Synthesis of novel chiral phosphoric acid-bearing two acidic phenolic hydroxyl groups and its catalytic evaluation for enantioselective Friedel-Crafts alkylation of indoles and enones

Article abstract of DOI:10.1002/jhet.1949

A novel chiral phosphoric acid catalyst bearing two acidic phenolic hydroxyl groups was synthesized. Its catalytic activity as a chiral Br?sted acid has been examined in the enantioselective Friedel-Crafts alkylation of indoles and enones as a model reaction. In comparison with the other chiral phosphoric acid catalysts, the reaction catalyzed by the novel chiral catalyst afforded the desired 3-substituted indoles in a higher enantioselectivity (up to 69% ee).

Full text of DOI:10.1002/jhet.1949

Month 2014 Synthesis of Novel Chiral Phosphoric Acid-Bearing Two Acidic Phenolic
Hydroxyl Groups and its Catalytic Evaluation for Enantioselective Friedel-
Crafts Alkylation of Indoles and Enones
a
b
a
a
a
a
*
*
Xiong-Li Liu, Zhang-Biao Yu, Bo-Wen Pan, Lin Chen, Ting-Ting Feng, and Ying Zhou
aTraditional Chinese Medicine and Natural Medicine Research & Development Center, College of Life Sciences, Guizhou
University, Guiyang 550025, China
bPhysical Education Department, Guizhou University, Guiyang 550025, China
*
E-mail: ls.liuxl@gzu.edu.cn
Received October 23, 2012
DOI 10.1002/jhet.1949
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A novel chiral phosphoric acid catalyst bearing two acidic phenolic hydroxyl groups was synthesized. Its
catalytic activity as a chiral Brøsted acid has been examined in the enantioselective Friedel-Crafts alkylation
of indoles and enones as a model reaction. In comparison with the other chiral phosphoric acid catalysts,
the reaction catalyzed by the novel chiral catalyst afforded the desired 3-substituted indoles in a higher
enantioselectivity (up to 69% ee).
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
lead to an improvement of catalytic ability. In principal, in-
troducing any substituent at 3,30-positions of chiral phospho-
ric acid should alter the dihedral angle and electronic
properties to a certain degree. At the same time, considering
that the phenolic hydroxyl group has an acidic O—H proton
and hydrogen bonding can play a key role in organocatalysis,
we supposed introducing acidic phenolic hydroxyl group
substituents at 3,30-positions of chiral phosphoric acid would
lead to an improvement of catalytic ability in some asymmet-
ric synthesis. In addition, the indole framework has become
widely identified as a “privileged” structure. [4,5] Many
biologically active compounds and natural products are
found to be 3-substituted indoles. [6] The Friedel-Crafts
alkylation of indoles and enones is an import approach to this
class of molecules.[7,8] However, indole serves as an ambi-
ent nucleophile, and selective targeting of C—H bonds in the
presence of a reactive N—H functionality represents a chal-
lenging goal. [9] Furthermore, the steric similarity of the two
carbonyl substituents renders the stereodifferentiation of the
two enantiotopic faces of the unsaturated ketone a difficult
task.[10] Recently, enantioselective versions of this funda-
mental transformation have been reported, including metal-
Owing to being comparably enviromentally benign and
fundamentally interesting, organocatalyzed asymmetric
synthesis is of great attention recently, and thus at its golden
age. [1] Because an atropisomeric C2-symmetric 1-(2-hydroxy-
naphthalen-1-yl)naphthalen-2-ol (BINOL)-based chiral phos-
phoric acid has been reported in asymmetric synthesis by
Akiyama et al. and Terada et al. independently in 2004, [2] it
is expected that chiral phosphoric acid catalysts would electro-
philically activate carbon–oxygen or carbon–nitrogen double
bonds and chiral induction would be realized. [3] The prepara-
tion of chiral phosphoric acids and their application in the
asymmetric catalysis play very important roles in the catalytic
asymmetric area. To date, the diverse approaches applied to
chiral phosphoric acids modification may be useful and inspir-
ing for applications in asymmetric synthesis. Many modified
BINOL-based chiral phosphoric acids have also been devel-
oped by fine-tuning both the steric and electronic properties of
BINOL scaffold to obtain higher efficiency and selectivity. [3]
The subtle modulation of the dihedral angle and electronic
properties of BINOL-based chiral phosphoric acid maybe
© 2014 HeteroCorporation

X.-L. Liu, Z.-B. Yu, B.-W. Pan, L. Chen, T.-T. Feng, and Y. Zhou
Vol 000
based and organocatalytic methods.[11] In this context,
searching for highly efficient chiral, organocatalysts is the
key objective to obtain high reactivity and enantioselectivity
in some asymmetric synthesis. Herein, we describe the first
synthesis of novel chiral phosphonic acid-bearing two acidic
phenolic hydroxyl groups and choose the enantioselective
Friedel-Crafts alkylation of indoles and enones as a model
reaction to evaluate its catalytic, enantioselective ability.
Figure 1. Chiral phosphoric acid evaluated in this study.
