Regio- A nd Enantioselective Friedel-Crafts Benzhydrylation of Indoles in Carbocyclic Ring with ortho-Quinomethanes: Access to Chiral Diarylindolylmethanes

Article abstract of DOI:10.1021/acs.joc.9b03479

The functionalization of indoles in the carbocyclic ring has been achieved via organocatalytic enantioselective Friedel-Crafts benzhydrylation of hydroxyindoles with in situ generated ortho-quinomethanes in oil-water biphases, allowing an efficient access to varied diarylindolylmethanes with a wide substrate scope. The high yields, excellent stereoselectivities, mild conditions, low catalyst loading, and easy scalability also demonstrated the interest of this novel methodology.

Full text of DOI:10.1021/acs.joc.9b03479

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Article
Regio- and Enantioselective Friedel-Crafts
Benzhydrylation of Indoles in Carbocyclic Ring with ortho-
Quinomethanes: Access to Chiral Diarylindolylmethanes
Ming-Ming Chu, Xue-Yang Chen, Yi-Feng Wang, Suo-
Suo Qi, Zhen-Hui Jiang, Dan-Qian Xu, and Zhen-Yuan Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03479 • Publication Date (Web): 21 Jul 2020
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Page 1 of 12
The Journal of Organic Chemistry
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Regio- and Enantioselective Friedel-Crafts Benzhydrylation of
Indoles in Carbocyclic Ring with ortho-Quinomethanes: Access to
Chiral Diarylindolylmethanes
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Ming-Ming Chu, Xue-Yang Chen, Yi-Feng Wang,* Suo-Suo Qi, Zhen-Hui Jiang, Dan-Qian Xu,* and
Zhen-Yuan Xu
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Key Laboratory of Green Pesticides and
Cleaner Production Technology of Zhejiang Province, Department of Green Chemistry and Technology, Zhejiang University
of Technology, Hangzhou 310014, P. R. China.
Supporting Information Placeholder
R2
HO
amine-squaramide
(1.5 mol% )
HO
R2
Ar
R1
+
K2CO3, DCE, H2O, N2, r.t.
N
N
O
H
H
o-QMs
-TsH
three regioisomers
4-hydroxyindole
5-hydroxyindole
7-hydroxyindole
27 examples
up to 95% yield
up to 99% ee
Ts
The in situ generated ortho-quinomethanes
The regio- and enantioselective benzhydrylation of indoles in the benzene ring
Mild conditions Low catalyst loading Easy scalability
R2
OH
R1
ABSTRACT: The functionalization of indoles in the carbocyclic ring has been achieved via organocatalytic enantioselective
Friedel–Crafts benzhydrylation of hydroxyindoles with in situ generated ortho-quinomethanes in oil-water biphases, allowing an
efficient access to varied diarylindolylmethanes with a wide substrate scope. The high yields, excellent stereoselectivities, mild
conditions, low catalyst loading and easy scalability also demonstrated the fascination of this novel methodology.
Scheme 1. General outline of the strategy employed herein
and previous related work.
INTRODUCTION
The indole skeleton was a prominent structural motif that exists
a) The enantioselective functionalization of indoles
in a wide range of natural products and pharmaceutically active
C4
compounds,1 and the synthesis and modification of indole have
C3
C5
easy to
functionalize
challenging to
functionalize
therefore been extensively studied over the past centuries.2 In
this respect, the venerable Friedel-Crafts-type functionalization
of indole, including enantioselective transformations, occurred
preferentially at the more-reactive C3 position and have been
well-developed.3 Additionally, different methodologies to
perform the asymmetric functionalization at the C2 position4 or
the nitrogen atom5 were continually being reported (Scheme 1,
a). In sharp contrast, only sporadic methods to access the direct
functionalization of the indole’s benzene ring have been
established in the nonenantioselective fashion, which were
confined to the directing group facilitated C-H activation
processes6 or the C6-nucleophilic substitution of the 2,3-
disubstituted indoles.7 Until 2015, Jørgensen and co-workers
have achieved the first organocatalytic asymmetric Friedel-
Crafts alkylation of 4-hydroxyindole at the C5 position of the
benzene ring.8 Subsequently, with the careful selection of
electrophiles and catalysts, alkylating the different position of
C2
C6
N
H
C7
b) The enantioselective benzhydrylation of indoles in the pyrrole ring
X
via
R2
O
R2
X
X

N
H
chiral phosphoric acid
R2
O
Ar
R1
o-QMs
+
ref 4f, 13c and 15a
N
N
O

O
O
O
H
H
P
X= H or OH
H
c) Our hypothesis: the benzhydrylation of indoles in benzene ring
R2
via
O
O

HO
HO
R2
R
N
H
N
H
N
chiral squaramide
oil-water phases

R1
+
H
O
N
H
N
Ar'
O
O
H
varied regioisomers
Oil-water phases
The in situ generated
N
H
R2
quinomethanes
ortho-
The benzhydrylation of indoles in the benzene ring in a regioselective manner
alkylation, furnishing the 4,7-disubstituted indole derivatives in
excellent regio and stereoselectivity.12 Despite these impressive
achievements, when considering the formidable challenge that
the C3 position still dominated the functionalization of indoles
within this topic13 as well as the significant pharmaceutical
relevance of indole derivates, finding suitable reaction partners
and catalysts to enrich the stereoselective protocols for the
9
the benzene ring of hydroxyindole were reported by Pedro,
Zhao10 and Deng11, showing great efficacy in constructing the
indole derivatives bearing chiral side chains on the benzene ring.
Recently, with the installation of an alkylamine group at the C4-
position of indole, the Zhao’s group succeeded in the direct
functionalization of C7-position via a chiral phosphoric acid
catalyzed Friedel−Crafts
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functionalization of the indole’s benzene ring was arguably in
high demand.
concentration offered the optimal result as the 2.5 mol %
catalyst loading did (entry 21).
Table 1. Reaction Optimization.a
The ortho-quinomethanes (o-QMs), serving as a vital class of
highly reactive 1-oxabutadiene, were reported to readily
participate in many chemical reactions such as conjugate
Ts
Ph
OH
OH
Ph
amine-squaramide (2.5 mol%)
+
additions,
hetero
Diels-Alder
reactions,
and
6π-
base, organic solvent, H2O
N2, r.t., 24 h
N
H
OH
OH
N
H
electrocyclizations.14-15 Among them, the chiral phosphoric acid-
catalyzed Friedel-Crafts benzhydrylation reaction of indole with
o-QMs has been realized by the groups of Shi4f, Schneider13c
and Sun15a to afford broadly substituted triarylmethanes (Scheme
1, b), whereas only the formal adduct products functionalized at
the more-reactive pyrrole ring could be obtained in the
transformation despite using the hydroxyindole as the
substrate.13c As a subject of our ongoing interest in the
utilization of o-QMs,16 contrasting to the acid conditions
employed in above wok, a chiral amine squaramide catalyzed
conjugate addition of hydroxyindoles to the in situ generated o-
QMs, was expected to achieve the direct functionalization of
indole benzene ring with the concept that it maybe the OH
moiety of hydroxyindole not the NH provided a dominated
hydrogen-bonding interaction with the tertiary amine nitrogen
atom of the catalyst (Scheme 1, c).
OMe
1a
OMe
O
2a
3aa
O
9
O
O
O
O
F3
C
C
F3
C
C
F3
C
C
10
11
12
13
14
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16
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Ph
N
NH
NH
N
N
H
N
H
N
H
Ph
N
H
O
F3
N
F3
F3
III
I
II
N
O
O
O
O
F3
C
C
Ar NH
R
NH
NH
NH
IVa R = OCH3, Ar = 3,5-(CF3
)2-C6H3
N
N
IVb R = H, Ar = 3,5-(CF3 2-C6H3
)
O
F3
IVc R = OCH3, Ar = 4-CF3-C6H4
IVd R = OCH3, Ar = C6H5
V
N
N
entry
cat
organic
solvent
base
yieldb
(%)
eec
(%)
1
I
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
CHCl3
EA
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
NaOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
71
56
83
85
84
75
73
93
87
87
35
54
89
90
89
51
trace
87
93
91
93
-89
-60
-89
96
95
94
81
97
96
96
89
0
2
II
III
RESULTS AND DISCUSSION
3
The 2-methoxy-6-(phenyl(tosyl)methyl)phenol 1a and 4-
hydroxyindole 2a were chosen as the model substrates. As
shown in Table 1, the initial investigation, proceeding in
biphasic solvent in presence of 2.5 mol% chiral squaramide
catalyst I at room temperature, provided the desired product 3aa
in 71% yield and -89% ee within 24 h ( entry 1). Encouraged by
this result, the trial of its structural analogue II was performed,
while an eroded result was observed (entry 2). Changing the
chiral amine moiety to a cinchona alkaloid scafford to form the
amine-squaramides III-IVb was then considered (entries 3-5).
