Ion Trap) m/z [M + H]+ calcd for C16H26BO3 277.1975, found 277.1976.; 91% ee was measured by chiral HPLC on an AD-H column with the corresponding diol obtained after oxidation (i-PrOH:hexanes = 5:95, 0.5 mL/min); tR = 30.01 min (major), tR = 28.29 min (minor).

(S)-3-(3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-1-ol (2f): Following the general procedure, 2f was obtained in 81% yield (113.6 mg, 0.41 mmol, colorless oil). Rƒ = 0.4



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(EtOAc/hexane = 1/1). 1H NMR (500 MHz, CDCl3) δ 7.23–7.19 (m, 1H), 6.99–6.93 (m, 2H), 6.85–6.82 (m, 1H), 3.71–3.65 (m, 1H), 3.60–3.55 (m, 1H), 2.46 (t, J = 7.5 Hz, 1H), 2.15–2.08 (m, 1H), 1.93–1.87 (m, 1H), 1.53 (s, 1H), 1.21 (s, 6H), 1.19 (s, 6H);

13C{1H}

NMR (125 MHz, CDCl3) δ 163.0 (d, J = 244

Hz), 145.4 (d, J = 6.3 Hz), 129.7 (d, J = 8.8 Hz), 124.1 (d, J = 2.5 Hz), 115.1 (d, J = 21.3 Hz), 112.3 (d, J = 21.3 Hz), 83.7, 62.2, 35.4, 24.59, 24.56. The carbon bonded to boron was not detected due to quadrupolar relaxation; IR (neat) 3460, 2965, 1455, 1383, 1321, 1118 cm-1; HRMS (ESI-Ion Trap) m/z [M + H]+ calcd for C15H23BFO3 281.1724, found 281.1722.; 88% ee was measured by chiral HPLC on an AS-H column with the corresponding diol obtained after oxidation (i-PrOH:hexanes = 10:90, 0.5 mL/min); tR = 16.33 min (major), tR = 18.92 min (minor).

(S)-1-(2-chlorophenyl)propane-1,3-diol (3g): Following the general procedure, 3g was obtained in 74% yield (69.3 mg, 0.37 mmol, colorless oil). The characterization data for 3g was concordant with that previously reported in the literature.12a Rƒ = 0.2 (EtOAc/hexane = 1/1). 1H NMR (500 MHz, CDCl3) δ 7.65–7.63 (m, 1H), 7.33–7.30 (m, 2H), 7.23–7.20 (m, 1H), 5.38–3.36 (m, 1H), 3.96– 3.89 (m, 2H), 3.09 (brs, 1H), 2.28 (brs, 1H), 2.08–2.04 (m, 1H), 1.97–1.89 (m, 1H);

13C{1H}

NMR (125

MHz, CDCl3) δ 141.5, 131.4, 129.4, 128.5, 127.2, 127.1, 71.2, 61.8, 38.5; 87% ee was measured by chiral HPLC on an OJ-H column (i-PrOH:hexanes = 5:95, 0.5 mL/min); tR = 47.78 min (major), tR = 53.22 min (minor).

(S)-1-(o-tolyl)propane-1,3-diol (3h): Following the general procedure, 3h was obtained in 79% yield (61.7 mg, 0.37 mmol, colorless oil). The characterization data for 3h was concordant with


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that previously reported in the literature.12b Rƒ = 0.2 (EtOAc/hexane = 1/1). 1H NMR (500 MHz, CDCl3) δ 7.54–7.53 (m, 1H), 7.25–7.24 (m, 1H), 7.20–7.13 (m, 2H), 5.22–5.20 (m, 1H), 3.95–3.85 (m, 2H), 2.55 (brs, 1H), 2.38 (brs, 1H), 2.33 (s, 3H), 2.01–1.90 (m, 1H);

13C{1H}

NMR (125 MHz, CDCl3) δ

142.3, 134.1, 130.5, 127.3, 126.4, 125.2, 71.0, 61.8, 39.2, 18.9; IR (neat) 3397, 2960, 1487, 1380, 1326, 1124 cm-1; 90% ee was measured by chiral HPLC on an AD-H column (i-PrOH:hexanes = 5:95, 0.5 mL/min); tR = 44.90 min (major), tR = 38.59 min (minor).

(S)-1-(benzofuran-2-yl)propane-1,3-diol (3i): Following the general procedure, 3i was obtained in 82% yield (78.6 mg, 0.41 mmol, colorless oil). The characterization data for 3i was concordant with that previously reported in the literature.12b Rƒ = 0.2 (EtOAc/hexane = 1/1). 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.28–7.25 (m, 1H), 7.23–7.20 (m, 1H), 6.67 (s, 1H), 5.14–5.11 (m, 1H), 3.97–3.90 (m, 2H), 3.12 (brs, 1H), 2.22–2.18 (m, 2H), 2.16 (brs, 1H); 13C{1H}

NMR (125 MHz, CDCl3) δ 159.0, 154.8, 128.1, 124.2, 122.8, 121.1, 111.2, 102.6, 68.0, 61.0,

36.9; 87% ee was measured by chiral HPLC on an AS-H column (i-PrOH:hexanes = 5:95, 0.5 mL/min); tR = 29.30 min (major), tR = 34.97 min (minor).