We then continuously explored the effect of solvent,
benzene, toluene, CH2Cl2, and 1,2-dichloroethane (DCE)
were used, the results indicated that DCE was slightly
better than the other solvents (entries 14–18). We also
found that addition of activated, powdered molecular
sieves (M. S.) 4 Å gave relatively lower enantiomeric ex-
cess value and yield (Table 1, entry 19). A further survey
of reaction temperature revealed that lowering the reaction
temperature to 0ꢀC had no any improvement in the ee
value (entry 20). Interestingly, increasing the reaction
temperature from 25ꢀC to 35ꢀC had a little positive effect
on the enantioselectivity (entry 21). By decreasing the
catalyst 2d to 10 mol%, enantioselectivity was decreased
to 64% (entry 23). Finally, a set of optimal reaction condi-
tions was found to be as follows: using 15 mol%, the cata-
lyst 2d, indole (0.22 mmol), was reacted with chalcone
(0.2 mmol) in DCE (2.0 mL) at 35ꢀC for 120 h.
With these optimized reaction conditions in hand, we
next turned our interest to the reaction generality. The
scope of the enantioselective Friedel-Craft alkylation of
indoles with a variety of enones under these optimized
reaction conditions was explored (Table 2). Through ex-
ploring the reaction generality, we have shown the catalytic
activity of the catalyst 2d in comparison with the catalyst
1c. The reaction catalyzed by the catalyst 2d afforded the
desired product in a higher enantioselectivity (with moder-
ate to good enantioselectivities).
RESULTS AND DISCUSSION
The catalysts (1a–1l) were prepared starting from (R)-
BINOL in light of the reported methods[2,3] to search
for highly efficient chiral organocatalysts in some asym-
metric synthesis. We designed and synthesized the novel
catalyst 2d from 1c followed by deprotecting the methyl
group with BBr3 and subsequent acidifing with 4N
HCl (Scheme 1). Next, we choose the enantioselective
Friedel-Crafts alkylation of indoles and enones as a model
reaction to evaluate its catalytic, enantioselective ability.
In our initial study, for evaluating the chiral phosphoric acid
(2d), indole (0.22 mmol), as an electron-rich heteroaromatic
substrate, was chosen to react with chalcone (0.2 mmol) in
dry CHCl3 (2 mL) at 25ꢀC for 96 h, a variety of other chiral
Brøsted acid catalysts 1a–1l (15 mmol%) in Figure 1 were
also evaluated in the illustrated reaction, and the results are
summarized in Table 1. As shown in Table 1, in the absence
of catalyst, the reaction did not occur under otherwise identical
experimental conditions (entry 1). The simplest catalyst 1a
could catalyze the reaction smoothly (67% yield ) but afforded
nearly a racemic product (entry 2). The catalysts 1b and 1c
afforded the desired product in a modest yields and enantios-
electivities (entries 3 and 4), whereas the other chiral Brøsted
acid catalysts 1d–1l resulted in poor enantioselectivities and
moderate yields (entries 5–13). In comparison with the chiral
Brøsted acid catalysts 1a–1l, the catalyst 2d afforded the
desired 3-substituted indoles in a higher enantioselectivity
(entry 14, 63% ee). Hence, the chiral Brøsted acid catalyst
2d was selected for further studies.
Aryl enone (4a) was firstly used as a standard substrate
to probe the reactivity of different indoles (3a–3d) in
this reaction. The reaction of indole (3a) afforded the
corresponding product 5aa in good yield and ee value (entry
Scheme 1. Synthesis of chiral phosphoric acid (2d) starting from (R)-1-(2-hydroxynaphthalen-1-yl)naphthalen-2-ol(BINOL).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel Chiral Phosphoric Acid and Application in the Asymmetric
Friedel-Crafts Alkylation
Table 1
alkyl group, it also provided satisfactory yield but low
enantioselectivity (entry 9, Table 2).
Catalyst evaluation and optimization of reaction conditions.a
The generality of the reaction was further demonstrated by
variation of the enones partner (entries 10–15, Table 2). The
highest selectivity (69% ee) was displayed by containing
electron-withdrawing substituent of para-chloride in 4d, albeit
with the high yield. However, a slight decrease in enantios-
electivity and yield were observed with 4e bearing an
electron-donating substituent (entries 10 and 11, Table 2).
The use of 4f with b-2-naphthyl group (entry 12, Table 2)
in the reaction gave the alkylated product in satisfactory
enantioselectivity. Furthermore, the present catalytic system
allowed for heteroaromatic-substituted enones and also
afforded the Friedel-Craft product in satisfactory yield, al-
though with a slight reduction in reaction enantioselectivity
(entries 13–15, Table 2). The configuration of 5aa was
assigned as R by comparing the optical rotation of the synthe-
sized compound with the literature data.[11] The configura-
tions of all other products were assigned by analogy with
this product.
To search for the more effective catalyst than the catalyst
2d, we were also interested to synthesize chiral phosphoric
acid catalyst (2n) bearing four acidic phenolic hydroxyl
groups. Unfortunately, the instability of 2n has made it dif-
ficult to obtain the pure compound, and we always gained
intractable product mixtures (Scheme 2). The HRMS spec-
tra of the intractable product mixtures revealed the pres-
ence of the desired catalyst 2n [HRMS (ESI) exact mass
Calcd for (C32H20O8P1 + Na2)+ requires m/z 609.0686,
found m/z 609.0627]. Further studies on the reason of in-
stability of 2n are now in progress in our laboratory.