To our delight, the desired product 3aa could be obtained in a
higher level of yield and enantioselectivity with the quinine-
derived squaramide IVa as catalyst (entry 4). The fine-tuning of
aryl group associated with the catalyst IVa to modulate the
acidity of the N−H bonds could not enhance their performance,
resulting in the comparable efficiency and enantioselectivity
(entries 6-7). Gratifyingly, when the more hydrophobic
4
IVa
IVb
IVc
IVd
V
5
6
7
8
9
V
10
11
12
13
14
15
16d
17e
18 f
19g
20h
21i
V
V
V
THF
DCE
DCE
DCE
DCE
no
V
95
95
75
95
nd
96
97
96
97
V
V
V
dihydroquinine-derived squaramide
V
was used, the
transformation provided 3aa in much improved 93% yield and
optimal 97% ee (entry 8). Afterwards, the further optimization
of other parameters such as bases and solvents identified the
K2CO3 and 1,2-dichloroethane (DCE) to be more competent for
the reaction protocol (entries 9-15). Noteworthily, employing
THF as the organic solvent delivered no enantioselectivity (entry
12), indicating that the ineffective phase separation between
catalyst and inorganic base might lead to a racemic background
reaction. Negative result was obtained when either DCE or H2O
was used as the sole solvent (entries 16-17), which further
proved that the biphasic solvent system should be more
favorable to the reaction. Furthermore, when varying the amount
of water used in the reaction, the product 3aa was delivered with
no remarkable change in terms of yield and enantioselectivity
(entries 18-19 vs entry 8). Subsequently, the decrease to 1.5
mol% catalyst still enabled the transformation to work well,
providing the 3aa in slightly declined yield and
enantioselectivity (entry 20). DCE to increase the catalyst
V
V
DCE
DCE
DCE
DCE
V
V
V
aUnless indicated otherwise, the reactions were conducted
with 1a (0.1 mmol), 4-hydroxyindole 2a (0.15 mmol),
catalyst (0.0025 mmol, 2.5 mol%) and base (0.15 mmol) in
1.5 mL organic solvent and 0.5 mL of H2O at room
b
temperature for 24 h under N2 atmosphere. Yield of the
c
isolated product. Determined using HPLC analysis with
chiral stationary phase. d1.5 mL DCE was used as sole solvent.
f
e1.5 mL H2O was used as sole solvent. 0.25 mL H2O was used.
g1.0 mL H2O was used. h1.5 mol% of catalyst V was used. i1.0
mL DCE, 1.5 mol% of catalyst
V
were used.
With this optimized set of conditions, we initially assessed the
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generality of the reaction for different benzylsulfones 1 and the
results were listed in Table 2. In detail, the 2-
2
3
4
(phenyl(tosyl)methyl)phenols bearing either electron-
5
6
Table 2. Substrate Scope.a
proceed in reasonably lower enantioselectivity and yield
(3ea), presumedly owning to the fact that the high electron
cloud density of phenol moiety could enhance the stability of
the in situ generated o-QMs and exert a significantly positive
impact on the preferable interaction between the highly
reactive o-QMs and the chiral catalyst. Generally, the
presence of 2-(phenyl(tosyl)methyl)phenols bearing either
electron-donating or -withdrawing substituent at the different
positions of the phenyl moiety allowed the addition reaction to
achieve good efficiency (84%-95% yields) and excellent
enantioselectivities (96%-99% ee) (3fa-3pa). Besides, a
comparable result was obtained when expanding the phenyl
substituent R2 to the more sterically demanding 1-naphthyl, 2-
naphthyl groups (3qa-3ra), and the heteroaromatic groups
such as 2-furyl, 2-thienyl nature didn't change the
enantioselectivity significantly (3sa-3ta).
7
8
9
Ts
HO
HO
R2
R2
V (1.5 mol%), K2CO3
R1
+
DCE, H2O, N2, r.t.
N
N
H
Ar
OH
H
10
11
12
13
14
15
16
17
18
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22
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1
2
3
Enantioselective benzhydrylation of 4-hydroxyindole (2a)
Ph
OH
Ph
OH
Ph
OH
N
H
N
H
N
H
OH
OH
MeO
OH
OMe
OEt
3aa
3ba
3ca
87% yield, 78% ee
93% yield, 97% ee
91% yield, 95% ee
Ph
OH
R2
OH
Ph
OH
Br
N
H
OH
N
H
N
H
OH
OH
OMe
OMe
3da
3ea
94% yield, 90% ee
R2 = 3-MeC6H4, 91% yield, 99% ee
2 = 4-MeC6H4, 85% yield, 97% ee
2 = 3-MeOC6H4, 84% yield, 97% ee
R2 = 3-CF3OC6H4, 93% yield, 98% ee
R2 = 4-CF3OC6H4, 93% yield, 98% ee
2 = 4-FC6H4, 87% yield, 96 ee
R2 = 4-ClC6H4, 91% yield, 99% ee
2 = 2-CF3C6H4, 95% yield, 99% ee
75% yield, 60% ee
Having
successfully
realized
the
Friedel-Crafts
2 = 3-CF3C6H4, 92% yield, 98% ee
2 = 4-CF3C6H4, 90% yield, 98% ee
2 = 4-PhC6H4, 91% yield, 97% ee
2 = 1-naphthyl, 90% yield, 98% ee
3fa
3na
R
R
R
R
benzhydrylation of 4-hydroxyindoles at the C5 position, we
directed our efforts to test the other three regioisomeric
hydroxyindoles for the functionalization of every position at the
benzenoid moiety. As revealed in Table 2, the 5-hydroxyindoles
and the 7-hydroxyindoles proved well amenable to the reaction
protocol and underwent the expected Friedel−Crafts
benzhydrylation reaction at the C4 and C6 position respectively,
furnishing the corresponding adduct products (3ab-3cb and 3ac-
3cc ) in moderate to high yields (63-89%) with good to high
enantioselectivities (86-93% ee). Disappointingly, with using
the 6-hydroxyindole 2d as the nucleophile, the complicated
mixture was obtained under the optimal conditions, probably
due to the competitive hydrogen bonding of the NH group of 6-
hydroxyindole. Finally, the 4-hydroxycarbazole 2e was also
excellent candidate of the conjugated addition to generate the
desired products 3ae in moderate yield with excellent
enantiomeric excess.
3ga
3ha
3ia
3oa
3pa
3qa
3ra
3sa
3ta
R
R
R2 = 2-naphthyl, 76% yield, 98% ee
3ja
3ka
3la
R
R
2 = 2-furyl, 78% yield, 94% ee
R2 = 2-thienyl, 85% yield, 91% ee
3ma
R
Enantioselective benzhydrylation of 5-hydroxyindole (2b)
H
N
H
N
H
N
OH
OH
OH
OH
OH
OH
Cl
OMe
OMe
OMe
3ab
63% yield, 93% ee
3bb
3cb
78% yield, 93% ee
75% yield, 92% ee
Enantioselective benzhydrylation of 7-hydroxyindole (2c)
OH
Et
OH
F3C
OH
H
N
H
N
H
N
Scheme 2. Scale-up experiment and synthetic
transformation.
OH
OH
OH
OMe
OMe
OMe
Ts
Ph OH
OH
3ac
3bc
3cc
78% yield, 88% ee
89% yield, 86% ee
65% yield, 92% ee
Ph
V
(1.5 mol%), K2CO3
DCE, H2O, N2, r.t.
Enantioselective benzhydrylation of 6-hydroxyindole (2d) and 4-hydroxycarbazole (2e)
a)
+
N
OH
OH
N
H
H
N
H
OH
Ph
OH
OMe
OMe
1a
2a
3aa
1.11 g (3.0 mmol) 0.6 g (4.5 mmol)
94% yield, 98% ee
N
H
OH
OH
Ph OH
Ph OTf
OMe
OMe
3ad
3ae
complex mixture
75% yield, 96% ee
4-DMAP
CH2Cl2
b)
Tf2NPh
aAll reactions were conducted with 1 (0.1 mmol), 2 (0.15
mmol), catalyst V (1.5 mol%) and K2CO3 (0.15 mmol) in
1.0 mL DCE and 0.5 mL H2O at room temperature for 24 h
N
N
OH
OTf
H
H
OMe
OMe
3aa
4
96% ee
77% yield, 95% ee
under
N2
atmosphere.
donating groups or halogen groups at their phenol moieties
underwent the conjugate additions smoothly, providing the
desired products in high yields (up to 94%) and with
satisfactory enantioselectivities of up to 97% ee (3aa-3da).
Besides, the 2- (phenyl(tosyl)methyl)phenol 1e in which no
substituents were tethered to the phenol moiety was found to
The reaction of 2-methoxy-6-(phenyl(tosyl)methyl)phenol 1a
and 4-hydroxyindole 2a was carried out on gram scale to
demonstrate the utility of this catalytic asymmetric
transformation, and the maintained efficiency and
stereochemical outcome was observed, (Scheme 2, a), implying
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that an asymmetric organocatalytic method to achieve Friedel-
Page 4 of 12
CONCLUSIONS
1
2
3
4
5
6
7
8
Crafts benzhydrylation of indoles in the carbocyclic ring have
the potential for a large-scale production without a decrease in
chemical yield or stereoselectivity. The absolute configuration
of resulting 3aa was determined to be (R) by the single crystal
X-ray analysis of its derivative product 4 (Scheme 2, b).17
In summary, an organocatalytic enantioselective Friedel-
Crafts benzhydrylation of indoles in the carbocyclic ring with
the in situ generated ortho-quinomethanes have been developed,
highlighting an efficient approach to the diarylindolylmethanes
in mild conditions. Switching the position of hydroxy group in
the starting hydroxyindoles, this reaction delivered the novel
diarylindolylmethanes functionalizated at the C4, C5, and C6
positions of indoles with satisfactory yields, regio-, and
enantioselectivities. Moreover, the gram-scale synthesis in a low
catalyst loading showed the practical utility of this protocol, and
more organocatalytic asymmetric reactions involving these
hydroxyindoles are currently ongoing in our laboratory.
Scheme 3. The control experiments of o-QMs with indole
and 4-methoxy indole.
