Enantioselective conjugate hydrosilylation of α,β-unsaturated ketones

Article abstract of DOI:10.1039/c9ra01180c

Enantioselective conjugate hydrosilylation of β,β-disubstituted α,β-unsaturated ketones was realized. In the presence of a chiral picolinamide-sulfonate Lewis base catalyst, the reactions provided various chiral ketones bearing a chiral center at the β-po

Full text of DOI:10.1039/c9ra01180c

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Enantioselective conjugate hydrosilylation of a,b-
unsaturated ketones†
Cite this: RSC Adv., 2019, 9, 11627
Huan Yang,‡a Guanglin Weng,‡a Dongmei Fang,b Changjiang Peng,a
a
a
Yuanyuan Zhang,a Xiaomei Zhang
and Zhouyu Wang
*
*
Received 15th February 2019
Accepted 25th March 2019
Enantioselective conjugate hydrosilylation of b,b-disubstituted a,b-unsaturated ketones was realized. In the
presence of a chiral picolinamide–sulfonate Lewis base catalyst, the reactions provided various chiral
DOI: 10.1039/c9ra01180c
ketones bearing
a chiral center at the b-position in up to quantitative yields with moderate
rsc.li/rsc-advances
enantioselectivities.
Chiral ketones are important intermediates for the synthesis of
First, various chiral Lewis base catalysts 2 were screened in
natural products or chiral drugs, and some themselves are the enantioselective hydrosilylation of (E)-1,3-diphenylbut-2-en-
useful chiral drugs.1 Asymmetric conjugate reduction of a,b- 1-one 1a in acetonitrile at 0 ꢀC. As shown in Fig. 2, L-piperazine-
unsaturated carbonyl compounds is an attractive and chal- 2-carboxylic acid derived N-formamide 2a,12a R-(+)-tert-butyl-
lenging transformation for the construction of chiral ketones. sulnamide derived catalyst 2b12b and picolinamide 2c12c were
During the past few decades, many groups have devoted found to be totally inactive for the reaction. Meanwhile picoli-
considerable efforts to this area and made great improvement, namide–tosylate catalyst 2d was highly active to afford the
for instance, transition metal catalyzed asymmetric hydroge- product with excellent yield in moderate ee value. Aerwards,
nation of a,b-unsaturated carbonyl compounds, including several picolinamide–tosylate catalysts 2f–2h bearing electron-
palladium,2 iridium,3 copper,4 ruthenium,5 rhodium6 and withdrawing group in 4-position of pyridine were employed in
cobalt.7 Besides, some organocatalyzed asymmetric conjugate the reaction and 4-bromo picolinamide 2f delivered a slightly
transfer hydrogenations using Hantzsch ester8 or pinacolbor- higher ee value. 5-Methoxy picolinamide 2i gave the product
ane9 as the hydride source have also been reported. However, with the same ee value as that of 2d but in much lower yield.
very few examples about chiral Lewis base catalyzed conjugate Lower enantioselectivities were observed with 4-phenyl picoli-
hydrosilylation of a,b-unsaturated carbonyl compounds have namide 2j and 3-methyl picolinamide 2k. When (R)-1-(2-
been reported and only chiral phosphine oxide Lewis base
catalysts were used in these reactions (Scheme 1).10 Therefore,
exploration of the application of other kinds of chiral Lewis
base catalysts in this reaction is still highly desirable.
Recently, we developed a kind of easily accessible chiral
picolinamide–sulfonate Lewis base catalysts and used them in
asymmetric hydrosilylation of a-acyloxy-b-enamino esters,11
one of them exhibiting excellent reactivity, diastereoselectivity
and enantioselectivity. Herein we present the enantioselective
conjugate hydrosilylation of b,b-disubstituted a,b-unsaturated
ketones using this kind of Lewis base as catalysts, leading to
various chiral ketones bearing a chiral center at b-position
(Fig. 1).
aDepartment of Chemistry, Xihua University, Chengdu, 610039, China. E-mail:
xmzhang@cioc.ac.cn; zhouyuwang77@163.com; Fax: +86-028-8772-3006; Tel: +86-
028-8772-9463
bChengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral and analytical data for products 3. See DOI: 10.1039/c9ra01180c
‡ These authors contributed equally to this work and should be considered
co-rst authors.
Scheme 1 Enantioselective conjugate hydrosilylation of a,b-unsatu-
rated ketones by chiral Lewis base catalysts.
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aminonaphthalen-1-yl)naphthalen-2-ol derived catalyst 2l was sulfonamide catalysts 2n and 2o were also used in the reaction
used, no product was observed. When (1S,2R)-1-amino-2,3- and almost racemic products were obtained. Hence, 2f was
dihydro-1H-inden-2-ol derived catalyst 2m gave the product in determined as the optimal catalyst and was used through out
both poor yield and ee value. Moreover, two picolinamide– our study.
Subsequently, the other reaction conditions were optimized.
The results are summarized in Table 1. First, various solvents
were evaluated. Surprisingly, reactions in some polar solvents
generated R-products (Table 1, entries 1–4), while S-products
were obtained in some non-polar solvents (Table 1, entries 6,
9, 10 and 13) with the exception of 1,2-dichloroethane (Table 1,
entry 7). Reaction in toluene delivered the product in excellent
yield with the best ee value (Table 1, entry 10). However, no
product was detected in xylene or mesitylene (Table 1, entries 11
Fig. 1 Three typical chiral drugs containing chiral ketone moiety.
and 12). Hence, toluene was determined as the optimal solvent
for the reaction. In order to improve the enantioselection, we
tried to perform the reaction at lower temperatures. Lowering
the temperature to ꢁ10 ꢀC led to an increased ee value (Table 1,
entry 14). However, further lowering the temperature to ꢁ20
ꢀ
and ꢁ40 C did not provide better results (Table 1, entries 15
and 16). Therefore, ꢁ10 ꢀC was determined as the optimal
temperature for the reaction.