Temp.
(ꢀC)
Entry
1
solvent
CHCl3
Time (h) Yieldb/%
eec/%
1
2
3
4
5
6
7
8
–
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
96
96
0
67
67
60
59
72
54
67
54
62
59
67
54
68
67
71
71
68
63
62
91
92
85
–
1a CHCl3
1b CHCl3
1c CHCl3
1d CHCl3
1e CHCl3
1f CHCl3
1g CHCl3
1h CHCl3
<5
54
52
40
27
28
32
21
43
26
39
27
63
60
62
59
65
62
61
67
59
64
96
96
96
96
96
96
96
96
9
10
11
12
13
14
15
16
17
18
19d
20
21
22
23e
1i
CHCl3
1j CHCl3
1k CHCl3
1l
96
96
96
96
CHCl3
2d CHCl3
2d CH2Cl2
2d toluene
2d benzene
2d DCE
2d DCE
2d DCE
2d DCE
2d DCE
2d DCE
96
96
96
96
96
120
120
120
120
35
50
35
DCE, 1,2-dichloroethane.
aUnless noted, reactions were carried out with 0.22 mmol of indole and
0.2 mmol of chalcone and catalyst (15 mol%) in 2.0 mL of solvent.
bIsolated yield after flash chromatography.
CONCLUSIONS
cDetermined by HPLC analysis on Chiralpak AD-H columns.
dAdding 30 mg of powered molecular sieves 4 Å.
In summary, we designed and synthesized the first novel
chiral phosphonic acid catalyst (2d) bearing two acidic pheno-
lic hydroxyl groups. Its catalytic activity as a chiral Brøsted
acid has been examined in the enantioselective Friedel-Crafts
alkylation of indoles and enones as a model reaction. We
found that two acidic phenolic hydroxyl groups on the phos-
phoric acid based on the BINOL scaffold play an important
role in controlling of stereochemistry. The dependence of cat-
alytic performance of the catalyst 2d could be due to variation
of bite angle and hydrogen bonding of acidic phenolic hy-
droxyl groups. Therefore, our preliminary results have dem-
onstrated that the new catalyst 2d was useful in asymmetric
catalysis. Further studies on the mechanism of the present re-
action catalyzed by the catalyst 2d and its application to other
asymmetric reactions are now in progress in our laboratory.
eThis reaction was carried out with 0.22 mmol of indole, 0.2 mmol of
chalcone, and catalyst 2d (10 mol%) in 2.0 mL of DCE.
1, Table 2), and the Friedel-Craft alkylation of electron-rich
5-methoxyindole (3b) and 2-methylindole (3c) proceeded
also at a reasonable reaction rate, furnishing the corresponding
derivatives 5ba and 5ca in good yields but relatively lower
ee value (entries 2 and 3, Table 2). However, an electron-
withdrawing group such as bromine in the 5-position of in-
dole ring in 3d caused a slight decrease in the yield of 5da,
without loss in reaction enantiocontrol (entry 4, Table 2).
We then tested alkyl enone (4b) and a variety of indoles
3a–3d bearing different groups in the reaction, and the
reactions all proceeded smoothly in good yields and moder-
ate enantioselectivities (entries 5–8, Table 2). In the case of
3c with Me- in the 2-position of indole ring, The reaction
still proceeded cleanly, but the ee was distinctly decreased
(entries 3 and 7, Table 2).
EXPERIMENTAL
All other commercially obtained reagents were used as re-
ceived. The silica gel used for the column chromatography was
purchased from Qingdao Haiyang Chemistry Plant. Thin-Layer
In addition, we continuously explored the Friedel-Craft
alkylation of 2-methylindole (3c) and 4c with b-aryl R4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

X.-L. Liu, Z.-B. Yu, B.-W. Pan, L. Chen, T.-T. Feng, and Y. Zhou
Vol 000
Table 2
Direct organocatalytic asymmetric Friedel-Crafts type alkylation of indoles and enones.a
Entry
Indole
R1, R2
Ketone
R3, R4
Product
Cat. 1c
Cat. 2d
5
Yield/% (ee/%)
Yield/% (ee/%)
1
2
3
4
3a, H, H
4a, Ph, Ph
4a, Ph, Ph
4a, Ph, Ph
4a, Ph, Ph
5aa
5ba
5ca
5da
5ab
5bb
5cb
5db
5cc
5ad
5ae
5af
91 (55)
90 (54)
92 (45)
75d (51)
91 (56)
90 (50)
93 (39)
86 (56)
78 (42)
91 (51)
76d (43)
89 (53)
77d (41)
71d (48)
70d (43)
91 (67)
91 (65)
93 (58)
77d (68)
93 (55)
91 (48)
92 (42)
85 (54)
77 (46)
91 (69)
78d (63)
86 (68)
76d (59)
75d (63)
75d (58)
3b, OCH3, H
3c, H, CH3
3d, Br, H
3a, H, H
3b, OCH3, H
3c, H, CH3
3d, Br, H
3c, H, CH3
3a, H, H
3a, H, H
3a, H, H
3a, H, H
3a, H, H
5e
6e
7e
8e
9
4b, n-Pr, CH3
4b, n-Pr, CH3
4b, n-Pr, CH3
4b, n-Pr, CH3
4c, Ph, CH3
4d, Ph, p-ClC6H4
4e, Ph, p-CH3OC6H4
4f, 2-Naphthyl, Ph
4g, 2-Thienyl, Ph
4h, Ph, 2-Thienyl
4i, 2-Furyl, Ph
10
11
12
13
14
15
5ag
5ah
5ai
3a, H, H
DCE, 1,2-dichloroethane.
