Stereoselective synthesis of optically active hydrobenzoins via asymmetric hydrogenation of benzils with Ru(OTf)(TsDPEN)(I·6- cymene) as the pre-catalyst

Article abstract of DOI:10.1002/cjoc.201200393

Optically active hydrobenzoins are very important building blocks for further derivation of biologically active complexes, natural products, and pharmaceutical compounds. In this paper, A practical approach has been developed for asymmetric hydrogenation

Full text of DOI:10.1002/cjoc.201200393

FULL PAPER
DOI: 10.1002/cjoc.201200393
Stereoselective Synthesis of Optically Active Hydrobenzoins
via Asymmetric Hydrogenation of Benzils with
Ru(OTf)(TsDPEN)(η6-cymene) as the Pre-catalyst
Huang, Xiaofei(黄晓飞)
Li, Naikai(李乃凯)
Geng, Zhicong(耿志聪)
Pan, Fengfeng(潘锋锋)
Wang, Xingwang∗(王兴旺)
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering,
Suzhou University, Suzhou, Jiangsu 215123, China
Optically active hydrobenzoins are very important building blocks for further derivation of biologically active
complexes, natural products, and pharmaceutical compounds. In this paper, A practical approach has been devel-
oped for asymmetric hydrogenation of benzils with Ru(OTf)(TsDPEN)(η6-cymene) as a pre-catalyst in methanol.
Therefore, a series of chiral hydrobenzoins was synthesized in good yields with good to moderate diastereoselectiv-
ities and good to excellent enantioselectivities.
Keywords asymmetric catalysis, benzil, ruthenium, hydrogenation, hydrobenzoin
Introduction
arene-N-tosyl-ethylenediamine-Ru(II) (Ru-TsDPEN) as
a catalyst and the HCOOH/Et3N＝5∶2 as a hydrogen
source in DMF, which yielded hydrobenzoins of high
diastereomeric and enantiomeric purities (Scheme 1).[9]
In the past several years, Noyori and Ohkuma have
discovered that Ru(OTf)(cymene)(TsDPEN) and
Cp*Ir(OTf)(MSDPEN) complexes, well-known cata-
lysts for asymmetric transfer hydrogenation (ATH),[10]
could be employed to catalyze the asymmetric hydro-
genation of simple ketones through a slightly functional
modification of the catalyst and by changing the reac-
tion conditions.[11] Later on, Fan et al. and Xiao’s group
have respectively reported that the complexes of the
same ligand system with various metal centers (Rh, Ir
and Ru) and different counteranions were highly effec-
tive catalysts for the asymmetric hydrogenation of qui-
noline derivatives and prochiral imine compounds with
excellent enantiomeric excess.[12] As a good example of
phosphine-free catalyst, Ru-TsDPEN has deserved more
studies on its catalytic activity, especially in the field
where phosphine complexes have not performed well
(Scheme 1).[8] In search for an efficient way to synthe-
size 1,2-diols via hydrogenation, herein, we reported our
preliminary results on the asymmetric hydrogenation
reactions of benzils catalyzed by an η6-arene/N-tosyl-
ethylenediamine-ruthenium(II) catalyst, by which a se-
ries of hydrobenzoins were provided in good yields with
good to excellent enantioselectivities as well as moder-
ate to good diastereoselectivities (Scheme 1).
Optically active 1,2-diols, particularly, hydroben-
zoins are versatile intermediates for the synthesis of
biologically active compounds and also are related to
the research area of asymmetric synthesis as ligands[1]
and auxiliaries.[2] Chiral hydrobenzoins have been
commonly prepared by asymmetric dihydroxylation
(AD) reactions,[3] pinacol couplings of aldehydes or
ketones,[4] resolutions of racemic hydrobenzoins[5] and
asymmetric reductions.[6] Among various methods,
asymmetric hydrogenation of benzils and benzoins rep-
resent one of the most direct and atom-economic ap-
proaches. To the best of our knowledge, limited litera-
tures have been explored for this purpose so far, al-
though asymmetric hydrogenation of simple ketones has
been extensively studied.[7] The first asymmetric hy-
drogenation of 1,2-diketones was reported by Noyori
and coworkers in the presence of (R)-BINAP-Ru(II)
complexes. The hydrogenation of diacetyl furnishes a
26∶74 mixture of enantiomerically pure (R,R)-2,3-bu-
tanediol and the meso-diol. Unsatisfactorily,
(R)-BINAP-Ru catalyzed hydrogenation of the benzil
offers the meso-hydrobenzoin in 100% yield.[8] Mecha-
nistically, it is explained in the way that the substrate
control in the second hydrogenation step of the hydroxy
ketone intermediate favored meso-diol formation. Sub-
sequently, the asymmetric transfer hydrogenation (ATH)
of benzils was reported by Ikariya et al. using chiral
*
E-mail: wangxw@suda.edu.cn; Tel.: 0086-0512-6588-0378; Fax: 0086-0512-6588-0378
Received April 25, 2012; accepted June 9, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200393 or from the author.