R
Ph
R
Ph
Ts
R
9

V
(1.5 mol%), K2CO3
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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49
50
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52
53
54
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60
+
DCE, H2O, N2, r.t., 24 h
< 20% conv.
NH
N
OH
no
OH
N
OH
H
H
OMe
OMe
OMe
1a
trace
R = H or CH3O
EXPERIMENTAL SECTION
The control experiments of o-QMs with simple indole and 4-
methoxy indole were conducted under the optimized reaction
conditions, without the hydroxyl group attached at the
carbocyclic ring of indole, these transformations didn’t proceed
smoothly and no desired products functionalized at the
carbocyclic ring were delivered, indicating that the influence of
the catalyst/OH-group interaction could be ascertained and the
Friedel-Crafts benzhydrylation of hydroxyindole in carbocyclic
ring with o-QMs was mainly controlled by the neighbouring
hydroxyl group and not the pyrrole moiety (Scheme 3).
General Methods. All reactions were carried out in
reaction tube. Reactions were monitored by TLC on silica gel
precoated on glass plates, and spots were visualized with UV
light at 254 nm. The flash column chromatography was
1
performed using silica gel (200-300 mesh). H NMR spectra
were recorded on Bruker AVANCE III (500 MHz) or Bruker
ASCEND (600 MHz) in CDCl3 using residual solvent signals
as the internal standard (CDCl3 δ = 7.26 ppm). 13C{1H} NMR
spectra were recorded at 126 MHz (Bruker AVANCE III) or
151 MHz (Bruker ASCEND) in CDCl3 or CD3OD-d4 using
solvent signals as the internal standard (CDCl3 δ = 77.16 ppm,
CD3OD-d4 δ = 49.00 ppm). Data for 1H NMR are recorded as
follows: chemical shift (δ, ppm), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet) and coupling
constant(s) in hertz (Hz). Data for 13C{1H} NMR and reported
in terms of chemical shift (δ, ppm). High-resolution
electrospray ionization mass spectra (HR-ESI-MS) were
recorded on an Agilent 6545 Q-TOF LCMS spectrometer
equipped with an ESI source and controlled by using Mass
Hunter software. Specific rotations were performed on a
Rudolph Autopol IV automatic polarimeter. Melting points
(m.p.) were obtained using a Büchi B-545 apparatus and
uncorrected. Chiral HPLC analyses were performed using
JASCO LC-2000 Plus and Agilent 1260 chromatography (for
the compound 4). Chiralpak IA, IC, ID, and AD-H columns
were purchased from Daicel Chemical Industries (Shanghai,
Scheme 4. Proposed mechanism of the Friedel-Crafts
benzhydrylation of indoles in the oil-water phases.
K2CO3
KTs+KHCO3
Water
Oil
Ph OH
OH
+
-
V
V
+H] Ts
[
N
H
OMe
O
3aa
(R)-
OH
N
OH Ts
O
MeO
+
Ph
OMe
N
H
Ar
N
H
N
H
O
O
N
OMe
H
Ar NH
O
NH
O
O
China). Anhydrous THF was freshly distilled over calcium
hydride. Unless otherwise stated, all reagents and solvents
were purchased from commercial suppliers and used without
further purification.
N
NH
Re
Ph
V
N
Procedure for Preparation of 2-(phenyl(tosyl)methyl)-
phenols 1.15a 1) Under argon atmosphere, to a solution of the
corresponding hydroxybenzaldehydes (10 mmol) in
anhydrous THF (20 mL) was added the 25 mmol Grignard
reagents (1.0 mol/mL in THF) dropwise by syringe at 0 °C.
After being stirred at room temperature for 6 h, the reaction
was monitored by thin layer chromatography (TLC). After
completion, the reaction mixture was quenched by a saturated
NH4Cl (20 mL) and extracted with EtOAc. The combined
organic phases was concentrated in vacuo and purified by the
flash column chromatography on silica gel (petroleum ether:
EtOAc = 5:1) to afford the desired hydroxybenzyl alcohol (30
- 63% yields). 2) To the stirred solution of TolSO2Na (2.05 g,
11.5 mmol) and TsOH (3.36 g, 17.5 mmol) in 40 mL CH2Cl2
was added the solution (20 mL) of above
hydroxyalkylphenols (10.0 mmol) in CH2Cl2 and stirred for
1.5 h, the reaction was monitored by thin layer
chromatography (TLC). After completion, the reaction
On the basis of experimental results, a plausible reaction
mechanism for this enantioselective Friedel−Crafts
benzhydrylation of indoles in the carbocyclic ring was
suggested (Scheme 4). In organic phase, the appropriately
substituted benzylsulfones underwent the elimination of TsH (p-
toluenesulfinic acid) under the deprotonation of the nitrogen
moiety of catalyst V to generated o-QMs in situ. The subsequent
conjugate addition was promoted and controlled by the dual
activating nature of the bifunctional catalyst, which
simultaneously activated the o-QMs and 4-hydroxyindole via
forming multiple hydrogen bonds. Noteworthy, in this
transformation, the OH moiety of hydroxyindole not the NH
provided a dominated hydrogen-bonding interaction with the
tertiary amine nitrogen atom of the catalyst. Furthermore, the Re
face approach of the hydroxyindole led to the formation of the
major stereoisomer. In aqueous phase, the neutralization
reactions of K2CO3 with the ammonium salts of [V+H]+Ts-
enabled the regeneration of the catalyst V.
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The Journal of Organic Chemistry
mixture was quenched and adjusted to pH = 8 by a saturated 2-methoxy-6-(m-tolyl(tosyl)methyl)phenol (1f). Compound
1
2
3
4
5
6
7
8
NaHCO3 and extracted with CH2Cl2, the combined organic
phases were washed with 1.0 M HCl and brine, then
concentrated in vacuo and purified by the flash column
chromatography on silica gel (petroleum ether: EtOAc = 4:1)
to afford the corresponding 2-(phenyl(tosyl)methyl)-phenols 1
(35 - 75% yields).
was isolated via flash column chromatography on silica-gel
with petroleum ether/EtOAc (4/1) as eluent; H NMR (500
1
MHz, CDCl3) δ 7.71 (dd, J = 8.1, 1.4 Hz, 1H), 7.61 – 7.51 (m,
2H), 7.41 – 7.32 (m, 2H), 7.23 – 7.15 (m, 3H), 7.11 (ddt, J =
7.6, 1.8, 0.9 Hz, 1H), 6.93 (t, J = 8.1 Hz, 1H), 6.80 (dd, J =
8.1, 1.4 Hz, 1H), 5.95 (s, 1H), 5.75 (s, 1H), 3.81 (s, 3H), 2.38
(s, 3H), 2.31 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
146.3, 144.1, 143.9, 138.1, 135.8, 132.9, 131.0, 129.2, 129.1,
129.0, 128.3, 127.3, 121.7, 119.7, 119.6, 110.6, 67.2, 56.0,
21.6, 21.4. HRMS (ESI) m/z: [M + Na]+ Calcd for
C22H22SO4Na 405.1131; Found 405.1139.
2-methoxy-6-(phenyl(tosyl)methyl)phenol (1a). Compound
was isolated via flash column chromatography on silica-gel
1
with petroleum ether/EtOAc (4/1) as eluent; H NMR (500
9
MHz, CDCl3) δ 7.72 (dd, J = 8.1, 1.4 Hz, 1H), 7.56 (dt, J =
6.1, 2.0 Hz, 4H), 7.33 – 7.28 (m, 3H), 7.19 – 7.14 (m, 2H),
6.94 (t, J = 8.1 Hz, 1H), 6.81 (dd, J = 8.1, 1.4 Hz, 1H), 5.98 (s,
1H), 5.77 (s, 1H), 3.81 (s, 3H), 2.38 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 146.3, 144.2, 143.9, 135.8, 133.1, 130.3,
129.1, 129.0, 128.5, 128.4, 121.6, 119.8, 119.6, 110.6, 67.3,
56.0, 21.6. HRMS (ESI) m/z: [M + Na]+ Calcd for
C21H20SO4Na 391.0975; Found 391.0982.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-methoxy-6-(p-tolyl(tosyl)methyl)phenol (1g). Compound
was isolated via flash column chromatography on silica-gel
1
with petroleum ether/EtOAc (4/1) as eluent; H NMR (500
MHz, CDCl3) δ 7.71 (dd, J = 8.1, 1.4 Hz, 1H), 7.62 – 7.52 (m,
2H), 7.48 – 7.41 (m, 2H), 7.20 – 7.08 (m, 4H), 6.92 (t, J = 8.1
Hz, 1H), 6.79 (dd, J = 8.1, 1.3 Hz, 1H), 5.96 (s, 1H), 5.78 (s,
1H), 3.80 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 146.3, 144.1, 143.8, 138.2, 135.9, 130.2,
130.0, 129.2, 129.1, 128.9, 121.6, 119.7, 119.7, 110.5, 67.0,
56.0, 21.6, 21.1. HRMS (ESI) m/z: [M + Na]+ Calcd for
C22H22SO4Na 405.1131; Found 405.1136.
2-methoxy-6-((3-methoxyphenyl)(tosyl)methyl)phenol (1h).