With the optimized conditions in hand, the scope and
limitations of the reaction were explored. The results are
summarized in Fig. 3. In the presence of 20 mol% of chiral
Lewis base catalyst 2f and 2 equivalents of trichlorosilane,
various a,b-unsaturated ketones were hydrosilylated. We rst
tested the effect of various 3-aryl groups of 1. 3-(4-Methoxy-
phenyl) substrate 3e (Fig. 3) and 3-(naphthalen-2-yl) substrate
3i (Fig. 3) underwent the reaction to give the products with good
Table 1 Optimization of the reactiona
Entrya
Solvent
T (ꢀC)
Time [h]
Yieldb [%]
eec,d [%]
1
2
3
4
5
6
7
8
CH3CN
0
0
0
0
0
0
0
0
0
0
0
0
0
ꢁ10
ꢁ20
ꢁ40
24
24
24
24
24
24
24
24
24
24
24
24
24
48
60
72
77
84
83
92
63
92
96
90
95
95
N.R.
N.R.
95
97
92
N.R.
51 (R)
50 (R)
24 (R)
11 (R)
5 (R)
25 (S)
3
10 (R)
35 (S)
55 (S)
—
CH3CH2CN
C6H5CN
THF
1,4-Dioxane
CHCl3
CH2Cl2
ClCH2CH2Cl
CCl4
9
10
11
12
13
14
15
16
Toluene
Xylene
Mesitylene
C6H5CF3
Toluene
Toluene
Toluene
—
31 (S)
64 (S)
65 (S)
—
Fig. 2 Evaluation of the chiral Lewis base catalysts 2 in conjugate
hydrosilylation of (E)-1,3-diphenylbut-2-en-1-one 1a. Unless other-
wise specified, the reactions were carried out with 1a (0.1 mmol), tri-
chlorosilane (0.2 mmol) and catalyst 2 (0.02 mmol) in 1 mL of
acetonitrile at 0 ꢀC for 24 hours. Isolated yield based on 1a. The ee
values were determined by using chiral HPLC.
a
Unless otherwise specied, the reactions were carried out with 1a (0.1
mmol), trichlorosilane (0.2 mmol) and catalyst 2f (0.02 mmol) in 1 mL of
solvent. b Isolated yield based on 1a. c The ee values were determined by
d
using chiral HPLC. The absolute conguration of 3a was determined
by comparison of the retention times of the two enantiomers on the
stationary phase with those in the literatures.
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Fig. 3 Substrate scope of the reaction. Unless otherwise specified, the reactions were carried out with 1 (0.1 mmol), trichlorosilane (0.2 mmol)
and catalyst 2f (0.02 mmol) in 1 mL of toluene at ꢁ10 ꢀC for 48 hours. Isolated yield based on 1. The ee values were determined by using chiral
HPLC. The absolute configuration of 3a was determined by comparison of the retention times of the two enantiomers on the stationary phase
with the literatures. The absolute configurations of other products were determined in analogy. aThe reaction time was 60 hours. bThe reaction
time was 72 hours.
yields in enantioselectivities close to 3a, while lower ee values was obtained with good yield but very poor enantioselection
were observed with 3b–3d, 3h, 3k and 3l (Fig. 3). No product was (Fig. 3). Trace amount of the product was detected with 3-
obtained with 3-(2-chloro-phenyl) substrate 3f and 3- (pyridin-2-yl) substrate 3m (Fig. 3). Next, some 3-phenyl-but-2-
(naphthalen-1-yl) substrate 3j, perhaps due to the high steric en-1-ones with different 1-aryl groups were also employed in
hindrance (Fig. 3). When 3-(2-methoxy-phenyl) substrate 3g was the reaction. The 4-substituted or 3-substituted substrates
used, by prolonging the reaction time to 60 hours, the product delivered good yields of the products with similar or slightly
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lower enantioselectivities (Fig. 3), while much lower ee value accessible. The absolute conguration of one product was
was observed with 2-substituted substrate 3s (Fig. 3). For some determined by comparison of the retention times of the two
other 3-alkyl chalcones, moderate to good yields and moderate enantiomers on the stationary phase with those in the
ee values were obtained (Fig. 3), except for the bulkier tertiary literature.
butyl substituted 3w that gave trace amount of the product
(Fig. 3). Reaction of 3y with two different 3,3-aryl groups affor-
ded the product with moderate yield in very low enantiose-
lectivity (Fig. 3). Finally, cyclic substrate 3z was subjected in the
reaction and provided the product with excellent yield but in
Experimental section
General procedure of enantioselective conjugate hydrosilylation
of a,b-unsaturated ketones
A solution of trichlorosilane (21 mL, 0.2 mmol, 2.0 equiv.) in
0.5 mL of toluene was added to a stirred solution of the corre-
sponding a,b-unsaturated ketones (0.1 mmol) and the catalyst
2f (0.02 mmol) in toluene (2.0 mL) at ꢁ10 C. The mixture was
poor ee value (Fig. 3).