Chin. J. Chem. 2012, XX, 1—7
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Huang et al.
FULL PAPER
Scheme 1 Asymmetric hydrogenation (AH) and asymmetric transfer hydrogenation (ATH) of the benzil
O
OH
OH
Ru-BINAP
AH
Ru-TsDPEN
ATH
O
OH
OH
100% yield
100% yield
98.6:1.4/dl:meso
>99% ee
Ru-TsDPEN
This work
AH
OH
OH
91% yield
85:15/dl:meso
98% ee
Experimental
excess was determined by HPLC on Daicel Chiralpak
AD-H with hexane/i-PrOH (90∶10) as the eluent. Flow:
0.3 mL/min; λ＝210 nm: tminor＝47.3 min, tmajor＝48.8
min, tmeso＝55.9 min. [α]2D8 ＝－43 (c 1.76 in C2H5OH).
1H NMR (300 MHz, CDCl3) δ: 2.71 (s, 2H, meso), 3.12
(s, 2H, dl), 4.53 (s, 2H, dl), 4.76 (s, 2H, meso), 6.98 (dd,
J＝8.1 Hz, 4H), 7.20 (dd, J＝9.0 Hz, 4H); 13C NMR (75
MHz, CDCl3) δ: 78.7, 128.5, 128.6, 134.1, 137.9, 138.1.
ESI-HRMS m/z: [M＋Na]＋ calcd for C14H12Cl2NaO2:
305.0107; found 305.0107.
General procedure for asymmetric hydrogenation of
benzils
Benzils (0.2 mmol), (R,R)-1a (3 mg, 4 µmol), and
degassed MeOH (2 mL) were added to a glass tube un-
der nitrogen. The tube was then placed into a stainless
steel autoclave, which was purged with hydrogen gas
for three times before pressurized with H2 to 30 atm.
Subsequently, the mixture was stirred under this H2
pressure at r.t. for 24 h. After careful release of the hy-
drogen, organic layer was concentrated to afford the
crude product. Purification was performed with a silica
gel column eluted with petroleum ether/ethyl acetate
(4∶1, V/V) to give the pure product.
1,2-Bis-(4-bromo-phenyl)-ethane-1,2-diol
(3d)
96% yield, 81% ee, d.r.＝53∶47. The enantiomeric
excess was determined by HPLC on Daicel Chiralpak
AD-H with hexane/i-PrOH (90∶10) as the eluent. Flow:
0.3 mL/min; λ＝210 nm: tminor＝53.9 min., tmajor＝57.4
min., tmeso＝63.5 min. [α]2D8 ＝－35 (c 1.95 in C2H5OH);
1H NMR (300 MHz, CDCl3) δ: 2.68 (s, 2H, meso), 3.24
(s, 2H, dl), 4.51 (s, 2H, dl), 4.74 (s, 2H, meso), 6.94 (dd,
J＝7.2 Hz, 4H), 7.36 (t, J＝7.8 Hz, 4H); 13C NMR (75
MHz, CDCl3) δ: 78.4, 122.0, 128.6, 131.2, 131.3, 138.2,
138.4. ESI-HRMS m/z: [M＋Na]＋ calcd for C14H12Br2-
NaO2: 394.9078, 396.9058; found 394.9078, 396.9058.