Compound was isolated via flash column chromatography on
silica-gel with petroleum ether/EtOAc (4/1) as eluent; 1H
NMR (500 MHz, CDCl3) δ 7.70 (dd, J = 8.1, 1.4 Hz, 1H),
7.60 – 7.55 (m, 2H), 7.21 (t, J = 7.9 Hz, 1H), 7.18 – 7.13 (m,
3H), 7.13 – 7.10 (m, 1H), 6.92 (t, J = 8.1 Hz, 1H), 6.84 (ddd, J
= 8.1, 2.6, 1.0 Hz, 1H), 6.80 (dd, J = 8.1, 1.4 Hz, 1H), 5.96 (s,
1H), 5.80 (s, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 2.37 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 159.4, 146.3, 144.2,
143.9, 135.8, 134.5, 129.4, 129.1, 129.0, 122.7, 121.6, 119.7,
119.4, 115.8, 114.1, 110.6, 67.1, 56.0, 55.2, 21.6. HRMS (ESI)
m/z: [M + Na]+ Calcd for C22H22SO5Na 421.1080; Found
421.1088.
2-ethoxy-6-(phenyl(tosyl)methyl)phenol (1b). Compound
was isolated via flash column chromatography on silica-gel
1
with petroleum ether/EtOAc (4/1) as eluent; H NMR (500
MHz, CDCl3) δ 7.71 (dd, J = 8.1, 1.3 Hz, 1H), 7.63 – 7.50 (m,
4H), 7.34 – 7.28 (m, 3H), 7.16 (d, J = 8.1 Hz, 2H), 6.91 (t, J =
8.1 Hz, 1H), 6.79 (dd, J = 8.1, 1.3 Hz, 1H), 5.98 (s, 1H), 5.81
(s, 1H), 4.04 (qq, J = 9.4, 7.0 Hz, 2H), 2.37 (s, 3H), 1.37 (t, J
= 7.0 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 145.5,
144.1, 144.1, 135.8, 133.2, 130.3, 129.1, 129.0, 128.4, 128.4,
121.5, 119.7, 119.5, 111.5, 67.3, 64.6, 21.6, 14.8. HRMS
(ESI) m/z: [M + Na]+ Calcd for C22H22SO4Na 405.1131;
Found 405.1137.
5-methoxy-2-(phenyl(tosyl)methyl)phenol (1c). Compound
was isolated via flash column chromatography on silica-gel
1
with petroleum ether/EtOAc (4/1) as eluent; H NMR (600
MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 2H), 7.53 (dd, J = 6.6, 3.0
Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 7.33 – 7.29 (m, 3H), 7.18
(d, J = 8.0 Hz, 2H), 7.16 – 7.05 (m, 1H), 6.49 (dd, J = 8.8, 2.6
Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 5.85 (s, 1H), 3.73 (s, 3H),
2.37 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 161.1,
155.8, 144.7, 135.0, 132.7, 131.6, 130.2, 129.4, 128.9 128.6,
128.5, 112.0, 107.4, 103.2, 70.0, 55.3, 21.6. HRMS (ESI) m/z:
2-methoxy-6-(tosyl(3-(trifluoromethoxy)phenyl)methyl)-
phenol (1i). Compound was isolated via flash column
chromatography on silica-gel with petroleum ether/EtOAc
1
(4/1) as eluent; H NMR (500 MHz, CDCl3) δ 7.68 (dd, J =
[M
391.0979.
4-bromo-2-methoxy-6-(phenyl(tosyl)methyl)phenol
+
Na]+ Calcd for C21H20SO4Na 391.0975; Found
8.1, 1.3 Hz, 1H), 7.58 – 7.51 (m, 3H), 7.37 – 7.31 (m, 2H),
7.20 – 7.13 (m, 3H), 6.95 (t, J = 8.1 Hz, 1H), 6.83 (dd, J = 8.1,
1.4 Hz, 1H), 5.97 (s, 1H), 5.79 (s, 1H), 3.83 (s, 3H), 2.38 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 149.0, 146.4, 144.6,
144.0, 135.5, 135.4, 129.8, 129.3, 128.9, 128.7, 123.1, 121.3,
120.8, 120.4 (q, J = 257.6 Hz), 120.0, 118.9, 110.8, 66.7,
56.1, 21.6. HRMS (ESI) m/z: [M + Na]+ Calcd for
C22H19F3SO5Na 475.0798; Found 475.0803.
(1d).
Compound was isolated via flash column chromatography on
silica-gel with petroleum ether/EtOAc (4/1) as eluent; 1H
NMR (600 MHz, CDCl3) δ 7.85 (t, J = 1.7 Hz, 1H), 7.56 (dd,
J = 8.2, 1.4 Hz, 2H), 7.55 – 7.49 (m, 2H), 7.33 – 7.29 (m, 3H),
7.17 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 2.0 Hz, 1H), 5.94 (s,
1H), 5.88 (s, 1H), 3.76 (s, 3H), 2.37 (s, 3H).13C{1H} (151
MHz, CDCl3) δ 147.0, 144.5, 143.2, 135.5, 132.6, 130.2,
129.3, 129.0, 128.6, 128.6, 124.0, 121.1, 114.1, 111.7,
66.9, 56.3, 21.6. HRMS (ESI) m/z: [M + Na]+ Calcd for
C21H19SO4BrNa 469.0080; Found 469.0024.
2-methoxy-6-(tosyl(4-(trifluoromethoxy)phenyl)methyl)-
phenol (1j). Compound was isolated via flash column
chromatography on silica-gel with petroleum ether/EtOAc
1
(4/1) as eluent; H NMR (500 MHz, CDCl3) δ 7.69 (dd, J =
8.1, 1.4 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.58 – 7.53 (m, 2H),
7.21 – 7.12 (m, 4H), 6.95 (t, J = 8.1 Hz, 1H), 6.82 (dd, J = 8.1,
1.3 Hz, 1H), 5.99 (s, 1H), 5.77 (s, 1H), 3.81 (s, 3H), 2.38 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 149.2, 146.4, 144.5,
143.9, 135.5, 131.8, 131.8, 129.2, 128.9, 123.4, 121.3, 120.8,
120.4 (q, J = 257.5 Hz), 119.9, 119.1, 117.3, 110.8, 66.4, 56.0,
21.6. HRMS (ESI) m/z: [M + Na]+ Calcd for C22H19F3SO5Na
475.0798; Found 475.0806.
2-(phenyl(tosyl)methyl)phenol (1e). Compound was isolated
via flash column chromatography on silica-gel with petroleum
1
ether/EtOAc (4/1) as eluent; H NMR (500 MHz, CDCl3) δ
7.68 (dd, J = 7.9, 1.6 Hz, 1H), 7.58 – 7.52 (m, 4H), 7.33 –
7.28 (m, 3H), 7.19 – 7.14 (m, 3H), 6.93 (td, J = 7.6, 1.3 Hz,
1H), 6.81 (dd, J = 8.1, 1.2 Hz, 1H), 6.73 (s, 1H), 5.93 (s, 1H),
2.37 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 154.3,
144.7, 135.0, 132.4, 130.7, 130.3, 130.0, 129.3, 128.9, 128.6,
128.6, 121.2, 120.0, 117.5, 69.8, 21.6. HRMS (ESI) m/z: [M +
Na]+ Calcd for C20H18SO3Na 361.0869; Found 361.0875.
2-((4-fluorophenyl)(tosyl)methyl)-6-methoxyphenol
(1k).
Compound was isolated via flash column chromatography on
silica-gel with petroleum ether/EtOAc (4/1) as eluent; 1H
NMR (500 MHz, CDCl3) δ 7.69 (dd, J = 8.1, 1.3 Hz, 1H),
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The Journal of Organic Chemistry
Page 6 of 12
7.59 – 7.48 (m, 4H), 7.17 (d, J = 8.0 Hz, 2H), 7.03 – 6.96 (m, 6.96 (t, J = 8.1 Hz, 1H), 6.82 (dd, J = 8.2, 1.3 Hz, 1H), 6.04
(s, 1H), 5.80 (s, 1H), 3.82 (s, 3H), 2.38 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 146.3, 144.2, 143.9, 141.2, 140.5, 135.8,
132.0, 130.7, 129.2, 129.0, 128.8, 127.5, 127.2, 127.1, 121.6,
119.8, 119.5, 110.6, 67.0, 56.1, 21.6. HRMS (ESI) m/z: [M +
Na]+ Calcd for C27H24SO4Na 467.1288; Found 467.1299.
1
2
3
4
5
6
7
8
2H), 6.94 (t, J = 8.1 Hz, 1H), 6.81 (dd, J = 8.2, 1.3 Hz, 1H),
5.96 (s, 1H), 5.78 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ
162.7 (d, J = 248.0 Hz), 146.3, 144.4, 143.8 135.6, 132.1 (d, J
= 8.4 Hz), 129.2, 128.9, 128.9, 121.3, 119.9, 119.4, 115.4 (d,
J = 21.7 Hz), 110.7, 66.4, 56.0, 21.6. HRMS (ESI) m/z: [M +
Na]+ Calcd for C21H19FSO4Na 409.0880; Found 409.0888.
2-methoxy-6-(naphthalen-1-yl(tosyl)methyl)phenol
(1q).
2-((4-chlorophenyl)(tosyl)methyl)-6-methoxyphenol
(1l).
Compound was isolated via flash column chromatography on
silica-gel with petroleum ether/EtOAc (4/1) as eluent; 1H
NMR (500 MHz, CDCl3) δ 8.54 (dd, J = 7.3, 1.2 Hz, 1H),
8.03 (dq, J = 6.9, 3.4 Hz, 1H), 7.83 – 7.78 (m, 2H), 7.59 –
7.55 (m, 3H), 7.52 (dd, J = 8.1, 1.4 Hz, 1H), 7.41 (dt, J = 6.4,
3.4 Hz, 2H), 7.13 – 7.08 (m, 2H), 6.90 – 6.84 (m, 2H), 6.78
(dd, J = 8.1, 1.4 Hz, 1H), 5.79 (s, 1H), 3.81 (s, 3H), 2.34 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.1, 144.2, 143.9,
136.1, 133.8, 132.0, 130.1, 129.0, 129.0, 128.9, 128.9, 127.2,
126.5, 125.5, 125.3, 122.7, 122.5, 119.9, 119.5, 110.7, 62.0,
56.1, 21.5. HRMS (ESI) m/z: [M + Na]+ Calcd for
C25H22SO4Na 441.1131; Found 441.1141.
