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DOI: 10.1055/s-0030-1259080
Enantioselective Reduction of Benzofuranyl Aryl Ketones
Publication History
Publication Date:
07 December 2010 (online)
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Abstract
Enantioselective transfer hydrogenation of benzofuranyl aryl ketones proceeds with moderate to good enantioselectivity even when the aryl group is not sterically differentiated by ortho-substituents. The best results are obtained with substrates that are functionalised by electron-withdrawing aryl groups that contrast with the electron-rich benzofuran, which is consistent with [Ru-ArC-H]˙Ar π interactions acting as a control element. Enantioselective pressure hydrogenation gives lower enantioselectivity irrespective of electronic effects, unless the aryl group is ortho-substituted, in which case up to 86% ee can be realised.
Key words
asymmetric transfer hydrogenation - asymmetric hydrogenation - heterocyclic ketones - asymmetric catalysis - electronic control
- Supporting Information for this article is available online:
- Supporting Information
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References and Notes
The catalysts used were formed from
either [RuCl2(benzene)]2, [RuCl2(p-cymene)]2 or [RhCl2Cp*]2 and (S,S)-Ts-DPEN
or (1R,2S)-(+)-cis-1-amino-2-indanol. Using [RuCl2(R)-BINAP(R,R)-DPEN], alcohol 16 was assigned as having R-configuration
by Mosher analysis6,8 on the mandelate ester (see the
Supporting Information). A similar analysis was carried out on alcohol 15. The other alcohols, which show similar
HPLC behaviour, are therefore proposed to have the (R)-configuration. Transfer hydrogenation reactions
using [RuCl2(benzene)]2, [RuCl2(p-cymene)]2 or [RhCl2Cp*]2 combined
with (S,S)-Ts-DPEN
or (1R,2S)-(+)-cis-1-amino-2-indanol as catalyst, gave
the opposite S-configured alcohols in
each case.
2-(Trimethylsilyl)benzofuran:7 A
solution of 2,3-benzo-furan (5.1 mL, 46 mmol)
in anhydrous THF (50 mL) was cooled to -78 ˚C
in a nitrogen atmosphere. n-BuLi (40 mL, 1.6 M
in hexanes, 64 mmol) was then added slowly to the solution.
After stirring at -78 ˚C for 1 h,
chlorotri-methyl-silane (9.5 mL, 75 mmol) was
added to the suspension. The mixture was then allowed to stir at -78 ˚C
for 1 h, then at r.t. for a further 16 h. The
reaction mixture was diluted with hexanes, filtered, and evacuated
in vacuo to give a crude yellow oil (9.108 g). The crude
product was purified by column chromatography (silica, hexane),
to give a colourless oil (7.368 g, 39 mmol, 84%). ¹H
NMR (400 MHz, CDCl3):
δ = 0.34
(s, 9 H, SiCH3), 6.84 (s, 1 H, CHCSiMe3), 7.13-7.29 (m,
2 H, 2 × ArH), 7.45-7.60
(s, 2 H, 2 × ArH); ¹³C
NMR (75 MHz, CDCl3): δ = 0.1 [Si(CH3)3],
113.1 [CHC(SiMe3)], 117.8
(ArCH), 122.8 (ArCH),
124.1 (ArCH), 126.1 (ArCH), 129.8
(ArC ipso-CH), 159.9 (CSiMe3),
165.3 (ArC ipso-Oxygen); MS (ES+): m/z = 213.12 [M + Na]+.
Acylation of 2-(trimethylsilyl)benzofuran;
General Procedure
A: To a solution of an acid chloride (1.1 equiv) in anhydrous
CH2Cl2 under a nitrogen atmosphere, trimethyl-silylbenzofuran
(1.0 equiv) was added. The solution was stirred vigorously at r.t.,
whilst TiCl4 (1.25 equiv) was added dropwise. The resulting
suspension was stirred at r.t. for 48 h, followed by addition
of water. The solution was extracted with Et2O, dried,
and concentrated in vaccuo to give the crude product. The crude
product was purified by column chromatography (hexane-CH2Cl2).