aUnless noted, reactions were carried out with 0.2 mmol of enones, 0.22 mmol of indoles in 2.0 mL anhydrous DCE with 15 mol% Cat. 2d at 35ꢀC
for 120 h.
bIsolated yield after flash chromatography.
cDetermined by chiral stationary phase HPLC.
dThe reaction was carried out for 150 h.
eEmployed 0.22 mmol of indoles and 1.5 equiv of 4b.
Scheme 2. Synthesis of chiral phosphoric acid catalyst (2n) bearing four
phenolic hydroxyl groups.
ppm. HPLC analysis was performed on BECKMAN (110B Solvent
Delivery Module and 168 Detector). Optical rotations were
measured on a PerPerkin-Elmer 241 Polarimeter. Melting points
were recorded on a Buchi Melting Point B-545 unit. Electrospray
ionization high resolution mass spectra (ESI-HRMS) were recorded
on a Bruker P-SIMS-Gly FT-ICR mass spectrometer. Binaphthol
derivatives were prepared by modified literature procedure.[2,3]
Preparation of the phosphoric acid catalysts (1a–1l). The
binaphthol derivative (0.5 mmol) was dissolved into 1 mL of
pyridine under N2 atmosphere. To the resulting solution was
added phosphorous oxychloride (2.0 equiv) at RT, and the
reaction mixture was stirred for 5 h at 70ꢀC. One milliliter of
water was added, and the resulting suspension was stirred for
2 h at 70ꢀC. Dichloromethane was added, and all pyridine was
removed by reverse extraction with 4N HCl. Organic phase was
dried over Na2SO4 and purified by column chromatography on
silica gel (MeOH/CH2Cl2) to afford the catalyst.
(R)-2,6-Bis-(2-methoxy-phenyl)-4-oxo-3,5-dioxa-415-phospha-
cyclohepta[2,1-a;3,4-a0]dinaphthalen-4-ol (1c). White solid; 1H-
NMR (300 MHz, CDCl3, d, ppm): 3.55 (s, 6H), 6.70–6.80 (m, 4H),
7.07 (d, J= 6.9 Hz, 2H), 7.22–7.31 (m, 2H), 7.46 (d, J=7.2Hz,
4H), 7.70 (s, 2H), 7.90 (d, J= 8.3 Hz, 4H); 13C-NMR (75 MHz,
CDCl3, d, ppm): 55.4, 110.7, 120.0, 121.5, 125.2, 125.7, 125.8,
126.8, 127.9, 128.9, 130.9, 131.0, 131.4, 131.7, 144.76, 144.9, 156.7.
chromatography (TLC): silica gel 60 GF254 plate. All reactions
were conducted in a closed system with an atomsphere of air
and were monitored by TLC unless otherwise stated. H NMR
1
and 13C NMR spectra were performed on a Bruker DRX-300
Avance spectrometer for products dissolved by CDCl3 with tetra-
methylsilane (TMS) as an internal standard. Data for 1H
are reported as follows: chemical shift (in ppm) and multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet).
Splitting patterns that could not be clearly distinguished are
designated as multiplets (m). Data for 13C NMR are reported in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel Chiral Phosphoric Acid and Application in the Asymmetric
Friedel-Crafts Alkylation
(R)-2,6-Bis-(2,6-dimethoxy-phenyl)-4-oxo-3,5-dioxa-415-
(R)-3-(2-Methyl-1H-indol-3-yl)-1,3-diphenylpropan-1-one
(5ca) (Table 2, entry 3). The ee was determined by HPLC analysis
using a Chiralpak AD-H column (15/85 i-PrOH/hexane; flow rate
phospha-cyclohepta[2,1-a;3,4-a0]dinaphthalen-4-ol (1b). [a]
RT
D = ꢁ72.9 (c = 0.438, CHCl3 ); white solid; mp > 300ꢀC; 1H-
NMR (300 MHz, CDCl3, d, ppm): 3.52 (s, 6H), 3.64 (s, 6H),
6.51 (d, J = 8.2Hz, 2H), 6.44 (d, J = 8.2 Hz, 2H), 7.12–7.18 (t,
J = 8.2 Hz, 2H), 7.25 (m, 2H), 7.40–7.46 (m, 4H), 7.88 (d,
J = 6.9 Hz, 4H); 13C-NMR (75 MHz, CDCl3, d, ppm): 55.4, 55.8,
103.3, 104.3, 114.1, 121.2, 124.8, 125.4, 126.5, 127.1, 127.9,
129.0, 131.0, 131.6, 132.5, 145.3, 145.4, 157.7, 157.8; HRMS
(ESI) exact mass Calcd for (C36H28O8P1 + Na2)+ requires m/z
665.1395, found m/z 665.1306.