Compound was isolated via flash column chromatography on
silica-gel with petroleum ether/EtOAc (4/1) as eluent; 1H
NMR (500 MHz, CDCl3) δ 7.67 (dd, J = 8.1, 1.4 Hz, 1H),
7.58 – 7.55 (m, 2H), 7.52 – 7.45 (m, 2H), 7.29 – 7.26 (m, 2H),
7.21 – 7.15 (m, 2H), 6.93 (t, J = 8.1 Hz, 1H), 6.81 (dd, J =
8.1, 1.4 Hz, 1H), 5.95 (s, 1H), 5.78 (s, 1H), 3.81 (s, 3H), 2.38
(s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.3, 144.4,
143.9, 135.5, 134.5, 131.7, 131.6, 129.2, 128.9, 128.6, 121.4,
119.9, 119.2, 110.7, 66.5, 56.0, 21.6. HRMS (ESI) m/z: [M +
Na]+ Calcd for C21H19ClSO4Na 425.0585; Found 425.0588.
2-methoxy-6-(tosyl(2-(trifluoromethyl)phenyl)methyl)-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
phenol (1m). Compound was isolated via flash column
chromatography on silica-gel with petroleum ether/EtOAc
(4/1) as eluent; 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 8.0
Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.62 (dd, J = 8.0, 1.4 Hz,
1H), 7.59 – 7.52 (m, 2H), 7.48 – 7.42 (m, 1H), 7.40 (dd, J =
8.1, 1.4 Hz, 1H), 7.20 – 7.14 (m, 2H), 6.88 (t, J = 8.1 Hz, 1H),
6.82 (dd, J = 8.1, 1.4 Hz, 1H), 6.57 (s, 1H), 5.73 (s, 1H), 3.83
(s, 3H), 2.38 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
146.4, 144.8, 144.4, 135.7, 132.1, 131.9, 131.4, 129.7 (q, J =
29.5 Hz), 129.1, 129.1, 128.4, 126.5 (q, J = 5.9 Hz), 123.8 (q,
J = 274.2 Hz), 122.2, 119.5, 117.8, 110.9, 61.9, 56.1, 21.6.
HRMS (ESI) m/z: [M + Na]+ Calcd for C22H19F3SO4Na
459.0848; Found 459.0857.
2-methoxy-6-(naphthalen-2-yl(tosyl)methyl)phenol
(1r).
Compound was isolated via flash column chromatography on
silica-gel with petroleum ether/EtOAc (4/1) as eluent; 1H
NMR (500 MHz, CDCl3) δ 8.02 (d, J = 1.8 Hz, 1H), 7.83 –
7.76 (m, 4H), 7.70 (dd, J = 8.6, 1.8 Hz, 1H), 7.62 – 7.57 (m,
2H), 7.50 – 7.44 (m, 2H), 7.17 – 7.11 (m, 2H), 6.96 (t, J = 8.1
Hz, 1H), 6.81 (dd, J = 8.1, 1.4 Hz, 1H), 6.18 (s, 1H), 3.80 (s,
3H), 2.35 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.3,
144.2, 143.9, 135.8, 133.1, 133.0, 130.6, 129.9, 129.1, 129.1,
129.0, 128.2, 128.1, 127.5, 127.4, 126.4, 126.1, 121.7, 119.8,
119.6, 110.6, 67.4, 56.0, 21.5. HRMS (ESI) m/z: [M + Na]+
Calcd for C25H22SO4Na 441.1131; Found 441.1135.
2-(furan-2-yl(tosyl)methyl)-6-methoxyphenol
(1s).
2-methoxy-6-(tosyl(3-(trifluoromethyl)phenyl)methyl)-
Compound was isolated via flash column chromatography on
silica-gel with petroleum ether/EtOAc (4/1) as eluent; 1H
NMR (500 MHz, CDCl3) δ 7.58 – 7.48 (m, 3H), 7.41 (d, J =
1.9 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.91 (t, J = 8.0 Hz, 1H),
6.84 (dd, J = 8.1, 1.4 Hz, 1H), 6.54 (d, J = 3.3 Hz, 1H), 6.36
(dd, J = 3.4, 1.8 Hz, 1H), 6.16 (s, 1H), 3.84 (s, 3H), 2.40 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.3, 146.1, 144.4,
144.3, 143.3, 135.1, 129.1, 129.1, 122.6, 119.7, 116.8, 112.0,
111.1, 110.8, 61.9, 56.1, 21.6. HRMS (ESI) m/z: [M + Na]+
Calcd for C19H18SO5Na 381.0767; Found 381.0770.
phenol (1n). Compound was isolated via flash column
chromatography on silica-gel with petroleum ether/EtOAc
1
(4/1) as eluent; H NMR (500 MHz, CDCl3) δ 7.84 (dt, J =
7.9, 1.4 Hz, 1H), 7.71 (dd, J = 8.1, 1.3 Hz, 1H), 7.66 (d, J =
1.9 Hz, 1H), 7.58 – 7.52 (m, 3H), 7.45 (t, J = 7.8 Hz, 1H),
7.20 – 7.16 (m, 2H), 6.96 (t, J = 8.1 Hz, 1H), 6.83 (dd, J =
8.2, 1.3 Hz, 1H), 6.02 (s, 1H), 5.79 (s, 1H), 3.82 (s, 3H), 2.38
(s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.4, 144.7,
143.9, 135.2, 134.3, 133.5, 130.7 (q, J = 32.5 Hz), 129.3,
129.0, 128.9, 127.3 (q, J = 4.0 Hz), 125.2 (q, J = 3.7 Hz),
123.8 (q, J = 272.5 Hz), 121.2, 120.0, 118.8, 110.9, 66.8,
56.0, 21.5. HRMS (ESI) m/z: [M + Na]+ Calcd for
C22H19F3SO4Na 459.0848; Found 459.0859.
2-methoxy-6-(thiophen-2-yl(tosyl)methyl)phenol
(1t).
Compound was isolated via flash column chromatography on
silica-gel with petroleum ether/EtOAc (4/1) as eluent; 1H
NMR (500 MHz, CDCl3) δ 7.61 – 7.55 (m, 3H), 7.30 (dd, J =
5.1, 1.2 Hz, 1H), 7.22 (dt, J = 3.5, 0.9 Hz, 1H), 7.17 (d, J =
8.0 Hz, 2H), 6.99 – 6.90 (m, 2H), 6.82 (dd, J = 8.1, 1.3 Hz,
1H), 6.30 (s, 1H), 5.80 (s, 1H), 3.83 – 3.81 (m, 3H), 2.38 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.2, 144.4, 144.0,
135.0, 134.2, 129.8, 129.1, 129.1, 126.9, 126.7, 121.8, 119.8,
118.9, 110.97, 63.0, 56.1, 21.6. HRMS (ESI) m/z: [M + Na]+
Calcd for C19H18S2O4Na 397.0539; Found 397.0549.
2-methoxy-6-(tosyl(4-(trifluoromethyl)phenyl)methyl)-
phenol (1o). Compound was isolated via flash column
chromatography on silica-gel with petroleum ether/EtOAc
(4/1) as eluent; 1H NMR (500 MHz, CDCl3) δ 7.73 – 7.67 (m,
3H), 7.60 – 7.54 (m, 4H), 7.21 – 7.16 (m, 2H), 6.95 (t, J = 8.1
Hz, 1H), 6.82 (dd, J = 8.1, 1.3 Hz, 1H), 6.04 (s, 1H), 5.77 (s,
1H), 3.81 (s, 3H), 2.38 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 146.3, 144.6, 143.9, 137.2, 135.4, 130.7, 130.5 (q, J
= 32.6 Hz), 129.3, 128.9, 125.4 (q, J = 3.7 Hz), 123.9 (q, J =
272.0 Hz), 121.3, 120.0, 118.9, 110.8, 66.7, 56.0, 21.6. HRMS
(ESI) m/z: [M + Na]+ Calcd for C22H19F3SO4Na 459.0848;
Found 459.0859.
2-([1,1'-biphenyl]-4-yl(tosyl)methyl)-6-methoxyphenol (1p).
Compound was isolated via flash column chromatography on
silica-gel with petroleum ether/EtOAc (4/1) as eluent; 1H
NMR (500 MHz, CDCl3) δ 7.77 (dd, J = 8.1, 1.3 Hz, 1H),
7.66 – 7.62 (m, 2H), 7.62 – 7.59 (m, 2H), 7.58 – 7.52 (m, 4H),
7.46 – 7.41 (m, 2H), 7.38 – 7.33 (m, 1H), 7.20 – 7.15 (m, 2H),
2-((2-ethylphenyl)(tosyl)methyl)-6-methoxyphenol
(1u).