(S)-1-(thiophen-2-yl)propane-1,3-diol (3j): Following the general procedure, 3j was obtained in 85% yield (67.1 mg, 0.42 mmol, colorless oil). The characterization data for 3j was concordant with that previously reported in the literature.12c Rƒ = 0.2 (EtOAc/hexane = 1/1). 1H NMR (500 MHz, CDCl3) δ 7.26–7.25 (m, 1H), 6.99–6.97 (m, 2H), 5.24–5.21 (m, 1H), 3.94–3.86 (m, 2H), 2.97 (brs, 1H), 2.19 (brs, 1H), 2.16–2.04 (m, 2H);

13C{1H}

NMR (125 MHz, CDCl3) δ 148.3, 126.7, 124.6, 123.5, 70.1, 61.2,



40.7; 88% ee was measured by chiral HPLC on an AS-H column (i-PrOH:hexanes = 5:95, 0.5 mL/min); tR = 45.76 min (major), tR = 38.82 min (minor).

(S)-3-phenyl-3-(p-tolyl)propan-1-ol (4): A mixture of Pd2(dba)3 (1 mol %, 0.005 mmol), RuPhos (2 mol %, 0.010 mmol), and KOH (3 equiv, 1.5 mmol) in toluene (1 mL) were stirred for 15 min under an atmosphere of nitrogen. 2a (1 equiv, 0.5 mmol), 4-bromotoluene (1.5 equiv, 0.75 mmol), THF (1 mL) and H2O (0.2 mL) were added. The reaction mixture was stirred for 24 h at 70 °C. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The product was purified by silica gel chromatography, and 4 was obtained in 80% yield (90.4 mg, 0.40 mmol, colorless oil). The characterization data for 3j was concordant with that previously reported in the literature.10 Rƒ = 0.3 (EtOAc/hexane = 1/5). 1H NMR (500 MHz, CDCl3) δ 7.29–7.24 (m, 4H), 7.19–7.14 (m, 3H), 7.10–7.09 (m, 2H), 4.10 (t, J = 8.0 Hz, 1H), 3.63–3.60 (m, 2H), 2.33–2.29 (m, 5H), 1.21 (brs, 1H);

13C{1H}

NMR (125 MHz, CDCl3) δ 144.8, 141.5, 135.8, 129.3, 128.5, 127.8,

127.7, 126.2, 61.2, 47.0, 38.3, 21.0. [α]D20 +10.2 (c 0.52, CHCl3); [lit.10 (93% ee): [α]D20 +4.3 (c 1.24, CHCl3)]; 90% ee was measured by chiral HPLC on an AS-H column (i-PrOH:hexanes = 2:98, 1.0 mL/min); tR = 21.59 min (major), tR = 18.99 min (minor).

2-(cinnamyloxy)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (II): A mixture of CuCl (5 mol %, 0.025 mmol), (R)-DTBM-Segphos (5.5 mol %, 0.0275 mmol) and NaOt-Bu (10 mol %, 0.05 mmol) in benzene-d (0.5 mL) was stirred for 5 min in a Schlenk tube under an atmosphere of nitrogen.


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Pinacolborane (1.1 equiv, 0.55 mmol) was added to the reaction mixture and stirring was continued for another 15 min at room temperature. Substrate 1 dissolved in benzene-d (0.5 mL) was added to the reaction mixture. The reaction mixture was stirred at 60 ℃ for 1 h. Aliquot was taken by removing a small amount of the reaction solution and passing it through a filter, eluting with benzene-d. The characterization data for II was concordant with that previously reported in the literature.13 1H NMR (500 MHz, C6D6) δ 7.18–7.16 (m, 2H), 7.09–7.06 (m, 2H), 7.03–7.01 (m, 1H), 6.61 (d, J = 16.0 Hz, 1H), 6.17 (dt, J = 16.0, 5.5 Hz, 1H), 4.54 (dd, J = 5.5, 1.5 Hz, 2H), 1.06 (s, 12H);

13C{1H}

NMR (125 MHz, C6D6) δ 137.0, 130.6, 128.4, 127.3, 127.2, 126.5, 82.3, 65.2, 24.4.

Supporting Information HPLC, NMR spectra of products. This material is available free of charge via the Internet at http://pubs.acs.org. Author Information Corresponding Author *[email protected]. Author Contributions † W.J.J and S.M.S contributed equally. Acknowledgement This research was supported by a National Research Foundation of Korea grant (NRF2016R1A2B4011719), funded by the Korean government (MEST).