1.0 mL/min; l = 254 nm; tminor = 11.59 min; tmajor = 12.36 min).
[a]RDT =+9.3 (c= 0.85, CHCl3, 58% ee). 1H-NMR (300 MHz,
CDCl3, d, ppm): 2.36 (s, 3H), 3.87 (dd, J= 6.1, 16.4 Hz, 1H),
3.95 (dd, J= 6.8, 16.3 Hz, 1H), 5.08 (t, J=6.9Hz, 1H), 6.98–
7.47 (m, 12H), 7.73 (br, 1H), 7.86 (d, J = 0.53, 2H); 13C-NMR
(75 MHz, CDCl3, d, ppm): 11.6, 36.3, 43.1, 110.0, 113.1,
118.7, 118.8, 120.3, 125.4, 127.0, 127.1, 127.6, 127.8, 128.0,
131.3, 132.4, 135.0, 136.7, 143.7, 198.6.
Preparation of the phosphoric acid catalysts (2d).
The
(R)-3-(5-Bromo-1H-indol-3-yl)-1,3-diphenylpropan-1-one
phosphoric acid catalysts (1c) (1 mmol) was dissolved in dry
CH2Cl2 (30 mL) and cooled to 0ꢀC, BBr3 (4 mmol) was added,
and the reaction mixture was stirred for 18 h at 0ꢀC. The
solution was then quenched with the addition of water (2 mL).
The 4N HCl (40 mL) and dichloromethane (60 mL ꢂ 5) were
added. Organic phase was dried over Na2SO4 and purified by
column chromatography on silica gel (MeOH/CH2Cl2) to afford
the desired catalyst. Yield: 89%.
(R)-2,6-Bis-(2-hydroxy-phenyl)-4-oxo-3,5-dioxa-415-phospha-
cyclohepta[2,1-a;3,4-a0]dinaphthalen-4-ol (2d). [a]RDT = ꢁ184.5
(c = 0.358, CHCl3); white solid; mp> 300ꢀC; 1H-NMR (300 MHz,
CDCl3, d, ppm): 5.93 (s, 2H), 6.37–6.72 (m, 6H), 6.98–7.67
(m, 8H), 7.88 (s, 2H), 7.91 (s, 2H); 13C-NMR (75MHz, CDCl3,
d, ppm): 116.8, 120.3, 122.0, 124.1, 125.7, 126.4, 126.6, 128.0,
129.1, 129.6, 131.0, 131.2, 131.7, 132.0, 144.6, 152.5; HRMS
(ESI) exact mass Calcd for (C32H20O6P1 + Na2)+ requires m/z
577.0871, found m/z 577.0769.
General procedure for the organocatalytic asymmetric
Friedel-Crafts alkylation of indoles with enones. Under an
argon atmosphere, in an ordinary test tube equipped with a
magnetic stirring bar, enone (0.2 mmol) and indole (0.22 mmol)
were dissolved in 2.0 mL of freshly distilled DCE (CaH2), and
catalyst 2d (15 mg, 0.03 mmol) was added. Then, the tube was
closed with a rubber stopper, and the reaction mixture was
stirred for 120 h at 35ꢀC. Then, the solvent was removed in
vacuo, and the residue was purified by flash chromatography to
yield the desired product.
(5da) (Table 2, entry 4).
analysis using a Chiralpak AD-H column (15/85 i-PrOH/hexane;
The ee was determined by HPLC
flow
t
rate
1.0 mL/min;
l = 254nm;
tminor = 13.33min;
major = 14.42 min). [a]DRT = ꢁ7.9 (c = 0.68, CHCl3, 68% ee). 1H-
NMR (300 MHz, CDCl3, d, ppm): 3.68 (dd, J = 7.2, 16.9Hz, 1H),
3.76 (dd, J = 7.2, 16.9 Hz, 1H), 4.99 (t, J = 7.0 Hz, 1H), 6.97
(s, 1H), 7.12–7.56 (m,11H), 7.91 (d, J = 7.4 Hz, 2H), 8.02
(bs, 1H); 13C-NMR (75MHz, CDCl3, d, ppm): 37.5, 44.7, 112.1,
112.2, 118.4, 121.5, 122.1, 124. 6, 126.0, 127.2, 127.6, 127.9,
128.1, 128.2, 132.7, 134.7, 136.5, 143.3, 197.9.
(S)-4-(1H-Indol-3-yl)heptan-2-one (5ab) (Table 2, entry 5). The
ee was determined by HPLC analysis using a Chiralpak AD-H
column (5/95 i-PrOH/hexane; flow rate 1.0 mL/min; l = 254 nm;
t
minor = 15.94 min; t
major = 17.48min). [a]RDT = +11.8 (c = 0.61,
CHCl3, 55% ee). 1H-NMR (300 MHz, CDCl3, d, ppm): 0.84
(t, J = 7.2 Hz, 3H), 1.18–1.28 (m, 2H), 1.62–1.74 (m, 2H), 2.00
(s, 3H), 2.78 (dd, J = 6.8, 15.7 Hz, 1H), 2.85 (dd, J = 7.9,
15.6Hz,1H), 3.47 (t, J = 6.8 Hz, 1H), 6.90 (d, J = 1.5 Hz, 1H),
7.06–7.22 (m, 2H), 7.30 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 7.6 Hz,
1H), 8.08 (br s, 1H); 13C-NMR (75 MHz, CDCl3, d, ppm): 14.1,
20.8, 30.4, 32.7, 38.2, 50.3, 111.4, 118.9, 119.2, 119.3, 121.3,
121.9, 126.6, 136.6, 209.2.