Spectral data of 3a—4o
1,2-Diphenyl-ethane-1,2-diol (3a)
91% yield,
98% ee, d.r.＝85∶15. The enantiomeric excess was
determined by HPLC on Daicel Chiralpak OJ-H with
hexane/i-PrOH (90 ∶10) as the eluent. Flow: 0.8
mL/min; λ＝210 nm: tmajor＝17.3 min, tminor＝19.3 min,
t
meso＝23.6 min. [α]2D8 ＝－68.1 (c 0.99 in C2H5OH). 1H
1,2-Di-p-tolyl-ethane-1,2-diol (3e)
79% yield,
NMR (300 MHz, CDCl3) δ: 2.43 (s, 2H, meso), 3.1 (s,
2H, dl), 4.65 (s, 2H, dl), 4.79 (s, 2H, meso), 7.09 (s,
4H) , 7.21 (s, 6H); 13C NMR (75 MHz, CDCl3) δ: 79.0,
126.9, 127.1, 127.8, 128.1, 139.8. ESI-HRMS m/z: [M
＋Na] ＋ calcd for C14H14NaO2: 237.0886; found
237.0892.
98% ee, d.r.＝84∶16. The enantiomeric excess was
determined by HPLC on Daicel Chiralpak AD-H with
hexane/i-PrOH (90 ∶10) as the eluent. Flow: 0.5
mL/min; λ＝210 nm; tmajor＝29.4 min, tminor＝30.8 min,
t
meso＝35.7 min. [α]2D8 ＝－58.4 (c 1.27 in C2H5OH); 1H
NMR (300 MHz, CDCl3) δ: 2.30 (s, 6H), 2.35 (s, 2H,
meso), 2.98 (s, 2H, dl), 4.62 (s, 2H, dl), 4.71 (s, 2H,
meso), 7.01—7.14 (m, 8H); 13C NMR (75 MHz, CDCl3)
δ: 21.1, 78.7, 126.8, 127.0, 128.8, 128.9, 136.9, 137.4;
ESI-HRMS m/z: [M＋Na]＋ calcd for C16H18NaO2:
265.1199; found 265.1207.
1,2-Bis-(4-isopropyl-phenyl)-ethane-1,2-diol (3f)
74% yield, 98% ee, d.r.＝87∶13. The enantiomeric
excess was determined by HPLC on Daicel Chiralpak
AD-H with hexane/i-PrOH (90∶10) as the eluent. Flow:
0.5 mL/min; λ＝210 nm: tmajor＝23.0 min, tminor＝24.2
min, tmeso＝26.1 min. [α]2D8 ＝－96 (c 1.49 in C2H5OH).
1H NMR (300 MHz, CDCl3) δ: 1.19 (dd, J＝1.8, 6.9 Hz,
12H), 2.76—2.90 (m, 4H), 4.66 (s, 2H), 7.07—7.22 (m,
8H); 13C NMR (75 MHz, CDCl3) δ: 24.2, 34.0, 78.7,
1,2-Bis-(4-fluoro-phenyl)-ethane-1,2-diol
(3b)
92% yield, 83% ee, d.r.＝57∶43. The enantiomeric
excess was determined by HPLC on Daicel Chiralpak
OJ-H with hexane/i-PrOH (90∶10) as the eluent. Flow:
0.8 mL/min; λ＝210 nm: tminor＝16.7 min, tmajor＝18.9
min, tmeso＝21.9 min. [α]2D8 ＝－26 (c 0.51 in C2H5OH).
1H NMR (300 MHz, CDCl3) δ: 2.42 (s, 2H, meso), 3.02
(s, 2H, dl), 4.60 (s, 2H, dl), 4.81 (s, 2H, meso), 6.94 (t,
J＝8.4 Hz, 3H), 7.03 (s, 3H), 7.14(s, 2H); 13C NMR (75
MHz, CDCl3) δ: 78.9, 115.1, 115.4, 128.9, 135.6.
ESI-HRMS m/z: [M＋Na]＋calcd for C14H12F2NaO2:
273.0698; found 273.0700.
1,2-Bis-(4-chloro-phenyl)-ethane-1,2-diol
(3c)
95% yield, 86% ee, d.r.＝60∶40. The enantiomeric
2
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—7

Stereoselective Synthesis of Optically Active Hydrobenzoins
126.4, 126.7, 127.0, 127.4, 137.8, 148.7. ESI-HRMS
m/z: [M＋Na]＋ calcd for C20H26NaO2: 321.1825; found
321.1829.