Although detailed structural and mechanistic studies remain
to be carried out, based on the absolute conguration of the
product 3a, we propose a mechanism shown in Scheme 2. First,
the nitrogen atom of the pyridine ring and the carbonyl oxygen
atom of catalyst 2f are coordinated to Cl3SiH to create an acti-
vated hydrosilylation species. Substrate 1a may approache the
Cl3SiH-catalyst complex to generate two transition states A and
B. In transition state A, the N–H of catalyst 2f activates the
carbonyl group of 1a through H-bonding. In addition, there
could be p–p stackings between the two aromatic systems of the
catalyst and the substrate. Then Si-face conjugate attack of the
hydride to 1a generate (S)-product 3a. On the contrary, in
transition state B through which (R)-product will be obtained,
the carbonyl group of 1a can not be connected with the N–H of
catalyst 2f. Thus the fact that (S)-enriched product 3a was ob-
tained is consistent with the suggestion that the hydrosilylation
predominantly proceeds through the pathway involving transi-
tion state A rather than transition state B.
In conclusion, we have developed a facile, metal-free and
mild enantioselective conjugate hydrosilylation of b,b-disub-
stituted a,b-unsaturated ketones. By using chiral picolinamide–
sulfonate Lewis base as catalyst, the reactions provided various
optically active ketones bearing a chiral center at b-position
with moderate to good yields in moderate enantioselectivities.
Comparing with the chiral phosphine oxide Lewis base cata-
lysts, the chiral picolinamide–sulfonate is cheaper and easier
ꢀ
stirred at the same temperature for 48 hours. The reaction
mixture was then treated with saturated aqueous solution of
NaHCO3 at room temperature for 20 minutes. Then the mixture
was extracted with EtOAc. The combined extracts were washed
with brine and dried over anhydrous Na2SO4. The solvents were
removed under reduced pressure. The residue was puried by
silica-gel chromatography with ethyl acetate/petroleum ether to
give the pure product. The ee values were determined using
established HPLC techniques with chiral stationary phases.
(1R,2R)-2-(4-Phenylpicolinamido)cyclohexyl 4-methyl-benzene-
sulfonate (2j)
White solid, mp: 124–125 ꢀC, 32% yield. 1H NMR (300 MHz,
CDCl3) d 8.54 (d, J ¼ 5.1 Hz, 1H), 8.34 (d, J ¼ 1.5 Hz, 1H), 8.04 (d,
J ¼ 7.9 Hz, 1H), 7.74–7.64 (m, 5H), 7.55–7.48 (m, 3H), 7.03 (d, J ¼
8.3 Hz, 2H), 4.62–4.53 (m, 1H), 4.14–4.04 (m, 1H), 2.21 (s, 3H),
2.16–2.13 (m, 2H), 1.83–1.67 (m, 3H), 1.48–1.32 (m, 3H). 13C
NMR (100 MHz, DMSO) d 163.3, 150.8, 149.2, 148.9, 144.2,
137.1, 134.3, 131.3, 130.1, 129.9, 128.5, 127.4, 125.9, 124.0,
119.4, 84.5, 51.3, 33.1, 31.3, 24.3, 24.0, 21.4. [a]2D0.0 ¼ ꢁ27.6 (c ¼
0.5, CH2Cl2); HRMS (ESI): calcd for [C25H26N2O4S + H]+
451.1613, found 451.1686.
(1R,2R)-2-(3-Methylpicolinamido)cyclohexyl 4-methylbenzene-
sulfonate (2k)
White solid, mp: 75–76 ꢀC, 45% yield. 1H NMR (300 MHz,
CDCl3) d 8.35–8.33 (m, 1H), 8.09 (d, J ¼ 9.5 Hz, 1H), 7.66 (d, J ¼
8.3 Hz, 2H), 7.58–7.55 (m, 1H), 7.30 (dd, J ¼ 4.6 Hz, 1H), 7.01 (d,
J ¼ 8.0 Hz, 2H), 4.57–4.49 (m, 1H), 4.07–3.96 (m, 1H), 2.66 (s,
3H), 2.26 (s, 3H), 2.19–2.04 (m, 2H), 1.80–1.69 (m, 3H), 1.45–1.26
(m, 3H). 13C NMR (100 MHz, CDCl3) d 165.3, 146.8, 145.2, 144.0,
140.7, 135.5, 134.3, 129.4, 127.5, 125.6, 83.1, 51.6, 32.4, 31.7,
24.0, 24.0, 21.6, 20.6. [a]2D0.0 ¼ ꢁ53.6 (c ¼ 0.5, CH2Cl2); HRMS
(ESI): calcd for [C20H24N2O4S + H]+ 389.1457, found 389.1530.
(1S,2R)-1-(Picolinamido)-2,3-dihydro-1H-inden-2-yl 4-methyl-
benzene-sulfonate (2l)
White solid, mp: 123–124 ꢀC, 57% yield. 1H NMR (300 MHz,
DMSO) d 8.68 (d, J ¼ 4.1 Hz, 1H), 8.38 (d, J ¼ 9.6 Hz, 1H), 8.09–
8.04 (m, 1H), 8.02–7.94 (m, 1H), 7.83–7.52 (m, 3H), 7.50–7.14
(m, 4H), 7.10 (d, J ¼ 8.0 Hz, 2H), 5.72–5.67 (m, 1H), 5.33–5.30
(m, 1H), 3.40 (d, J ¼ 4.6 Hz, 1H), 3.10 (d, J ¼ 17.2 Hz, 1H), 2.22 (s,
3H).13C NMR (100 MHz, CDCl3) d 164.2, 149.2, 148.2, 144.5,
Scheme 2 A plausible reaction mechanism for hydrosilylation of 1a
catalyzed by 2f.