(S)-4-(5-Methoxy-1H-indol-3-yl)heptan-2-one (5bb) (Table 2,
entry 6).
The ee was determined by HPLC analysis using a
Chiralpak AD-H column (5/95 i-PrOH/hexane; flow rate 1.0 mL/
min; l = 254 nm; tminor = 21.07 min; tmajor = 23.39 min). [a]RDT =+8.6
1
(c = 0.76, CHCl3, 48% ee). H-NMR (300 MHz, CDCl3, d, ppm):
(R)-3-(1H-Indol-3-yl)-1,3-diphenylpropan-1-one (5aa) (Table 2,
0.84–0.88 (m, 3H), 1.23–1.29 (m, 2H), 1.66–1.74 (m, 2H),
2.02 (d, J = 2.1Hz, 3H), 2.75–2.90 (m, 2H), 3.44 (s, 1H), 3.86
(d, J = 2.2Hz, 3H), 6.84 (d, J = 8.6 Hz, 1H), 6.90 (s, 1H), 7.08
(s, 1H), 7.21 (t, J = 8.1 Hz, 1H), 8.08 (br, 1H); 13C-NMR
(75 MHz, CDCl3, d, ppm): 14.1, 20.7, 30.5, 32.5, 38.1, 50.2,
56.0, 101.6, 111.7, 111.9, 118.7, 122.1, 127.1, 131.8, 153.7, 209.1.
(S)-4-(2-Methyl-1H-indol-3-yl)heptan-2-one (5cb) (Table 2,
entry 1).
The ee was determined by HPLC analysis using a
Chiralpak AD-H column (80/20 hexane/i-PrOH; flow rate 0.75 mL/
min; l = 214, 254 nm; tminor = 16.9 min; tmajor = 18.9 min). [a]
RT
D =ꢁ23.2 (c= 0.67, CHCl3, 67% ee). 1H-NMR (300 MHz,
CDCl3, d, ppm): 3.67–3.76 (m, 1H), 3.81 (dd, J = 6.7,
16.6 Hz, 1H), 5.06 (t, J = 7.1 Hz, 1H), 6.98–7.53 (m, 13H),
7.91–7.93 (d, J = 7.5 Hz, 3H); 13C-NMR (75 MHz, CDCl3, d,
ppm): 37.8, 44.8, 110.7, 118.9, 119.1, 121.0, 121.7, 125.8,
126.2, 127.4, 127.6, 128.0, 128.1, 132.5, 136.2, 136.7,
143.8, 198.2.
entry 7).
The ee was determined by HPLC analysis using a
Chiralpak AD-H column (5/95 i-PrOH/hexane; flow rate
1.0 mL/min; l = 254 nm; tminor = 10.91 min; tmajor = 13.76 min).
[a]RDT =+8.1 (c =0.80, CHCl3, 42%ee). 1H-NMR (300 MHz,
CDCl3, d, ppm): 0.81 (t, J= 7.2Hz, 3H), 1.15 (t, J= 6.4 Hz, 2H),
1.64 (d, J = 6.6 Hz, 1H), 1.82–1.87 (m,1H), 1.92 (s, 3H), 2.33
(s, 3H), 2.79 (dd, J = 5.8, 15.8Hz, 1H), 3.04 (dd, J = 8.3, 15.8Hz,
1H), 3.34–3.38 (m, 1H), 7.00–7.09 (m, 2H), 7.21 (d, J = 7.1 Hz,
1H), 7.58 (d, J = 7.2 Hz, 1H), 7.82 (br s, 1H); 13C-NMR (75MHz,
CDCl3, d, ppm): 12.0, 14.0, 21.1, 30.8, 32.5, 37.4, 49.3, 110.5,
113.2, 118.8, 119.0, 120.6, 127.1, 131.5, 135.6, 209.2.
(S)-4-(5-Bromo-1H-indol-3-yl)heptan-2-one (5db) (Table 2,
entry 8). The ee was determined by HPLC analysis using an
OD-H column (5/95 i-PrOH/hexane; flow rate 1.0 mL/min;
l = 254 nm; tminor = 21.07 min; tmajor = 23.39 min). [a]RDT = +9.7
(c = 0.76, CHCl3, 54% ee). 1H-NMR (300 MHz, CDCl3, d,
(R)-3-(5-Methoxy-1H-indol-3-yl)-1,3-diphenylpropan-1-one
(5ba) (Table 2, entry 2).
The ee was determined by HPLC
analysis using an OD-H column (15/85 i-PrOH/hexane; flow rate
1.0 mL/min; l = 254 nm; tminor = 17.83min; tmajor = 19.32 min).