95% ee, d.r.＝67∶33. The enantiomeric excess was
determined by HPLC on Daicel Chiralpak AD-H with
hexane/i-PrOH (90∶10) as the eluent. Flow: 1 mL/min;
1,2-Bis(4-methoxyphenyl)ethane-1,2-diol
(3g)
λ＝210 nm; tmajor＝17.2 min, tminor＝18.1 min, tmeso＝
1
26% yield, ＞99% ee, d.r.＝87∶13. The enantiomeric
excess was determined by HPLC on Daicel Chiralpak
OJ-H with hexane/i-PrOH (80∶20) as the eluent. Flow:
1 mL/min; λ＝210 nm: tmajor＝23.8 min, tminor＝25.2
min, tmeso＝29. 4 min. [α]1D5 ＝－65 (c 0.13 in C2H5OH)
1H NMR (400 MHz, CDCl3) δ: 2.27 (s, 2 H), 3.76 (s,
6H, dl), 3.80 (s, 6H, meso), 4.64 (s, 2H, dl), 4.74 (s, 2H,
meso), 6.76 (d, J＝8.8 Hz, 4H, dl), 6.86 (d, J＝8.8 Hz,
4H, meso), 7.04 (d, J＝8.4 Hz, 4H, dl), 7.21 (d, J＝8.4
Hz, 4H, meso); 13C NMR (75 MHz, CDCl3) δ: 55.1,
78.8 , 113.5, 128.2, 128.3, 132.1. ESI-HRMS m/z: [M＋
Na]＋ calcd for C16H18NaO4: 297.1097; found 297.1103.
19.4 min. [α]1D5 ＝－14 (c 1.4 in C2H5OH); H NMR
(400 MHz, CDCl3) δ: 2.72 (br, 2H), 4.96 (s, 2H, dr),
5.01 (s, 2H, meso), 6.24 (d, J＝3.2 Hz, 1H), 6.26—6.29
(m, 2H), 6.32—6.34 (m, 1H), 7.48 (d, J＝0.8 Hz, 1H),
7.38 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 70.0, 70.3,
108.2, 108.4, 110.5, 110.6, 142.6, 142.7. ESI-HRMS
m/z: [M＋Na]＋calcd for C10H10NaO4: 217.0471; found
217.0479
1-(4-Chloro-phenyl)-2-phenyl-ethane-1,2-diol (3m)
72% yield, 97% ee, d.r.＝85∶15. The enantiomeric
excess was determined by HPLC on Daicel Chiralpak
OJ-H with hexane/i-PrOH (94∶6) as the eluent. Flow:
1,2-Bis-(3-chloro-phenyl)-ethane-1,2-diol
(3h)
0.8 mL/min; λ＝210 nm; major diastereoisomer tmajor
＝
97% yield, 88% ee, d.r.＝59∶41. The enantiomeric
excess was determined by HPLC on Daicel Chiralpak
AD-H with hexane/i-PrOH (90∶10) as the eluent. Flow:
0.3 mL/min; λ＝210 nm: tminor＝40.6 min, tmajor＝44.9
min, tmeso ＝48.4 min. [α]2D8 ＝－24.6 (c 2.10 in
32.1 min, tminor＝30.6 min; minor diastereoisomer tmajor
＝40.4 min, tminor＝46.3 min. [α]2D8 ＝－66 (c 1.07 in
C2H5OH); 1H NMR (300 MHz, CDCl3) δ: 2.57—3.2 (m,
2H), 4.58—4.78 (m, 2H), 6.98 (d, J＝7.2 Hz, 2H), 7.07
(s, 2H), 7.16 (d, J＝6.9 Hz, 2H), 7.22 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ: 78.7, 79.4, 127.2, 128.5, 128.6,
133.8, 138.5, 139.8. ESI-HRMS m/z: [M＋Na]＋ calcd
for C14H13ClNaO2: 271.0496; found 271.0486.
1-(4-Bromo-phenyl)-2-phenyl-ethane-1,2-diol (3n)
84% yield, 91% ee, d.r.＝67∶33. The enantiomeric
excess was determined by HPLC on Daicel Chiralpak
AD-H with hexane/i-PrOH (90∶10) as the eluent. Flow:
1
C2H5OH); H NMR (300 MHz, CDCl3) δ: 2.66 (s, 2H,
meso), 3.22 (s, 2H, dl), 4.57 (s, 2H, dl), 4.75 (s, 2H,
meso), 6.87 (d, J＝7.5 Hz, 1H), 7.00 (d, J＝7.8 Hz, 1H),
7.14 (t, J＝7.8 Hz, 3H), 7.19—7.22 (m, 3H), 7.24 (s,
1H); 13C NMR (75 MHz, CDCl3) δ: 78.5, 125.4, 127.1,
127.4, 128.5, 129.6, 141.6, 141.8. ESI-HRMS m/z: [M
＋Na] ＋ calcd for C14H12Cl2NaO2: 305.0107; found
305.0116.