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139.5, 138.5, 137.2, 133.3, 129.5, 128.6, 127.9, 127.5, 126.4, detection at 254 nm, trminor ¼ 6.96 min, trmajor ¼ 8.26 min; H
125.3, 123.6, 122.3, 83.6, 55.9, 38.5, 21.6. [a]2D0.0 ¼ ꢁ4.8 (c ¼ 0.5, NMR (300 MHz, d-DMSO) d 7.93–7.90 (m, 2H), 7.58–7.53 (m,
CH2Cl2); HRMS (ESI): calcd for [C22H20N2O4S + H]+ 409.1144, 1H), 7.47–7.42 (m, 2H), 7.26–7.20 (m, 2H), 7.01–6.93 (m, 2H),
found 409.1217.
3.56–3.44 (m, 1H), 3.31–3.13 (m, 2H), 1.32 (d, J ¼ 6.9 Hz, 3H).
(S)-3-(4-Chlorophenyl)-1-phenylbutan-1-one (3c)
(R)-1-(2-(Picolinamido)naphthalen-1-yl)naphthalen-2-yl 4-
methyl-benz-enesulfonate (2m)
Colorless oil, 94% yield, 48% ee. HPLC conditions: AD-H
column, hexane/iPrOH ¼ 95/5, ow rate 1.0 mL minꢁ1, UV
White solid, mp: 211–212 ꢀC, 40% yield. 1H NMR (300 MHz, d-
DMSO) d 9.64 (s, 1H), 8.61 (d, J ¼ 9.1 Hz, 1H), 8.29 (d, J ¼ 9.0 Hz,
1H), 8.17–8.11 (m, 3H), 8.07–7.93 (m, 3H), 7.66 (d, J ¼ 9.1 Hz,
1H), 7.55–7.43 (m, 3H), 7.36–7.24 (m, 2H), 7.13 (d, J ¼ 8.3 Hz,
2H), 7.01 (t, J ¼ 9.8 Hz, 3H), 6.84 (d, J ¼ 8.7 Hz, 1H), 2.21 (s, 3H).
13C NMR (100 MHz, CDCl3) d 161.9, 149.5, 147.8, 146.1, 144.6,
137.3, 134.8, 133.1, 132.7, 132.6, 132.4, 130.8, 130.6, 129.4,
129.2, 128.2, 127.8, 127.5, 127.4, 126.6, 126.5, 126.3, 126.1,
1
detection at 254 nm, trminor ¼ 7.01 min, trmajor ¼ 8.80 min; H
NMR (300 MHz, d-DMSO) d 7.93–7.90 (m, 2H), 7.58–7.53 (m,
1H), 7.47–7.42 (m, 2H), 7.28–7.27 (m, 1H), 7.25–7.19 (m, 3H),
3.55–3.44 (m, 1H), 3.31–3.13 (m, 2H), 1.32 (d, J ¼ 6.9 Hz, 3H).
(S)-1-Phenyl-3-(p-tolyl)butan-1-one (3d)
White solid, 97% yield, 53% ee. HPLC conditions: AD-H
125.8, 124.7, 124.5, 12.0, 121.9, 120.1, 119.7, 21.6. [a]D20.0
¼
column, hexane/iPrOH ¼ 95/5, ow rate 1.0 mL minꢁ1, UV
1
ꢁ87.6 (c ¼ 0.5, CH2Cl2); HRMS (ESI): calcd for [C33H24N2O4S +
detection at 254 nm, trminor ¼ 5.88 min, trmajor ¼ 7.24 min; H
H]+ 545.1547, found 545.1530.
NMR (300 MHz, d-DMSO) d 7.93 (d, J ¼ 7.5 Hz, 2H), 7.55 (t, J ¼
7.3 Hz, 1H), 7.44 (t, J ¼ 7.6 Hz, 2H), 7.16–7.10 (m, 4H), 3.53–3.41
(m, 1H), 3.32–3.13 (m, 2H), 2.32 (s, 3H), 1.32 (d, J ¼ 6.9 Hz, 3H).
N-((1R,2R)-2-(4-Methylphenylsulfonamido)cyclohexyl)picolin-
amide (2n)
White solid, mp: 173–174 ꢀC, 60% yield. 1H NMR (300 MHz,
CDCl3): d 8.41 (d, J ¼ 4.5 Hz, 1H), 8.11 (d, J ¼ 7.8 Hz, 1H), 7.91–
7.85 (m, 1H), 7.63 (d, J ¼ 8.0 Hz, 1H), 7.53 (d, J ¼ 8.2 Hz, 2H),
7.47–7.43 (m, 1H), 6.75 (d, J ¼ 9.0 Hz, 2H), 5.97 (d, J ¼ 5.3 Hz,
1H), 3.85–3.74 (m, 1H), 3.04–2.94 (m, 1H), 2.25 (d, J ¼ 13.9 Hz,
1H), 2.12 (s, 3H), 1.99–1.95 (m, 1H), 1.77–1.72 (m, 2H), 1.52–1.39
(m, 1H), 1.37–1.25 (m, 3H). [a]2D0.0 ¼ ꢁ8.6 (c ¼ 0.5, CH2Cl2);
HRMS (ESI): calcd for [C19H23N3O3S + H]+ 374.1460, found
374.1533.