[a]RDT = ꢁ11.4 (c = 0.54, CHCl3, 65% ee). 1H-NMR (300 MHz,
CDCl3, d, ppm): 3.71 (s, 3H), 3.73–3.77 (m, 2H), 5.01
(t, J = 7.0Hz, 1H), 6.80 (t, J = 8.3 Hz, 2H), 6.92 (s, 1H), 7.14–7.52
(m, 9H), 7.92 (t, J = 7.6 Hz, 3H); 13C-NMR (75MHz, CDCl3, d,
ppm): 38.2, 45.2, 55.8, 101.6, 111.8, 112.2, 119.0, 122.2, 126.3,
127.1, 127.9, 128.1, 128.5, 128.6, 131.8, 133.1, 137.2, 144.2,
153.8, 198.7; HRMS (ESI) exact mass Calcd for (C24H21NO2 +
Na) requires m/z 378.1572, found m/z 378.1459.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

X.-L. Liu, Z.-B. Yu, B.-W. Pan, L. Chen, T.-T. Feng, and Y. Zhou
Vol 000
ppm): 0.84 (t, J = 7.1 Hz, 3H), 1.16–1.25 (m, 2H), 1.59–1.78 (m,
2H), 2.02 (s, 3H), 2.74–2.84 (m, 2H), 3.36–3.43 (m,1H), 6.92 (s,
1H), 7.20 (dd, J = 8.4, 18.1 Hz, 2H), 7.75 (s, 1H), 8.25 (br s, 1H);
13C-NMR (75 MHz, CDCl3, d, ppm): 14.0, 20.7, 30.5, 32.5, 38.1,
50.0, 112.5, 112.8, 118.6, 121.8, 122.6, 124.7, 128.3, 135.2,
208.9.
(R)-4-(2-Methyl-1H-indol-3-yl)-4-phenylbutan-2-one (5cc)
(Table 2, entry 9). The ee was determined by HPLC analysis
using a Chiralpak AD-H column (15/85 i-PrOH/hexane; flow
rate 1.0 mL/min; l = 254 nm; tminor = 7.66 min; tmajor = 8.39 min).
[a]RDT = +4.5 (c = 0.48, CHCl3, 46% ee). 1H-NMR (300 MHz,
CDCl3, d, ppm): 1.98 (s, 3H), 2.33 (s, 3H), 3.29 (dd, J = 6.2,
16.2 Hz, 1H), 3.42 (dd, J = 8.5, 16.0 Hz, 1H), 4.84 (t, J = 6.9 Hz,
1H), 6.98–7.29 (m, 8H), 7.44 (d, J = 7.5 Hz, 1H), 7.77 (br, 1H);
13C-NMR (75 MHz, CDCl3, d, ppm): 11.6, 30.3, 36.4, 47.8,
110.0, 112.7, 118.6, 118.7, 120.3, 125.5, 126.9, 127.8, 131.3,
135.0, 143.6, 207.5.
Calcd for (C21H17NOS + Na)+ requires m/z 354.1031, found m/z
354.0922.
(R)-3-(1H-Indol-3-yl)-3-phenyl-1-(thiophen-2-yl)propan-1-one
(5ah) (Table 2, entry 14).
The ee was determined by HPLC
analysis using an AD-H column (15/85 i-PrOH/hexane; flow rate
1.0 mL/min; l = 254nm; tminor =19.74 min; tmajor = 21.52 min).
[a]RDT = ꢁ20.7 (c = 0.52, CHCl3, 63% ee). 1H-NMR (300MHz,
DMSO-d6, d, ppm): 3.70 (dd, J = 7.0, 15.9 Hz, 1H), 3.86 (dd,
J = 6.9, 15.9 Hz, 1H), 4.88 (d, J = 6.5 Hz, 1H), 6.89–7.41 (m,11H),
7.94 (s, 1H), 8.11 (s, 1H), 10.86 (s, 1H); 13C-NMR (75MHz,
DMSO-d6, d, ppm): 38.0, 44.6, 111.3, 117.7, 118.3, 118.7, 121.0,
121.9, 125.9, 126.3, 127.7, 128.1, 128.6, 133.4, 134.8, 136.3,
144.3, 144.9, 191.4. HRMS (ESI) exact mass Calcd for
(C21H17NOS + Na)+ requires m/z 354.1031, found m/z 354.0919.
(S)-3-(Furan-2-yl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one
(5ai) (Table 2, entry 15). The ee was determined by HPLC
analysis using an OD-H column (15/85 i-PrOH/hexane; flow rate
1.0 mL/min; l = 254 nm; tminor = 13.37 min; tmajor = 15.96 min).
[a]RDT = +8.3 (c = 0.52, CHCl3, 58% ee). 1H-NMR (300 MHz,
CDCl3, d, ppm): 3.66 (dd, J = 6.6, 16.7Hz, 1H), 3.86 (dd, J = 7.2,
16.6Hz, 1H), 5.13 (t, J = 6.6 Hz, 1H), 6.05 (s, 1H), 6.15 (s, 1H),
7.00–7.58 (m, 9H), 7.91 (d, J= 7.3 Hz, 2H), 8.01 (s, 1H); 13C-NMR
(75 MHz, CDCl3, d, ppm): 31.8, 42.7, 105.2, 109.7, 110.8, 116.2,
118.9, 119.1, 121.6, 125.8, 127.6, 128.1, 132.5, 136.1, 136.6,
140.7, 156.5, 197.8. HRMS (ESI) exact mass Calcd for
(C21H17NO2 + Na)+ requires m/z 338.1259, found m/z 338.1153.