0.5 mL/min; λ＝210 nm; major diastereoisomer tmajor
＝
1,2-Dim-tolylethane-1,2-diol (3i) 76% yield, 98%
ee, d.r.＝83∶17. The enantiomeric excess was deter-
mined by HPLC on Daicel Chiralpak OJ-H with hexane/
i-PrOH (97∶3) as the eluent. Flow: 0.5 mL/min; λ＝
210 nm: tminor＝60.8 min, tmajor＝67.6 min, tmeso＝95.5
33.1 min, tminor＝35.1 min; minor diastereoisomer tmajor
＝36.9 min, tminor＝43.1 min. [α]2D8 ＝－49 (c 1.68 in
1
C2H5OH). H NMR (300 MHz, CDCl3) δ: 2.66—3.34
(m, 2H), 4.51—4.74 (m, 2H), 6.89 (d, J＝8.1 Hz, 2H)
7.01 (t, J＝8.7 Hz, 2H), 7.13 (s, 1H), 7.25 (t, J＝8.7 Hz,
3H), 7.31—7.37 (m, 1H); 13C NMR (75 MHz, CDCl3) δ:
78.4, 79.0, 121.7, 121.9, 128.1, 128.2, 131.1, 138.7,
139.4. ESI-HRMS m/z: [M＋Na]＋ calcd for C14H13Br-
NaO2: 314.9991, 316.9991; found 314.9969, 316.9950
Phenyl-2-p-tolyl-ethane-1,2-diol (3o) 69% yield,
＞99% ee, d.r.＝85∶15. The enantiomeric excess was
determined by HPLC on Daicel Chiralpak OJ-H with
hexane/i-PrOH (97∶3) as the eluent. Flow: 1 mL/min;
λ＝210 nm: major diastereoisomer tmajor＝42.3 min,
1
min. [α]2D8 ＝－57 (c 1.00 in C2H5OH); H NMR (300
MHz, CDCl3) δ: 2.27 (s, 6H, dl), 2.32 (s, 6H, meso),
2.41 (s, 2H, meso), 3.19 (s, 2H, dl), 4.62 (s, 2H, dl),
4.71 (s, 2H, meso), 6.89 (d, J＝7.2 Hz, 2H), 6.98 (s, 2H),
7.02 (d, J＝7.8 Hz, 2H), 7.10 (t, J＝7.2 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ: 21.3, 78.7, 124.0, 127.5,
127.8, 128.4, 137.6, 140.0. ESI-HRMS m/z: [M＋Na]＋
calcd for C16H18NaO2: 265.1199; found 265.1197.
1,2-Bis(3-nitrophenyl)ethane-1,2-diol (3j) 97%
yield, 22% ee, d.r.＝48∶52. The enantiomeric excess
was determined by HPLC on Daicel Chiralpak AD-H
with hexane/i-PrOH (90∶10) as the eluent. Flow: 1
t
t
minor＝40.6 min; minor diastereoisomer tmajor＝59.6 min,
1
minor＝66.2 min. [α]2D8 ＝－73 (c 1.02 in C2H5OH); H
NMR (300 MHz, CDCl3) δ: 2.26 (s, 3H), 2.31—2.99 (m,
2H), 4.66—4.76 (m, 2H), 6.87 (d, J＝5.4 Hz, 1H), 6.96
(s, 1H), 7.04 (s, 1H), 7.10—7.12 (m, 3H), 7.22 (s, 3H);
13C NMR (75 MHz, CDCl3) δ: 21.6, 79.2, 79.2, 124.3,
127.2, 127.8, 128.1, 128.2, 128.3, 128.9, 138.0, 140.1,
140.2. ESI-HRMS m/z: [M＋Na]＋ calcd for C15H16Na-
O2: 251.1048; found 251.1049.