(S)-3-(4-Methoxyphenyl)-1-phenylbutan-1-one (3e)
Colorless oil, 91% yield, 62% ee. HPLC conditions: AD-H
column, hexane/iPrOH ¼ 95/5, ow rate 1.0 mL minꢁ1, UV
detection at 254 nm, trminor ¼ 8.92 min, trmajor ¼ 11.47 min; 1H
NMR (300 MHz, d-DMSO) d 7.94–7.91 (m, 2H), 7.58–7.52 (m,
1H), 7.47–7.42 (m, 2H), 7.21–7.17 (m, 2H), 6.87–6.82 (m, 2H),
3.78 (s, 3H), 3.54–3.41 (m, 1H), 3.31–3.11 (m, 2H), 1.31 (d, J ¼
6.9 Hz, 3H).
(S)-3-(2-Methoxyphenyl)-1-phenylbutan-1-one (3g)
N-((1R,2R)-2-(N,4-Dimethylphenylsulfonamido)cyclohexyl)picolin-
amide (2o)
Colorless oil, 92% yield, 20% ee. HPLC conditions: IC column,
hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV detection at
White solid, mp: 108–109 ꢀC, 43% yield. 1H NMR (300 MHz,
CDCl3): d 8.59 (d, J ¼ 4.6 Hz, 1H), 8.12 (t, J ¼ 9.3 Hz, 2H), 7.86–
7.80 (m, 1H), 7.62 (d, J ¼ 8.2 Hz, 2H), 7.44–7.40 (m, 1H), 7.06 (d, J
¼ 8.1 Hz, 2H), 4.13–3.99 (m, 1H), 3.89–3.80 (m, 1H), 2.77 (s, 3H),
2.30 (s, 3H), 2.22–2.18 (m, 1H), 1.86–1.69 (m, 2H), 1.53–1.50 (m,
1H), 1.46–1.23 (m, 4H).13C NMR (100 MHz, CDCl3) d 164.0,
149.8, 148.2, 142.8, 137.4, 137.1, 129.4, 127.0, 126.0, 122.1, 60.0,
49.0, 33.4, 29.3, 28.6, 25.2, 24.7, 21.5. [a]2D0.0 ¼ ꢁ12.4 (c ¼ 0.5,
CH2Cl2); HRMS (ESI): calcd for [C20H25N3O3S + H]+ 388.1617,
found 388.1689.
1
254 nm, trmajor ¼ 9.91 min, trminor ¼ 10.69 min; H NMR (300
MHz, CDCl3) d 8.00 (d, J ¼ 7.3 Hz, 2H), 7.56 (t, J ¼ 7.3 Hz, 1H),
7.45 (t, J ¼ 7.5 Hz, 2H), 7.26–7.18 (m, 2H), 6.94 (t, J ¼ 7.4 Hz, 1H),
6.87 (d, J ¼ 8.1 Hz, 1H), 3.91–3.79 (m, 4H), 3.41–3.01 (m, 2H),
1.31 (d, J ¼ 6.9 Hz, 3H).
(S)-3-(3-Methoxyphenyl)-1-phenylbutan-1-one (3h)
Colorless oil, 91% yield, 58% ee. HPLC conditions: IC column,
hexane/iPrOH ¼ 95/5, ow rate 1.0 mL minꢁ1, UV detection at
1
254 nm, trmajor ¼ 7.54 min, trminor ¼ 9.19 min; H NMR (300
MHz, CDCl3) d 7.95–7.92 (m, 2H), 7.58–7.53 (m, 1H), 7.47–7.42
(m, 2H), 7.22 (d, J ¼ 7.9 Hz, 1H), 6.88 (d, J ¼ 7.7 Hz, 1H), 6.83 (t, J
¼ 2.1 Hz, 1H), 6.77–6.73 (m, 1H), 3.80 (s, 3H), 3.56–3.43 (m, 1H),
3.34–3.14 (m, 2H), 1.33 (d, J ¼ 6.9 Hz, 3H).
(S)-1,3-Diphenylbutan-1-one (3a)
White solid, 97% yield, 65% ee. HPLC conditions: IC column,
hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV detection at
1
254 nm, trmajor ¼ 6.43 min, trminor ¼ 6.82 min; H NMR (300
MHz, CDCl3) d 7.95–7.92 (m, 2H), 7.58–7.52 (m, 1H), 7.47–7.42
(m, 2H), 7.34–7.29 (m, 4H), 7.23–7.17 (m, 1H), 3.57–3.45 (m,
1H), 3.35–3.15 (m, 2H), 1.34 (d, J ¼ 6.9 Hz, 3H).
(S)-3-(Naphthalen-2-yl)-1-phenylbutan-1-one (3i)
White solid, 97% yield, 65% ee. HPLC conditions: AD-H
column, hexane/iPrOH ¼ 95/5, ow rate 1.0 mL minꢁ1, UV
1
detection at 254 nm, trminor ¼ 8.00 min, trmajor ¼ 9.24 min; H
(S)-3-(4-Fluorophenyl)-1-phenylbutan-1-one (3b)
NMR (300 MHz, d-DMSO) d 7.99–7.96 (m, 2H), 7.86–7.78 (m,
Colorless oil, 98% yield, 50% ee. HPLC conditions: AD-H 4H), 7.65–7.60 (m, 1H), 7.55–7.40 (m, 5H), 3.57–3.40 (m, 3H),
column, hexane/iPrOH ¼ 95/5, ow rate 1.0 mL minꢁ1, UV 1.33 (d, J ¼ 6.5 Hz, 3H).
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MHz, CDCl3) d 7.72 (d, J ¼ 6.8 Hz, 2H), 7.35–7.28 (m, 6H), 7.22–
7.14 (m, 1H), 3.36–3.44 (m, 1H), 3.32–3.13 (m, 2H), 2.40 (s, 3H),
1.34 (d, J ¼ 6.9 Hz, 3H).