Compound was isolated via flash column chromatography on
silica-gel with petroleum ether/EtOAc (4/1) as eluent; 1H
NMR (500 MHz, CDCl3) δ 8.23 (dd, J = 7.7, 1.6 Hz, 1H),
7.63 (dd, J = 8.1, 1.3 Hz, 1H), 7.58 – 7.52 (m, 2H), 7.31 –
7.23 (m, 2H), 7.14 (ddd, J = 14.7, 8.1, 1.3 Hz, 3H), 6.91 (t, J
= 8.1 Hz, 1H), 6.79 (dd, J = 8.1, 1.4 Hz, 1H), 6.32 (s, 1H),
3.81 (s, 3H), 2.56 (dhept, J = 29.9, 7.5 Hz, 2H), 2.38 (s, 3H),
1.08 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
146.1, 144.1, 144.0, 143.6, 136.2, 131.3, 129.5, 129.1, 129.0,
128.6, 128.4, 126.0, 122.3, 119.8, 119.6, 110.5, 62.0, 56.1,
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The Journal of Organic Chemistry
25.4, 21.6, 14.7. HRMS (ESI) m/z: [M + Na]+ Calcd for
C23H24SO4Na 419.1288; Found 419.1296.
(R)-5-((5-bromo-2-hydroxy-3-methoxyphenyl)(phenyl)-
1
2
3
4
5
6
7
8
methyl)-1H-indol-4-ol (3da). Compound was isolated as a
colorless oil (39.8 mg, 94% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.30 (dd, J = 8.1,
6.6 Hz, 2H), 7.25 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 7.0 Hz, 2H),
7.07 (t, J = 2.8 Hz, 1H), 6.93 – 6.86 (m, 2H), 6.81 – 6.73 (m,
2H), 6.56 (s, 1H), 6.20 (s, 1H), 5.31 (s, 0H), 3.80 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 147.2, 146.6, 142.5,
General Procedure for Friedel-Crafts Benzhydrylation
of Indoles with o-QMs. To a test tube were added catalyst V
(0.015 eq, 0.0015 mmol), K2CO3 (1.5 equiv., 0.15 mmol), the
substituted 2-(phenyl(tosyl)methyl)phenol 1 (0.1 mmol) and
hydroxyindole 2 (1.5 equiv., 0.15 mmol), 1.0 mL DCE and
0.5 mL H2O were then added through syringe under N2
atmosphere. The resulting mixture was stirred at room
temperature for 24 h. Then it was extracted with CH2Cl2, and
the organic layer was concentrated under reduced pressure.
The crude product was purified by flash chromatography to
afford the product. The stereoselectivities were determined by
Chiral HPLC using a Chiralpak IA, IC, ID or AD-H columns.
(R)-5-((2-hydroxy-3-methoxyphenyl)(phenyl)methyl)-1H-
indol-4-ol (3aa). Compound was isolated as a colorless oil
(32.1 mg, 93% yield) after flash column chromatography on
silica-gel (petroleum ether: EtOAc = 4:1). 1H NMR (500 MHz,
CDCl3) δ 8.10 (s, 1H), 7.31 (dd, J = 8.7, 6.1 Hz, 2H), 7.27 –
7.23 (m, 3H), 7.10 (t, J = 2.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H),
6.82 – 6.77 (m, 3H), 6.68 (dd, J = 6.9, 2.4 Hz, 1H), 6.59 (ddd,
J = 3.2, 2.1, 1.0 Hz, 1H), 6.19 (s, 1H), 5.93 (s, 1H), 5.58 (s,
1H), 3.89 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.7,
146.4, 143.1, 142.8, 136.6, 129.3, 129.2, 128.3, 126.3, 124.6,
123.1, 122.4, 119.7, 118.4, 118.4, 108.9, 103.7, 99.2, 56.0,
43.4. [α]D30 = +26 (c = 1.0 in CH3OH). The enantiomers were
analyzed by HPLC using Daicel Chiralpak IA column at 254
142.4, 136.6, 131.6, 129.1, 128.3, 126.4, 125.0, 124.4, 123.3,
118.4, 117.8, 112.4, 111.4, 103.9, 99.0, 56.2, 43.1. [α]D
9
30
=
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+10 (c = 1.0 in CH3OH). The enantiomers were analyzed by
HPLC using Daicel Chiralpak IC column at 254 nm (n-
hexane/i-PrOH = 80/20), 1.0 mL/min; Major enantiomer: tR =
28.2 min, minor enantiomer: tR = 18.7 min. 90% ee. HRMS
(ESI) m/z: [M + Na]+ Calcd for C22H18BrNO3Na 446.0362;
Found: 446.0358.
(S)-5-((2-hydroxyphenyl)(phenyl)methyl)-1H-indol-4-ol
(3ea). Compound was isolated as colorless oil (23.6 mg, 75%
yield) after flash column chromatography on silica-gel
(petroleum ether: EtOAc = 4:1). 1H NMR (600 MHz, CDCl3)
δ 8.19 (s, 1H), 7.33 (d, J = 7.5 Hz, 2H), 7.28 (d, J = 3.5 Hz,
2H), 7.26 – 7.24 (m, 2H), 7.17 (td, J = 7.6, 1.8 Hz, 2H), 6.96
(dd, J = 10.3, 8.1 Hz, 2H), 6.90 – 6.86 (m, 2H), 6.81 (d, J =
8.4 Hz, 1H), 6.07 (s, 1H), 5.56 (s, 1H), 5.41 (s, 1H). 13C{1H}
NMR (151 MHz, CDCl3) δ 153.7, 146.5, 142.2, 136.8, 130.1,
129.4, 129.3, 128.5, 128.0, 126.6, 124.3, 123.5, 120.9, 118.3,
30
nm (n-hexane/i-PrOH
=
80/20), 1.0 mL/min; Major
117.1, 116.3, 104.4, 98.4, 44.3. [α]D = +7 (c = 1.0 in
enantiomer: tR = 15.9 min, minor enantiomer: tR = 20.9 min.
97% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for C22H19NO3Na
368.1257; Found 368.1254.
CH3OH). The enantiomers were analyzed by HPLC using
Daicel Chiralpak IA column at 216 nm (n-hexane/i-PrOH =
80/20), 1.0 mL/min; Major enantiomer: tR = 40.7 min, minor
enantiomer: tR = 30.6 min. 60% ee. HRMS (ESI) m/z: [M +
Na]+ Calcd for C21H17NO2Na 338.1151; Found 338.1152.
(R)-5-((2-hydroxy-3-methoxyphenyl)(m-tolyl)methyl)-1H-
indol-4-ol (3fa). Compound was isolated as a colorless oil
(32.7 mg, 91% yield) after flash column chromatography on
(R)-5-((3-ethoxy-2-hydroxyphenyl)(phenyl)methyl)-1H-
indol-4-ol (3ba). Compound was isolated as a colorless oil
(32.7 mg, 91% yield) after flash column chromatography on
silica-gel (petroleum ether: EtOAc = 4:1). 1H NMR (500 MHz,
CDCl3) δ 8.09 (s, 1H), 7.35 – 7.29 (m, 2H), 7.26 (t, J = 6.1 Hz,
3H), 7.11 – 7.05 (m, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.86 – 6.74
(m, 3H), 6.68 (dd, J = 6.8, 2.6 Hz, 1H), 6.60 (d, J = 2.7 Hz,
1H), 6.20 (s, 1H), 4.11 (qd, J = 7.0, 4.8 Hz, 2H), 1.44 (t, J =
7.0 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.7, 145.7,
143.2, 142.8, 136.6, 129.3, 129.2, 128.3, 126.2, 124.6, 123.1,
122.2, 119.6, 118.5, 118.4, 109.8, 103.7, 99.2, 64.5, 43.5, 14.9.
1
silica-gel (petroleum ether: EtOAc = 4:1). H NM R (500
MHz, CDCl3) δ 8.13 (s, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.14 –
6.98 (m, 4H), 6.91 (d, J = 8.4 Hz, 1H), 6.84 – 6.75 (m, 3H),
6.69 (dd, J = 7.0, 2.4 Hz, 1H), 6.63 – 6.56 (m, 1H), 6.16 (s,
1H), 5.94 (s, 1H), 5.62 (s, 1H), 3.88 (s, 3H), 2.31 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 146.7, 146.4, 143.0,
142.7, 137.9, 136.6, 130.0, 129.3, 128.2, 127.1, 126.2, 124.6,
123.1, 122.4, 119.6, 118.4, 108.9, 103.7, 100.0, 99.2, 56.0,
43.4, 21.5. [α]D30 = +13 (c = 1.0 in CH3OH). The enantiomers
were analyzed by HPLC using Daicel Chiralpak IC column at
300 nm (n-hexane/i-PrOH = 90/10), 1.0 mL/min; Major
enantiomer: tR = 60.2 min, minor enantiomer: tR = 68.9 min.
99% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for C23H21NO3Na
382.1414; Found 382.1421.
(R)-5-((2-hydroxy-3-methoxyphenyl)(p-tolyl)methyl)-1H-
indol-4-ol (3ga). Compound was isolated as a colorless oil
(30.5 mg, 85% yield) after flash column chromatography on
silica-gel (petroleum ether: EtOAc = 4:1). 1H NMR (500 MHz,
CDCl3) δ 8.12 (s, 1H), 7.14 (d, J = 1.8 Hz, 4H), 7.09 – 7.06
(m, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.83 – 6.77 (m, 3H), 6.69
(dd, J = 7.0, 2.3 Hz, 1H), 6.62 – 6.57 (m, 1H), 6.16 (s, 1H),
5.95 (s, 1H), 5.64 (s, 1H), 3.88 (s, 3H), 2.36 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 146.7, 146.4, 143.0, 139.7, 136.6,
135.8, 129.4, 129.1, 129.0, 124.5, 123.1, 122.3, 119.6, 118.4,
108.9, 103.7, 99.9, 99.2, 56.0, 43.1, 21.0. [α]D30 = +21 (c = 1.0
in CH3OH). The enantiomers were analyzed by HPLC using
Daicel Chiralpak IC column at 300 nm (n-hexane/i-PrOH =
80/20), 1.0 mL/min; Major enantiomer: tR = 17.0 min, minor
30
[α]D = +29 (c = 1.0 in CH3OH). The enantiomers were
analyzed by HPLC using Daicel Chiralpak IA column at 254
nm (n-hexane/i-PrOH
= 80/20), 1.0 mL/min; Major
enantiomer: tR = 29.9 min, minor enantiomer: tR = 59.3 min.
95% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for C23H21NO3Na
382.1414; Found 382.1408.
(S)-5-((2-hydroxy-4-methoxyphenyl)(phenyl)methyl)-1H-
indol-4-ol (3ca). Compound was isolated as a colorless oil
(30.0 mg, 87% yield) after flash column chromatography on
silica-gel (petroleum ether: EtOAc = 4:1). 1H NMR (500 MHz,
CDCl3) δ 8.17 (s, 1H), 7.32 (t, J = 7.3 Hz, 2H), 7.25 (d, J =
10.8 Hz, 3H), 7.11 (t, J = 2.8 Hz, 1H), 6.94 (dd, J = 8.4, 0.9
Hz, 1H), 6.81 (dd, J = 16.4, 8.8 Hz, 2H), 6.56 (s, 1H), 6.44
(dd, J = 6.5, 2.5 Hz, 2H), 5.96 (s, 1H), 3.74 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 159.6, 154.6, 146.5, 142.3, 136.8,
130.6, 129.3, 128.5, 126.6, 124.2, 123.5, 122.0, 118.3, 117.2,
30
106.4, 104.4, 102.4, 98.9, 55.3, 44.1. [α]D = +29 (c = 1.0 in
CH3OH). The enantiomers were analyzed by HPLC using
Daicel Chiralpak IA column at 254 nm (n-hexane/i-PrOH =
80/20), 1.0 mL/min; Major enantiomer: tR = 44.1 min, minor
enantiomer: tR = 69.4 min. 78% ee. HRMS (ESI) m/z: [M +
Na]+ Calcd for C22H19NO3Na 368.1257; Found 368.1258.
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The Journal of Organic Chemistry
Page 8 of 12
enantiomer: tR = 22.9 min. 97% ee. HRMS (ESI) m/z: [M + 136.6, 130.7 (d, J = 7.5), 129.2, 124.4, 123.3, 122.1, 119.7,
Na]+ Calcd for C23H21NO3Na 382.1414; Found 382.1416.
(R)-5-((2-hydroxy-3-methoxyphenyl)(3-methoxyphenyl)-
methyl)-1H-indol-4-ol (3ha). Compound was isolated as a
colorless oil (31.5 mg, 84% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
δ 1H NMR (500 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.32 (s, 1H),
7.17 – 7.08 (m, 2H), 6.82 – 6.73 (m, 2H), 6.70 (dd, J = 8.1,
2.6 Hz, 1H), 6.65 – 6.55 (m, 3H), 6.53 – 6.45 (m, 2H), 6.36
(dd, J = 7.8, 1.5 Hz, 1H), 6.21 (s, 1H), 3.77 (s, 3H), 3.64 (s,
3H). 13C{1H} NMR (126 MHz, CD3OD-d4) δ 161.6, 149.5,
149.2, 148.8, 146.0, 139.1, 133.6, 130.4, 126.1, 124.8, 124.5,
123.9, 120.7, 120.6, 120.3, 117.1, 112.6, 111.0, 104.6, 100.0,
114.9 (d, J = 21.3), 109.0, 103.8, 99.1, 56.0, 42.5. [α]D30 = +26
(c = 1.0 in CH3OH). The enantiomers were analyzed by
HPLC using Daicel Chiralpak ID column at 300 nm (n-
hexane/i-PrOH = 80/20), 1.0 mL/min; Major enantiomer: tR =
19.1 min, minor enantiomer: tR = 31.5 min. 96% ee. HRMS
(ESI) m/z: [M + Na]+ Calcd for C22H18FNO3Na 386.1163;
Found 386.1161.
1
2
3
4
5
6
7
8
(R)-5-((4-chlorophenyl)(2-hydroxy-3-methoxyphenyl)-
methyl)-1H-indol-4-ol (3la). Compound was isolated as
colorless oil (34.5 mg, 91% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 7.26 – 7.22 (m,
2H), 7.16 – 7.11 (m, 2H), 7.07 (dd, J = 3.3, 2.4 Hz, 1H), 6.89
(dd, J = 8.5, 1.0 Hz, 1H), 6.78 (d, J = 6.2 Hz, 2H), 6.73 (d, J =
8.5 Hz, 1H), 6.63 – 6.57 (m, 2H), 6.20 (s, 1H), 6.16 (s, 1H),
4.86 (s, 1H), 3.86 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
146.5, 146.5, 143.0, 141.9, 136.6, 131.7, 130.6, 129.3, 129.2,
128.2, 124.3, 123.3, 122.2, 119.6, 118.3, 118.0, 109.0, 103.8,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
30
57.3, 56.3, 44.8. [α]D = +26 (c = 1.0 in CH3OH). The
enantiomers were analyzed by HPLC using Daicel Chiralpak
IC column at 300 nm (n-hexane/i-PrOH = 90/10), 1.0 mL/min;
Major enantiomer: tR =51.4 min, minor enantiomer: tR = 47.8
min. 97% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for
C23H21NO4Na 398.1363; Found 398.1366.
(R)-5-((2-hydroxy-3-methoxyphenyl)(3-(trifluoromethoxy)-
phenyl)methyl)-1H-indol-4-ol (3ia). Compound was isolated
as colorless oil (39.9 mg, 93% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.30 (t, J = 7.9 Hz,
1H), 7.19 – 7.14 (m, 1H), 7.10 (d, J = 5.5 Hz, 3H), 6.92 (dd, J
= 8.5, 0.9 Hz, 1H), 6.84 – 6.74 (m, 3H), 6.65 (dd, J = 7.3, 2.1
Hz, 1H), 6.61 – 6.56 (m, 1H), 6.25 (s, 1H), 6.00 (s, 1H), 5.77
(s, 1H), 3.88 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
149.3, 146.6, 146.5, 145.8, 143.0, 136.6, 129.2, 128.8, 127.7,
30
98.9, 58.0, 42.5. [α]D = -24 (c = 1.0 in CH3OH). The
enantiomers were analyzed by HPLC using Daicel Chiralpak
IA column at 210 nm (n-hexane/i-PrOH = 80/20), 1.0
mL/min; Major enantiomer: tR = 36.3 min, minor enantiomer:
tR = 61.9 min. 99% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for
C22H18ClNO3Na 402.0867; Found 402.0867.
(R)-5-((2-hydroxy-3-methoxyphenyl)(2-(trifluoromethyl)-
phenyl)methyl)-1H-indol-4-ol (3ma). Compound was isolated
as a colorless oil (39.3 mg, 95% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 7.72 (dd, J = 7.9,
1.4 Hz, 1H), 7.43 (td, J = 7.6, 1.4 Hz, 1H), 7.37 – 7.29 (m,
2H), 7.07 (t, J = 2.8 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.83 –
6.74 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.56 –
6.52 (m, 1H), 6.45 (dd, J = 7.8, 1.5 Hz, 1H), 5.80 (s, 1H), 5.31
(s, 1H), 3.86 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
146.5, 146.1, 143.2, 142.0, 136.7, 131.7, 131.4, 129.0, 128.8
(q, J = 29.9 Hz), 126.4, 126.3 (q, J = 6.0 Hz), 124.6 (q, J =
274.8 Hz), 124.1, 123.3, 121.9, 119.0, 118.3, 117.8, 109.2,
124.2, 123.3, 122.1, 121.9, 120.5(q, J = 257.2 Hz), 119.8,
30
118.4, 118.3, 117.8, 109.1, 104.0, 99.0, 56.0, 42.7. [α]D
=
+17 (c = 1.0 in CH3OH). The enantiomers were analyzed by
HPLC using Daicel Chiralpak IA column at 276 nm (n-
hexane/i-PrOH = 80/20), 1.0 mL/min; Major enantiomer: tR =
29.5 min, minor enantiomer: tR = 53.9 min. 98% ee. HRMS
(ESI) m/z: [M + Na]+ Calcd for C23H18F3NO4Na 452.1080;
Found 452.1086.
(R)-5-((2-hydroxy-3-methoxyphenyl)(4-(trifluoromethoxy)-
phenyl)methyl)-1H-indol-4-ol (3ja). Compound was isolated
as colorless oil (39.9 mg, 93% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.27 – 7.20 (m,
2H), 7.17 – 7.06 (m, 3H), 6.95 – 6.88 (m, 1H), 6.79 (ddd, J =
16.4, 14.6, 8.2 Hz, 3H), 6.64 (dd, J = 7.0, 2.1 Hz, 1H), 6.59 (s,
1H), 6.23 (s, 1H), 5.99 (s, 1H), 5.77 (s, 1H), 3.88 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 147.5, 146.6, 146.5,
30
103.4, 98.7, 77.3, 56.0, 40.0. [α]D = -4 (c = 1.0 in CH3OH).