mL/min; λ＝210 nm: tminor＝32.8 min, tmajor＝45.2 min,
1
t
meso＝35.6 min. [α]1D5 ＝＋3 (c 0.6 in C2H5OH); H
NMR (300 MHz, DMSO) δ: 4.66 (s, 1H), 4.86 (d, J＝
3.3 Hz, 1H), 5.72 (s, 1H), 5.75 (d, J＝3.6 Hz, 1H) 7.54
(d, J＝7.5 Hz, 1H), 7.62 (d, J＝7.8 Hz, 1H), 7.94 (s,
1H), 7.99 (d, J＝5.1 Hz, 1H), 8.04 (d, J＝6.3 Hz, 2H);
13C NMR (75 MHz, DMSO) δ: 75.5, 76.1, 122.1, 122.2,
122.3, 122.4, 129.2, 129.4, 134.2, 134.6, 144.8, 145.6,
147.5, 147.7. ESI-HRMS m/z: [M＋Na]＋ calcd for
C14H12N2NaO6: 327.0588; found 327.0580.
Results and Discussion
Initially, several common catalysts were examined
for the enantioselective hydrogenation of benzil 2a un-
1,2-Di(furan-2-yl)ethane-1,2-diol (3l) 94% yield,
Chin. J. Chem. 2012, XX, 1—7
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3

Huang et al.
FULL PAPER
der a catalyst loading of 1.0 mol% in methanol under 50
atm of H2 at room temperature for 24 h. (R,R)-1a was
proved to be the potent catalyst, which afforded the
hydrobenzoin with high enantiomeric and diastereo-
meric purities (＞99% ee and 91∶9 dr), although the
yield was moderate (39%) (Table 1, Entry 1). Subse-
quently, different complexes (R,R)-1b—1d were exam-
ined under identical conditions, and the results were
summarized in Table1. (R,R)-1b and (R,R)-1d could
catalyze the reaction to furnish the desired products in
less than 21% yields albeit with the drs and ees main-
tained (Table 1, Entries 2 and 4). (R,R)-1c was found to
Table 1 Asymmetric hydrogenation of benzyl
O
OH
cat. (R,R)-1a — 1h
H2, temp. solvent
O
OH
3a
2a
Ts
Ts
Ms
Ms
N
N
N
N
Ru
Ru
OTf
Ir
Ir
OTf
NH2
NH2
OTf
NH2
OTf
NH2
(R,R)-1a
(R,R)-1b
(R,R)-1c
(R,R)-1d
Ts
Ts
Ts
N
Ru
NH2
N
Ru
NH2
N
Ru
NH2
Ts
N
O
O
O
Ru
O P
O O
O P
O O
O P
O O
NH
2 O
R
R
R
R
P
O
O
O
R=2,4,6-(i-C3H7)3C6H2
(R,R,R)-1g
(R,R)-1e
(R,R,R)-1f
R=2,4,6-(i-C3H7)3C6H2
(S,S,R)-1h
Entry
1
Cat.
1a
1b
1c
1d
1e
1f
Solvent
Temp/℃
Yieldb/%
39
dl∶mesod
91∶9
92∶8
nd
eec/%
＞99
99
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH2Cl2
toluene
MeOH
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
60
60
r.t.
r.t.
r.t.
50
65
r.t.
r.t.
r.t.
2
10
3
＜5
21
nd
4
97∶3
76∶24
84∶16
74∶26
80∶20
3∶97
nd
99.9
5
5
22
6
14
93
7
1g
1h
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
49.2
44.4
41
85
8
9f
－74
84
10f
11e
12e
13
14
15
16f
17g
18h
＜5
43
nd
90∶10
84∶16
79∶21
84∶16
85∶15
81∶19
85∶15
88∶12
＞99
＞99
96
MeOH/H2O＝90∶10
MeOH
67
90
MeOH
75
97
MeOH
64
97
MeOH
88
98
MeOH
91
98
MeOH
79
99
a Reaction conditions: 0.2 mmol 2a in 2 mL solvent, 1.0 mol% catalyst for Entries 1—8, 2.0 mol% catalyst for Entries 9—18, 50 atm of
H2. b Isolated yields. c Determined by HPLC analysis with a chiral column. d Determined by HPLC with a chiral column or 1H NMR. e For
46 h. f 40 atm pressure of H2. g 30 atm pressure of H2. h 20 atm pressure of H2.