(S)-3-(Furan-2-yl)-1-phenylbutan-1-one (3k)
White solid, 90% yield, 57% ee. HPLC conditions: AD-H
column, hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV
1
detection at 254 nm, trminor ¼ 6.97 min, trmajor ¼ 8.03 min; H
(S)-3-Phenyl-1-(o-tolyl)butan-1-one (3s)
NMR (300 MHz, CDCl3) d 7.90–7.87 (m, 2H), 7.52–7.46 (m, 1H),
7.41–7.36 (m, 2H), 7.23–7.22 (m, 1H), 6.21–6.19 (m, 1H), 6.02 (d,
J ¼ 3.2 Hz, 1H), 3.65–3.5 (m, 1H), 3.39–2.97 (m, 2H), 1.26 (d, J ¼
6.9 Hz, 3H).
Colorless oil, 90% yield, 28% ee. HPLC conditions: AD-H
column, hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV
1
detection at 254 nm, trminor ¼ 6.15 min, trmajor ¼ 6.90 min; H
NMR (300 MHz, CDCl3) d 7.46 (d, J ¼ 7.8 Hz, 1H), 7.39–7.28 (m,
2H), 7.25–7.15 (m, 6H), 3.51–3.40 (m, 1H), 3.25–3.07 (m, 2H),
2.35 (s, 3H), 1.32 (d, J ¼ 6.9 Hz, 3H).
(S)-1-Phenyl-3-(thiophen-2-yl)butan-1-one (3l)
White solid, 96% yield, 59% ee. HPLC conditions: AD-H
column, hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV
1
detection at 254 nm, trminor ¼ 8.23 min, trmajor ¼ 9.34 min; H
(S)-1,3-Diphenylpentan-1-one (3t)
NMR (300 MHz, CDCl3) d 7.96–7.94 (m, 2H), 7.57 (t, J ¼ 7.3 Hz,
1H), 7.46 (t, J ¼ 7.5 Hz, 2H), 7.14–7.12 (m, 1H), 6.94–6.87 (m,
2H), 3.92–3.80 (m, 1H), 3.42–3.17 (m, 2H), 1.43 (d, J ¼ 6.9 Hz,
3H).
White solid, 94% yield, 65% ee. HPLC conditions: AD-H
column, hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV
detection at 254 nm, trminor ¼ 7.95 min, trmajor ¼ 10.16 min; 1H
NMR (300 MHz, CDCl3) d 7.91–7.89 (m, 2H), 7.56–7.41 (m, 1H),
7.45–7.40 (m, 2H), 7.31–7.27 (m, 2H), 7.26–7.15 (m, 3H), 3.34–
3.19 (m, 3H), 1.86–1.57 (m, 2H), 0.80 (t, J ¼ 7.3 Hz, 3H).
(S)-1-(4-Chlorophenyl)-3-phenylbutan-1-one (3n)
Colorless oil, 95% yield, 64% ee. HPLC conditions: AD-H
column, hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV
detection at 254 nm, trminor ¼ 9.05 min, trmajor ¼ 10.71 min; 1H
NMR (300 MHz, CDCl3) d 7.88–7.84 (m, 2H), 7.43–7.39 (m, 2H),
7.34–7.27 (m, 3H), 7.25–7.17 (m, 1H), 3.55–3.43 (m, 1H), 3.31–
3.11 (m, 2H), 1.34 (d, J ¼ 6.9 Hz, 3H).
(S)-4-Bromo-1,3-diphenylbutan-1-one (3u)
Colorless oil, 76% yield, 67% ee. HPLC conditions: IC column,
hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV detection at
254 nm, trmajor ¼ 13.06 min, trminor ¼ 13.84 min; 1H NMR (300
MHz, CDCl3) d 8.03–7.93 (m, 2H), 7.66–7.43 (m, 4H), 7.36–7.27
(m, 3H), 7.25–7.23 (m, 1H), 3.84–3.78 (m, 1H), 3.76–3.66 (m,
2H), 3.62 (d, J ¼ 6.1 Hz, 1H), 3.47–3.39 (m, 1H).
(S)-3-Phenyl-1-(p-tolyl)butan-1-one (3o)
White solid, 94% yield, 58% ee. HPLC conditions: AD-H
column, hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV
detection at 254 nm, trminor ¼ 10.13 min, trmajor ¼ 13.40 min; 1H
NMR (300 MHz, CDCl3) d 7.84 (d, J ¼ 8.2 Hz, 2H), 7.33–7.28 (m,
4H), 7.25–7.17 (m, 3H), 3.56–3.44 (m, 1H), 3.31–3.12 (m, 2H),
2.40 (s, 3H), 1.33 (d, J ¼ 6.9 Hz, 3H).
(R)-4-Methyl-1,3-diphenylpentan-1-one (3v)
White solid, 88% yield, 65% ee. HPLC conditions: IC column,
hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV detection at
1
254 nm, trmajor ¼ 8.68 min, trminor ¼ 10.42 min; H NMR (300
MHz, CDCl3) d 7.90–7.87 (m, 2H), 7.56–7.50 (m, 1H), 7.45–7.39
(m, 2H), 7.28–7.27 (m, 2H), 7.25–7.12 (m, 3H), 3.37 (d, J ¼
7.0 Hz, 2H), 3.20–3.13 (m, 1H), 2.00–1.89 (m, 1H), 0.99 (d, J ¼
6.7 Hz, 3H), 0.79 (d, J ¼ 6.7 Hz, 3H).
(S)-1-(4-Methoxyphenyl)-3-phenylbutan-1-one (3p)
White solid, 94% yield, 59% ee. HPLC conditions: AD-H
column, hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV
detection at 254 nm, trminor ¼ 20.17 min, trmajor ¼ 27.94 min; 1H
NMR (300 MHz, CDCl3) d 7.93–7.90 (m, 2H), 7.33–7.28 (m, 4H),
7.22–7.16 (m, 1H), 6.91 (d, J ¼ 8.9 Hz, 2H), 3.86 (s, 3H), 3.56–3.43
(m, 1H), 3.28–3.09 (m, 2H), 1.33 (d, J ¼ 6.9 Hz, 3H).