Using general Procedure A: Using trimethylsilylbenzofuran
(5.00 g, 26.3 mmol), 2-methoxy-benzoyl chloride
(4.39 g, 28.5 mmol), and TiCl4 (3.6 mL, 33.2
mmol) in CH2Cl2 (100 mL), ketone 10 was obtained as a pale-yellow oil (4.10 g,
17.4 mmol, 66%). ¹H NMR (400 MHz,
CDCl3): δ = 2.43 (s, 3 H,
CH3), 7.26-7.33 (m, 4 H, 4 × ArH),
7.40-7.45 (m, 1 H, ArH), 7.46-7.51 (m,
1 H, ArH), 7.56 (m, 1 H, ArH), 7.62 (d, 1 H,
ArH), 7.60-7.64 (m, 1 H, ArH), 7.66-7.69
(m, 1 H, ArH); ¹³C NMR (75
MHz, CDCl3): δ = 20.2 (CH3),
113.2 (CHCC=O), 117.9 (ArCH), 123.9 (ArCH),
124.4 (ArCH), 125.7 (ArCH),
127.5 (ArC ipso-CH), 128.9 (ArCH), 129.0 (ArCH),
131.4 (ArCH), 131.7 (ArCH),
137.8 (ArC), 153.1 (OCC=O),
156.7 (ArC ipso-Oxygen), 187.4 (C=O); MS (ES+): m/z = 258.85 [M + Na]+;
HRMS: m/z calcd.
for C16H12O2Na: 259.0735; found: 259.0732;
IR: 3064, 1939, 1660, 1549,1445, 1328, 1219, 1186, 1114cm-¹;
Anal. Calcd for C16H12O2: C, 81.34;
H, 5.12. Found: C, 81.39; H, 5.05.
Transfer
Hydrogenation; General Procedure B: Under a nitrogen atmosphere,
the substrate, internal standard, 0.25 mol% metal complex,
0.5 mol% ligand and t-BuOK (1 M
in t-BuOH) were transferred into a microwave
vial and dissolved in anhydrous and degassed solvent (3 mL) and stirred
for 2 min. The reaction was then heated and stirred for16 h.
The vials were cooled and the crude reaction mixture was analysed
by ¹H NMR using tetraethylsilane as an internal standard
to calculate the conversion into product. In some instances, the
products were isolated using column chromatography, and the products
were fully characterised.
Pressure
Hydrogenation;
General
Procedure C: Under a nitrogen atmosphere, the substrate, internal
standard, 0.25 mol% metal complex and 0.5 mol% ligand
were transferred into a microwave vial and dissolved in anhydrous
and degassed solvent (3 mL) and stirred for 2 min. The
vials were then transferred to a steel autoclave and pressurised
with H2 gas. The reaction was then heated and stirred
for 16 h. The autoclave was immersed in cold water and
depressurised. The crude reaction mixture was then analysed by ¹H
NMR using tetraethylsilane as an internal standard to calculate
the conversion into product.
(
S
)-
o
-Methylphenyl(benzofuran-2-yl)methanol
(16): Using general procedure B with substrate (58.3 mg,
0.23 mmol), [RhCp*Cl2]2 (0.25
mol%), and aminoindanol (0.5 mol%), a yellow semi-solid
was obtained (69 mg, 0.228 mmol, 99%, >99% conversion,
74% ee [determined
by HPLC: OD-H (i-PrOH-hexane,
10:90; flow: 0.5 mL/min)]). Comparison
of the HPLC behaviour of this compound to an analogous sample that
had been treated with methoxyphenyl-acetic acid and analysed by
NMR, showed this sample to have (S)-configuration. [α]
d
²0 +28.2
(c = 2.2 g/100 mL, CHCl3); ¹H
NMR (300 MHz, CDCl3): δ = 2.28 (s,
3 H, CH3), 2.42 (br s, 1 H, OH), 6.07
(s, 1 H, CHOH), 6.34 (s, 1 H, ArH),
7.08-7.24 (m, 5 H, 5 × ArH),
7.35-7.45 (m, 2 H, 2 × ArH),
7.46-7.53 (m, 1 H, ArH); ¹³C
NMR (75 MHz, CDCl3): δ = 19.1 (CH3),
67.5 (CHOH), 104.6 (ArCH), 111.5 (CHCC=O), 121.3 (ArCH), 122.7 (ArCH),
124.5 (ArCH), 126.3 (ArCH),
128.4 (ArC ipso-CH), 128.7 (ArCH), 130.9 (ArCH),
136.0 (ArC), 138.7 (ArC),
156.0 (OCC=O), 159.2 (ArC ipso-oxygen); MS (ES+): m/z = 260.77 [M + Na]+.
For
full experimental details, spectroscopic and analytical data, along
with a discussion on the assignment of the configurations, see the
Supporting Information.