4
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Chin. J. Chem. 2012, XX, 1—7

Stereoselective Synthesis of Optically Active Hydrobenzoins
found that substitutions on phenyl ring and their posi-
tions had a great impact on the catalytic results.
be ineffective for the reaction, affording only trace
amount of the desired products (Table 1, Entry 3). Then
1e—1h containing chiral or achiral phosphate anions
were also investigated for the reaction. Unfortunately,
these catalysts displayed unsatisfactory catalytic results
in terms of both reactivity and stereoselectivity (Table 1,
Entry 1 vs. Entries 5—8). With the best pre-catalyst
(R,R)-1a, the other parameters were further optimized
for the asymmetric hydrogenation of benzil 2a, in-
cluding reaction medium, catalyst loading, hydrogen
pressure and reaction temperature. In aprotic solvents
such as CH2Cl2 and toluene, the reactions showed either
poor ratios of dl to meso or worse reactivity (Table 1,
Entries 9 and 10). In an attempt to improve the chemical
yield, the reaction time was prolonged to 46 h, which
gave slightly higher yield (43%) while the stereo-
selectivity was maintained (Table 1, Entry 11). Inter-
estingly, when the mixture of water and methnol (V/V＝
1/9) was used as the reaction medium, higher yield
(67%) was observed albeit the dr dropped to 84∶16
(Table 1, Entry 12), which implied that this catalytic
system was stable in aqueous solution and exhibited its
superiority to the phosphine catalysts. Improvement of
the catalyst loading to 2.0 mol% resulted in a better
yield (90%) within 24 h but slightly lower diastereo-
selectivity (79∶21 of dl to meso) (Table 1, Entry 13).
The influences of the hydrogen pressure and temper-
ature were investigated as well. At higher temperatures
of 50 and 65 ℃, the yields dropped to 75% and 64%,
respectively (Table 1, Entries 14 and 15), which indi-
cates that the active catalysts may be decomposed at
elevated temperatures. Furthermore, when the hydrogen
pressure was decreased from 50 atm to 30 atm, the ra-
tios of dl to meso increased and the enantioselectivities
and yields maintained (Table 1, Entry 13 vs. Entries 16
and 17). When the hydrogen pressure was further de-
creased to 20 atm, the chemical yield obviously dropped
(79%) (Table 1, Entry 18). Finally, we found that the
optimal reaction conditions for this transformation in-
volved the use of methanol as the reaction medium un-
der 30 atm of H2 at room temperature for 24 h in the
presence of the catalyst (2.0 mol%). As the Ru-TsDPEN
complexes are powerful catalysts for the asymmetric
transfer hydrogenation (ATH) of aromatic ketones and
methanol could be mediated as both hydrogen source
and solvent, the control reaction without hydrogen gas
was carried out under the optimal reaction conditions.
However, no expected products were observed at all
after 24 h in this case. This experiment unambiguously
demonstrated the asymmetric hydrogenation (AH) na-
ture of the catalytic systems.
Table 2 Substrate scope for asymmetric hydrogenation of ben-
zils
O
(R,R)-1a
OH
R2
R2
(2.0 mol%)
R1
R1
30 atm H2,
r.t., MeOH
O
__
OH
__
2a 2l
3a 3l
Entry Sub./R1, R2
Yield b/% dl∶mesod eec/%
1
2
3
4
5
6
7
8
9
2a/R1, R2＝C6H5
3a/91
3b/92
3c/95
3d/96
3e/79
3f/74
3g/26
3h/97
3i/76
85∶15
57∶43
60∶40
53∶47
84∶16
87∶13
98
83
86
81
98
98
2b/R1, R2＝p-FC6H4
2c/R1, R2＝p-ClC6H4
2d/R1, R2＝p-BrC6H4
2e/R1, R2＝p-CH3C6H4
2f/R1, R2＝p-i-PrC6H4
2g/R1, R2＝p-CH3OC6H4
2h/R1, R2＝m-ClC6H4
2i/R1, R2＝m-CH3C6H4
87∶13 ＞99
59∶41
83∶17
48∶52
—
88
98
22
—
95
10 2j/R1, R2＝m-NO2C6H4
11 2k/R1, R2＝o-ClC6H4
12 2l/R1, R2＝furan
3j/96
3k/＜5
3l/94
67∶33
2m/R1＝C6H5,
13
3m/72
3n/84
3o/69
85∶15
67∶33
97
91
R2＝p-ClC6H4
2n/R1＝C6H5,
14
R2＝p-BrC6H4
2o/R1＝C6H5,
15
85∶15 ＞99
R2＝m-CH3C6H4
a Reaction conditions: 0.2 mmol substrate in 2.0 mL methanol,
2.0 mol% catalyst, 30 atm of H2, stirred at room temperature for
24 h. b Isolated yields. c Determined by HPLC analysis with a
chiral column. d Determined by HPLC with a chiral column and
1H NMR.