(S)-1,3,4-Triphenylbutan-1-one (3x)
White solid, 91% yield, 59% ee. HPLC conditions: IC column,
hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV detection at
254 nm, trmajor ¼ 11.40 min, trminor ¼ 11.99 min; 1H NMR (300
MHz, CDCl3) d 7.96–7.83 (m, 2H), 7.58–7.49 (m, 1H), 7.44–7.33
(m, 2H), 7.31–7.14 (m, 8H), 7.10–7.07 (m, 2H), 3.72–3.62 (m,
1H), 3.40–3.24 (m, 2H), 3.05–2.86 (m, 2H).
(S)-1-(3-Fluorophenyl)-3-phenylbutan-1-one (3q)
White solid, 91% yield, 54% ee. HPLC conditions: IC column,
hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV detection at
1
254 nm, trmajor ¼ 6.18 min, trminor ¼ 6.56 min; H NMR (300
MHz, CDCl3) d 7.74–7.65 (m, 1H), 7.62–7.57 (m, 1H), 7.45–7.38
(m, 1H), 7.33–7.27 (m, 4H), 7.25–7.17 (m, 2H), 3.55–3.44 (m,
1H), 3.32–3.11 (m, 2H), 1.34 (d, J ¼ 6.9 Hz, 3H).
3-(4-Methoxyphenyl)-1,3-diphenylpropan-1-one (3y)
White solid, 70% yield, 11% ee. HPLC conditions: OD-H
column, hexane/iPrOH ¼ 90/10, ow rate 1.0 mL minꢁ1, UV
1
detection at 254 nm, trminor ¼ 7.17 min, trmajor ¼ 7.99 min; H
(S)-3-Phenyl-1-(m-tolyl)butan-1-one (3r)
NMR (300 MHz, CDCl3) d 7.96–7.93 (m, 2H), 7.59–7.531 (m, 1H),
White solid, 95% yield, 52% ee. HPLC conditions: IC column, 7.47–7.42 (m, 2H), 7.32–7.25 (m, 4H), 7.21–7.15 (m, 3H), 6.83–
hexane/iPrOH ¼ 98/2, ow rate 1.0 mL minꢁ1, UV detection at 6.81 (m, 2H), 4.79 (t, J ¼ 7.3 Hz, 1H), 3.76 (s, 3H), 3.72 (d, J ¼
1
254 nm, trmajor ¼ 7.23 min, trminor ¼ 7.89 min; H NMR (300 7.3 Hz, 2H).
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(e) M. Tissot, D. Poggiali, H. Henon, D. Muller, L. Guenee,
M. Mauduit and A. Alexakis, Chem.–Eur. J., 2012, 18, 8731–
8747; (f) S. Kehrli, D. Martin, D. Rix, M. Mauduit and
A. Alexakis, Chem.–Eur. J., 2010, 16, 9890–9904; (g) K. Endo,
D. Hamada, S. Yakeishi and T. Shibata, Angew. Chem., Int.
Ed., 2013, 52, 606–610.
1-Phenyl-2-(1,2,3,4-tetrahydronaphthalen-1-yl)ethan-1-one (3z)
White solid, 98% yield, 22% ee. HPLC conditions: OD-H
column, hexane/iPrOH ¼ 95/5, ow rate 1.0 mL minꢁ1, UV
1
detection at 254 nm, trminor ¼ 6.22 min, trmajor ¼ 6.61 min; H
NMR (300 MHz, CDCl3) d 8.00–7.98 (m, 2H), 7.61–7.55 (m, 1H),
7.50–7.47 (m, 2H), 7.20–7.08 (m, 4H), 3.68–3.60 (m, 1H), 3.39–
3.23 (m, 2H), 2.86–2.71 (m, 2H), 1.99–1.90 (m, 1H), 1.86–1.66
(m, 3H).
5 (a) O. Tetsuo, M. Tsutomu, S. Nobuo, K. Hidenori and
T. Hidemasa, J. Org. Chem., 1995, 60, 357–363; (b)
J. F. Matthias, C. Giambattista, S. Michelangelo and
S. Rudolf, J. Org. Chem., 1999, 64, 5768–5776; (c)
D. B. Zhao, B. Beiring and F. R. Glorius, Angew. Chem., Int.
Ed., 2013, 52, 8454–8458.
Conflicts of interest
There are no conicts to declare.
6 (a) Y. Kanazawa, Y. Tsuchiya, K. Kobayashi, T. Shiomi,
J. Itoh, M. Kikuchi, Y. Yamamoto and H. Nishiyama,
Chem.–Eur. J., 2006, 12, 63–71; (b) T. Ohshima, H. Tadaoka,
K. Hori, N. Sayo and K. Mashima, Chem.–Eur. J., 2008, 14,
2060–2066; (c) R. C. Joel, O. F. Michael, L. T. L. Dana,
R. R. Jacob and A. M. Scott, Org. Lett., 2012, 14, 1038–1041;
(d) T. Zhang, J. Jiang, L. Yao, H. L. Geng and X. M. Zhang,
Chem. Commun., 2017, 53, 9258–9261.
Acknowledgements
We are grateful for the nancial support from National Natural
Science Foundation of China (21672208), the Founds of Sichuan
Province (2017JQ0023 and 2017NZ0048), the Open Project of
Sichuan Province (szjj2017-031) and the Innovation Fund of
Postgraduate, Xihua University (ycjj2018008 and ycjj2018188).