(R)-1-(4-Chlorophenyl)-3-(1H-indol-3-yl)-3-phenylpropan-1-
one (5ad) (Table 2, entry 10). The ee was determined by HPLC
analysis using a Chiralpak AD-H column (15/85 i-PrOH/hexane;
flow rate 1.0 mL/min; l = 254 nm; tminor = 21.83 min; tmajor
=
24.65 min). [a]RDT = ꢁ28.2 (c = 0.58, CHCl3, 69% ee). 1H-NMR
(300 MHz, CDCl3, d, ppm): 3.66 (dd, J = 7.4, 16.6 Hz, 1H),
3.72–3.79 (m, 1H), 5.02 (t, J = 6.5 Hz, 1H), 6.60–7.43 (m,
12H), 7.80–7.89 (m, 2H), 7.94 (s, 1H); 13C-NMR (75 MHz,
CDCl3, d, ppm): 38.4, 45.2, 111.0, 111.2, 119.1, 119.2,
119.5, 121.4, 121.9, 122.2, 123.4, 126.4, 126.6, 127.8, 128.2,
128.5, 128.9, 129.5, 135.5, 136.7, 139.5, 144.0, 197.5. HRMS
(ESI) exact mass Calcd for (C23H18ClNO + Na)+ requires m/z
382.1077, found m/z 382.0965.
Acknowledgments. We are grateful for financial support from the
National Natural Science Foundation of China (No. 21062003)
and Modernization of Traditional Chinese Medicine special of
Guiyang ([2010] Zhu Ke Hetongzi 1-Zhong-18).
(R)-3-(1H-Indol-3-yl)-1-(3-methoxyphenyl)-3-phenylpropan-
1-one (5ae) (Table 2, entry 11). The ee was determined by HPLC
analysis using an OD-H column (30/70 i-PrOH/hexane; flow rate
1.0 mL/min; l = 254nm;
tminor = 10.7min; tmajor = 17.78 min).
[a]RDT = ꢁ24.0 (c = 0.65, CHCl3, 63% ee). 1H-NMR (300 MHz,
CDCl3, d, ppm): 3.67–3.74 (m, 2H), 3.83 (s, 3H), 5.05 (s, 1H),
6.87–7.43 (m, 12H), 7.91 (d, J = 7.2 Hz, 2H), 7.96 (bs, 1H); 13C-
NMR (75 MHz, CDCl3, d, ppm): 38.0, 44.4, 54.9, 110.6, 113.2,
118.9, 119.1, 121.0, 121.6, 125.7, 126.2, 127.4, 127.9, 129.9,
136.2, 143.9, 162.9, 196.6.
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1.0 mL/min; l = 254 nm; tminor = 22.10 min; tmajor = 25.37 min).
[a]RDT = ꢁ5.7 (c = 0.56, CHCl3, 68% ee). 1H-NMR (300 MHz,
CDCl3, d, ppm): 3.79–3.90 (m, 2H), 5.23 (t, J = 6.9 Hz, 1H), 6.62
(s, 2H), 6.94–7.51 (9H), 7.70–7.78 (m, 4H), 7.92 (d, J = 7.7 Hz,
3H). 13C-NMR (75 MHz, CDCl3, d, ppm): 38.4, 45.1, 111.1,
111.2, 119.2, 119.5, 119.6, 121.6, 122.2, 125.4, 125.9, 126.0,
126.7, 127.6, 127.8, 128.1, 128.6, 132.3, 133.0, 133.5, 136.7,
137.2, 141.7, 198.5. HRMS (ESI) exact mass Calcd for
(C27H21NO + Na)+ requires m/z 398.1623, found m/z 398.1519.
(S)-3-(1H-Indol-3-yl)-1-phenyl-3-(thiophen-2-yl)propan-1-one
(5ag) (Table 2, entry 13).
The ee was determined by HPLC
analysis using an AD-H column (15/85 i-PrOH/hexane; flow rate
1.0 mL/min; l = 254 nm; tminor = 18.49min; tmajor = 20.97 min).
[a]RDT = ꢁ6.5 (c = 0.74, CHCl3, 59% ee). 1H-NMR (300 MHz,
CDCl3, d, ppm): 3.80 (d, J = 6.7 Hz, 2H), 5.35 (t, J = 6.6 Hz, 1H),
6.84–7.54 (m, 11H), 7.90 (d, J = 7.3 Hz, 2H), 7.99 (s, 1H); 13C-
NMR (75MHz, CDCl3, d, ppm): 33.1, 45.7, 110.8, 118.5, 119.0,
119.1, 121.2, 121.7, 123.0, 123. 8, 125.8, 126.1, 127.7, 128.1,
132.6, 136.1, 136.6, 148.3, 197.7. HRMS (ESI) exact mass
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel Chiral Phosphoric Acid and Application in the Asymmetric
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DOI 10.1002/jhet