Among them, the substrates 2b—2d bearing electron
withdrawing substituents (F, Cl, Br) gave the desired
products 3b—3d in excellent yields (92%—96%) but
with moderate to good enantioselectivities and dia-
stereoselectivities (81%—86% ees, 53∶47 to 60∶40
drs) (Table 2, Entries 2—4). For the substrates bearing
electron-donating substituents (Me, i-Pr, OCH3) at the
para-position on the phenyl ring, although the desired
products 3e—3g could be obtained with good dia-
stereoselectivities and excellent enantioselectivities
(98% ees, 86—14 and 87—13 drs), the chemical yields
dramatically decreased (Table 2, Entries 5—7). Appar-
ently, electron-withdrawing substituents on the phenyl
ring of the benzils were favorable to the reactivities but
had a negative effect on the stereoselectivities, whereas
electron-donating substituents on the phenyl ring of the
benzils were good at the stereoselectivities but harmful
Having established the optimal reaction conditions,
the substrate scope of this reaction was subsequently
studied and the results were summarized in Table 2.
Some symmetrical benzils with either electron donating
or withdrawing substituents at ortho-, meta- and para-
positions on phenyl ring were firstly investigated. We
Chin. J. Chem. 2012, XX, 1—7
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Huang et al.
FULL PAPER
Superchi, S.; Rosini, C. J. Org. Chem. 1998, 63, 9392; (e) Ishimaru,
K.; Monda, K.; Yamamoto, Y.; Akiba, K. Tetrahedron 1998, 54,
727; (f) Ishihara, K.; Nakashima, D.; Hiraiwa, Y.; Yamamoto, H. J.
Am. Chem. Soc. 2003, 125, 24.
for the reactivities. For substrates 2h—2j respectively
bearing Cl, Me and NO2 at the meta-position on the
phenyl ring, the same regulation was observed (Table 2,
Entries 8—10). The substrate 2i with Me substituent
could provide the desired product 3i in 76% yield along
with 83∶17 dr and 98% ee. While 2j bearing NO2
group as substrate, the corresponding reaction was pro-
ceeded very well to produce the desired product 3j in
96% yield, only with 48∶52 dr and 22% ee (Entry 10).
Gratefully, the substrate 2l containing furan ring was
also proven to be suitable for this transformation, af-
fording the corresponding product 3l in 94% yield with
67∶33 dr and 95% ee (Entry 12). However, the sub-
strate 2k with Cl substituent at the ortho-position on the
phenyl ring was found to be ineffective for the trans-
formation, probably due to the effects of steric hin-
drance (Table 2, Entry 11). Furthermore, unsymmetrical
substrates 2m—2o were also tested under otherwise
identical conditions, and the corresponding hydroben-
zoins 3m—3o were provided in 69%—84% yields with
91—＞99% ees and 67∶33 to 85∶15 drs (Table 2,
Entries 13—15). Generally, electronic effect on the
catalytic reaction was obviously observed. Substrates
bearing electron-donating substituents provided the ex-
pected products in much lower yields. The reason may
be that the hyrobenzoin products could act as bidentate
ligands and further poison the Ru-TsDPEN catalyst, and
the hydrobenzoins with electron-donating substituents
would enhance its coordination ability.
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Conclusions
In summary, we have developed the asymmetric hy-
drogenation of benzils using the phosphine-free chiral
Ru(OTf)(TsDPEN)(η6-cymene) complex as the pre-
catalyst. A series of chiral hydrobenzoins were syn-
thesized in good yields, good to moderate diastereo-
selectivities and good to excellent enantioselectivities.
Further research on new catalyst and expansion of the
substrate scope of this transformation, as well as practi-
cal utilization of those enantiomerically entriched hy-
drobenzoins is in progress in our laboratory.
Acknowledgement
We are grateful for financial support from the Na-
tional Natural Science Foundation of China (NSFC)
(21072145), the Foundation for the Authors of National
Excellent Doctoral Dissertations of PR China (200931),
and the Natural Science Foundation of Jiangsu Province
of China (BK2009115). This project was also funded by
the Priority Academic Program Development of Jiangsu
Higher Education Institutions (PAPD).
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www.cjc.wiley-vch.de
7