7 T. Inagaki, L. T. Phong, A. Furuta, J. I. Assist and
H. Nishiyama, Chem.–Eur. J., 2010, 16, 3090–3096.
Notes and references
8 (a) J. B. Tuttle, S. G. Ouellet and D. W. C. MacMillan, J. Am.
Chem. Soc., 2006, 128, 12662–12663; (b) J. W. Yang,
M. T. H. Fonseca and B. List, Angew. Chem., Int. Ed., 2004,
43, 6660–6662; (c) J. W. Yang, M. T. H. Fonseca, N. Vignola
and B. List, Angew. Chem., Int. Ed., 2005, 44, 108–110; (d)
S. G. Ouellet, J. B. Tuttle and D. W. C. MacMillan, J. Am.
Chem. Soc., 2005, 127, 32–33.
1 (a) Y. Tshchiya, Y. Hamashima and M. Sodeoka, Org. Lett.,
2006, 8, 4851–4854; (b) P. R. Sundaresan, A. Shah and
M. Woodruff, Clin. Pharmacol. Ther., 1998, 63, 128–136; (c)
K. Sakitama, Y. Ozawa and N. Aoto, Eur. J. Pharmacol.,
1997, 337, 175–187; (d) R. F. Van Vollenhoven, Y. S. L. Lee
and R. E. Lambert, Arthritis Rheum., 1992, 35, 126–128.
9 S. Miaskiewicz, J. H. Reed, P. A. Donets, C. C. Oliveira and
N. Cramer, Angew. Chem., Int. Ed., 2018, 57, 4039–4042.
10 (a) M. Sugiura, N. Sato, S. Kotani and M. Nakajima, Chem.
Commun., 2008, 4309–4311; (b) Z. S. Han, L. Zhang, Y. Xu,
J. D. Sieber, M. A. Marsini, Z. Li, J. T. Reeves,
K. R. Fandrick, J. N. Desrosiers, B. Qu, D. M. Rudzinski,
L. P. Samankumara, S. Ma, N. Grinberg, F. Roschangar,
N. K. Yee, J. J. Song and C. H. Senanayake, Angew. Chem.,
Int. Ed., 2015, 54, 5474–5477.
´
2 (a) C. Thorey, S. Bouquillon, A. Helimi, F. Henin and
J. Muzart, Eur. J. Org. Chem., 2002, 13, 2151–2159; (b)
´
´
G. Fogassy, A. Tungler, A. Levai and G. Toth, J. Mol. Catal.
A: Chem., 2002, 179, 101–106; (c) Y. Tsuchiya,
Y. Hamashima and M. Sodeoka, Org. Lett., 2006, 8, 4851–
4854; (d) D. Monguchi, C. Beemelmanns, D. Hashizume,
Y. Hamashima and M. Sodeoka, J. Org. Chem., 2008, 693,
867–873; (e) D. S. Wang, D. W. Wang and Y. G. Zhou,
Synlett, 2011, 7, 947–950.
11 X. J. Dai, G. L. Weng, S. W. Yu, H. Chen, J. Y. Zhang,
S. B. Cheng, X. Y. Xu, W. C. Yuan, Z. Y. Wang and
X. M. Zhang, Org. Chem. Front., 2018, 5, 2787–2793.
12 (a) Z. Wang, M. Cheng, P. Wu, S. Wei and J. Sun, Org. Lett.,
2006, 8, 3045–3048; (b) P. Dong, Z. Wang, S. Wei, Y. Zhang
and J. Sun, Org. Lett., 2006, 8, 5913–5915; (c) D. Pei,
Y. Zhang, S. Wei, M. Wang and J. Sun, Adv. Synth. Catal.,
2008, 350, 619–623; (d) Z. Xue, Y. Jiang, W. Yuan and
X. Zhang, Eur. J. Org. Chem., 2010, 616–619; (e) H. Zheng,
W. Chen, Z. Wu, J. Deng, W. Lin, W. Yuan and X. Zhang,
Chem.–Eur. J., 2008, 14, 9864–9867; (f) Z. Y. Xue, Y. Jiang,
X. Z. Peng, W. C. Yuan and X. M. Zhang, Adv. Synth. Catal.,
2010, 352, 2132–2136; (g) X. Chen, Y. Zheng, C. Shu,
W. Yuan, B. Liu and X. Zhang, J. Org. Chem., 2011, 76,
9109–9115.
3 (a) S. M. Lu and C. Bolm, Chem.–Eur. J., 2008, 14, 7513–7516;
(b) W. J. Lu, Y. W. Chen and X. L. Hou, Angew. Chem., Int. Ed.,
2008, 47, 10133–10136; (c) W. J. Lu, Y. W. Chen and
X. L. Hou, Adv. Synth. Catal., 2010, 352, 103–107; (d)
D. Rageot, D. H. Woodmansee, B. Pugin and A. Pfaltz,
Angew. Chem., Int. Ed., 2011, 50, 9598–9601; (e) F. Maurer,
V. Huch, A. Ullrich and U. Kazmaier, J. Org. Chem., 2012,
77, 5139–5143.
4 (a) Y. Moritani, D. H. Appella, V. Jurkauskas and
S. L. Buchwald, J. Am. Chem. Soc., 2000, 122, 6797–6798; (b)
B. H. Lipshutz and J. M. Servesko, Angew. Chem., Int. Ed.,
2003, 42, 4789–4792; (c) B. H. Lipshutz, J. M. Servesko,
T. B. Petersen, P. P. Papa and A. A. Lover, Org. Lett., 2004,
6, 1273–1275; (d) B. H. Lipshutz, B. A. Frieman and
A. E. Tomaso, Angew. Chem., Int. Ed., 2006, 45, 1259–1264;
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