References

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Organomet. Chem. 1995, 500, 1−19. (2) For a review, see: (a) Crudden, C. M.; Edwards, D. Catalytic Asymmetric Hydroboration: Recent Advances and Applications in Carbon−Carbon Bond-Forming Reactions. Eur. J. Org. Chem. 2003, 4695 − 4712. (b) Carroll, A.-M.; O'Sullivan, T. P.; Guiry, P. J. The Development of Enantioselective Rhodium-Catalysed Hydroboration of Olefins. Adv. Synth. Catal. 2005, 347, 609−631. (3) (a) Contemporary Boron Chemistry; Davidson, M. G., Hughes, A. K., Marder, T. B., Wade, K., Eds.; Royal Society of Chemistry: Cambridge, 2000. (b) Boronic Acids: Preparation and Applications in

Organic Synthesis, Medicine and Materials, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011. (c) Crudden, C. M.; Glasspoole, B. W.; Lata, C. J. Expanding the Scope of Transformations of Organoboron Species: Carbon–Carbon Bond Formation with Retention of Configuration. Chem.

Commun. 2009, 6704−6716 (d) Scott, H. K.; Aggarwal, V. K. Highly Enantioselective Synthesis of Tertiary Boronic Esters and their Stereospecific Conversion to other Functional Groups and Quaternary Stereocentres. Chem. -Eur. J. 2011, 17, 13124−13132. (e) Leonori, D.; Aggarwal, V. K. Stereospecific Couplings of Secondary and Tertiary Boronic Esters. Angew. Chem., Int. Ed. 2015, 54, 1082−1096. (f) Sandford, C.; Aggarwal, V. K. Stereospecific Functionalizations and Transformations


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of Secondary and Tertiary Boronic Esters. Chem. Commun. 2017, 53, 5481−5494. (4) (a) Morrill, T. C.; D'Souza, C. A.; Yang, L.; Sampognaro, A. J. Transition-Metal-Promoted Hydroboration of Alkenes: A Unique Reversal of Regioselectivity. J. Org. Chem. 2002, 67, 2481− 2484. (b) Yamamoto, Y.; Fujikawa, R.; Umemoto, T.; Miyaura, N. Iridium-Catalyzed Hydroboration of Alkenes with Pinacolborane. Tetrahedron 2004, 60, 10695−10700. (c) Crudden, C. M.; Hleba, Y. B.; Chen, A. C. Regio- and Enantiocontrol in the Room-Temperature Hydroboration of Vinyl Arenes with Pinacol Borane. J. Am. Chem. Soc. 2004, 126, 9200 − 9201. (d) Obligacion, J. V.; Chirik P. J. Highly Selective Bis(imino)pyridine Iron-Catalyzed Alkene Hydroboration. Org. Lett. 2013, 15, 2680 −2683. (e) Zhang, L.; Zuo, Z.; Leng, X.; Huang, Z. A Cobalt-Catalyzed Alkene Hydroboration with Pinacolborane. Angew. Chem., Int. Ed. 2014, 53, 2696 − 2700. (f) Kisan, S.; Krishnakumar, V.; Gunanathan, C. Ruthenium-Catalyzed Anti-Markovnikov Selective Hydroboration of Olefins. ACS

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1465−1469. (7) When this reaction was carried out at room temperature or 40 ℃, only allylic alcohols were produced through 1,2-addition without the formation of the desired product 2a. (8) α,β-Unsaturated aldehydes with alkyl substituents at the β-position such as (E)-but-2-en-1-al and (E)-pent-2-en-1-al under the hydroboration conditions produced fully-reduced alcohols such as butanol and pentanol. (9) Ohmura, T.; Awano, T.; Suginome, M. Stereospecific Suzuki-Miyaura Coupling of Chiral α(Acylamino)benzylboronic Esters with Inversion of Configuration. J. Am. Chem. Soc. 2010, 132, 13191−13193. (10) The absolute configuration of 3b was determined by comparing optical rotation with the literature data. Shintani, R.; Takatsu, K.; Takeda, M.; Hayashi, T. Copper-Catalyzed Asymmetric Allylic Substitution of Allyl Phosphates with Aryl- and Alkenylboronates. Angew. Chem., Int. Ed. 2011, 50, 8656−8659. (11) Park, J.; Yun, J.; Kim, J.; Jang, D.-J.; Park, C. H.; Lee, K. Brønsted Acid–Catalyzed Meyer–Schuster Rearrangement for the Synthesis of α,β-Unsaturated Carbonyl Compounds. Synth. Commun. 2014,

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Thiophene‐2‐carbaldehyde: Formal Total Synthesis of Duloxetine. Adv. Synth. Catal. 2014, 356, 199 −204. (13) Weidner, V. L.; Barger, C. J.; Delferro, M.; Lohr, T. L.; Marks, T. J. Rapid, Mild, and Selective Ketone and Aldehyde Hydroboration/Reduction Mediated by a Simple Lanthanide Catalyst. ACS

Catal. 2017, 7, 1244−1247.

Table of Contents O Ar

H

HBpin L*CuH

Bpin Ar

OBpin

Ar

OH

74 85% yield 87  91% ee

t-Bu OCH3

O O

P

t-Bu

O

P

t-Bu

O

2

OCH3 t-Bu

2

L* = (R)-DTBM-Segphos


Asymmetric Synthesis of Î³-Hydroxy Pinacolboronates through Copper

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