The enantiomers were analyzed by HPLC using Daicel
Chiralpak IA column at 254 nm (n-hexane/i-PrOH = 80/20),
1.0 mL/min; Major enantiomer: tR = 36.0 min, minor
enantiomer: tR = 61.6 min. 99% ee. HRMS (ESI) m/z: [M +
Na]+ Calcd for C23H18F3NO3Na 436.1131; Found 436.1134.
(R)-5-((2-hydroxy-3-methoxyphenyl)(3-(trifluoromethyl)-
phenyl)methyl)-1H-indol-4-ol (3na). Compound was isolated
as a colorless oil (38.0 mg, 92% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.57 – 7.47 (m,
2H), 7.43 – 7.37 (m, 2H), 7.07 (t, J = 2.8 Hz, 1H), 6.91 (dd, J
= 8.5, 0.9 Hz, 1H), 6.84 – 6.73 (m, 3H), 6.64 (dd, J = 7.5, 1.9
Hz, 1H), 6.58 (d, J = 2.6 Hz, 1H), 6.30 (s, 1H), 4.80 (s, 2H),
3.85 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.6, 146.5,
144.4, 143.1, 136.6, 132.7, 130.4 (q, J = 32.1 Hz), 128.8,
125.9 (q, J = 3.7 Hz), 124.3 (q, J = 272.4 Hz), 124.2, 123.4,
123.0 (q, J = 3.9 Hz), 122.1, 119.8, 118.4, 117.8, 109.1, 104.0,
143.0, 141.9, 136.6, 130.5, 129.1, 124.3, 123.3, 122.1, 120.5,
30
119.7, 118.4, 118.0, 109.0, 103.9, 99.0, 56.0, 42.5. [α]D
=
+15 (c = 1.0 in CH3OH). The enantiomers were analyzed by
HPLC using Daicel Chiralpak IA column at 300 nm (n-
hexane/i-PrOH = 80/20), 1.0 mL/min; Major enantiomer: tR =
25.6 min, minor enantiomer: tR = 38.8 min. 98% ee. HRMS
(ESI) m/z: [M + Na]+ Calcd for C23H18F3NO4Na 452.1080;
Found 452.1086.
(R)-5-((4-fluorophenyl)(2-hydroxy-3-methoxyphenyl)-
methyl)-1H-indol-4-ol (3ka). Compound was isolated as a
colorless oil (31.6 mg, 87% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H), 7.22 – 7.17 (m,
2H), 7.09 (dd, J = 3.3, 2.4 Hz, 1H), 7.02 – 6.96 (m, 2H), 6.92
(dd, J = 8.4, 0.9 Hz, 1H), 6.82 – 6.75 (m, 3H), 6.65 (dd, J =
7.0, 2.3 Hz, 1H), 6.61 – 6.56 (m, 1H), 6.18 (s, 1H), 5.77 (s,
1H), 3.88 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 161.4
(d, J = 244.8), 146.5, 146.4, 143.0, 138.8, 138.6 (d, J = 3.3),
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99.0, 56.0, 42.8. [α]D = +30 (c = 1.0 in CH3OH). The
enantiomers were analyzed by HPLC using Daicel Chiralpak
IA column at 254 nm (n-hexane/i-PrOH = 80/20), 1.0 mL/min;
Major enantiomer: tR = 31.8 min, minor enantiomer: tR = 61.5
min. 98% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for
C23H18F3NO3Na 436.1131; Found 436.1133.
(R)-5-((2-hydroxy-3-methoxyphenyl)(4-(trifluoromethyl)-
phenyl)methyl)-1H-indol-4-ol (3oa). Compound was isolated
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The Journal of Organic Chemistry
as colorless oil (37.2 mg, 90% yield) after flash column
(s, 1H), 3.91 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
146.8, 146.5, 143.1, 140.5, 136.7, 133.4, 132.2, 129.1, 128.2,
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chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (500 MHz, CDCl3) δ 8.15 (s, 1H), 7.55 (d, J = 8.2
Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.10 (dd, J = 3.3, 2.4 Hz,
1H), 6.93 (dd, J = 8.5, 1.0 Hz, 1H), 6.86 – 6.79 (m, 2H), 6.75
(d, J = 8.4 Hz, 1H), 6.64 (dd, J = 6.8, 2.5 Hz, 1H), 6.58 (p, J =
1.0 Hz, 1H), 6.29 (s, 1H), 5.69 (s, 1H), 3.88 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 147.5, 146.5, 146.5, 143.1, 136.6,
129.6, 128.7, 128.3 (q, J = 32.2 Hz), 125.0 (q, J = 3.7 Hz, 2C),
124.4 (q, J = 272.0 Hz), 124.3, 123.4, 122.2, 119.8, 118.4,
127.9, 127.9, 127.5, 127.3, 125.8, 125.5, 124.7, 123.2, 122.5,
30
119.7, 118.4, 118.2, 109.0, 103.8, 99.3, 56.0, 43.4. [α]D
=
+57 (c = 1.0 in CH3OH). The enantiomers were analyzed by
HPLC using Daicel Chiralpak IC column at 296 nm (n-
hexane/i-PrOH = 90/10), 1.0 mL/min; Major enantiomer: tR =
19.7 min, minor enantiomer: tR = 27.9 min. 98% ee. HRMS
(ESI) m/z: [M + Na]+ Calcd for C26H21NO3Na 418.1414;
Found 418.1412.
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117.8, 109.2, 104.0, 99.0, 56.0, 43.0. [α]D = +26 (c = 1.0 in
(R)-5-(furan-2-yl(2-hydroxy-3-methoxyphenyl)methyl)-1H-
indol-4-ol (3sa). Compound was isolated as a colorless oil
(26.2 mg, 78% yield) after flash column chromatography on
silica-gel (petroleum ether: EtOAc = 4:1). 1H NMR (600 MHz,
CDCl3) δ 8.12 (s, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.08 (t, J =
2.8 Hz, 1H), 7.00 – 6.92 (m, 2H), 6.88 – 6.82 (m, 2H), 6.77
(dd, J = 7.5, 2.0 Hz, 1H), 6.67 – 6.60 (m, 1H), 6.36 (dd, J =
3.0, 1.9 Hz, 1H), 6.23 (s, 1H), 6.16 (s, 1H), 6.15 – 6.08 (m,
2H), 3.86 (d, J = 1.2 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 155.9, 146.6, 146.4, 142.3, 141.9, 136.7, 127.7,
123.5, 123.2, 121.4, 120.1, 118.6, 116.5, 110.1, 109.1, 108.4,
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CH3OH). The enantiomers were analyzed by HPLC using
Daicel Chiralpak IA column at 300 nm (n-hexane/i-PrOH =
80/20), 1.0 mL/min; Major enantiomer: tR = 25.5 min, minor
enantiomer: tR = 33.5 min. 98% ee. HRMS (ESI) m/z: [M +
Na]+ Calcd for C23H18F3NO3Na 436.1131; Found 436.1130.
(R)-5-([1,1'-biphenyl]-4-yl(2-hydroxy-3-methoxyphenyl)-
methyl)-1H-indol-4-ol (3pa). Compound was isolated as a
colorless oil (38.3 mg, 91% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (600 MHz, CDCl3) δ 8.17 (s, 1H), 7.65 – 7.61 (m,
2H), 7.56 (d, J = 8.2 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.35
(dd, J = 18.2, 7.6 Hz, 3H), 7.10 (t, J = 2.8 Hz, 1H), 6.94 (d, J
= 8.4 Hz, 1H), 6.85 (dd, J = 16.9, 8.2 Hz, 2H), 6.81 (dd, J =
8.1, 1.9 Hz, 1H), 6.75 (dd, J = 7.5, 1.8 Hz, 1H), 6.62 (d, J =
2.7 Hz, 1H), 6.27 (s, 1H), 6.01 (s, 1H), 5.74 (s, 1H), 3.90 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 146.7, 146.5, 143.1,
142.1, 141.0, 139.1, 136.7, 129.7, 129.3, 128.7, 127.1, 127.1,
127.0, 124.6, 123.3, 122.4, 119.7, 118.5, 118.4, 109.0, 103.9,
30
104.1, 99.4, 56.0, 37.6. [α]D = -8 (c = 1.0 in CH3OH). The
enantiomers were analyzed by HPLC using Daicel Chiralpak
ID column at 288 nm (n-hexane/i-PrOH = 80/20), 1.0 mL/min;
Major enantiomer: tR =30.0 min, minor enantiomer: tR = 49.7
min. 94% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for
C20H17F3NO4Na 358.1050; Found 358.1051.
(R)-5-((2-hydroxy-3-methoxyphenyl)(thiophen-2-yl)methyl)-
1H-indol-4-ol (3ta). Compound was isolated as colorless oil
(29.8 mg, 85% yield) after flash column chromatography on
silica-gel (petroleum ether: EtOAc = 4:1). 1H NMR (600 MHz,
CDCl3) δ 8.12 (s, 1H), 7.24 (dd, J = 5.1, 1.2 Hz, 1H), 7.09 (t,
J = 2.9 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.97 (dd, J = 5.1,
3.5 Hz, 1H), 6.95 – 6.90 (m, 2H), 6.86 – 6.83 (m, 2H), 6.79
(dd, J = 8.1, 1.5 Hz, 1H), 6.64 – 6.59 (m, 1H), 6.40 (s, 1H),
6.07 (s, 1H), 6.00 (s, 1H), 3.88 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 147.5, 146.5, 146.3, 142.4, 136.7, 129.6,
126.5, 126.5, 124.5, 123.8, 123.3, 121.6, 119.9, 118.6, 118.5,
109.1, 104.0, 99.4, 56.0, 38.6. [α]D30 = -9 (c = 1.0 in CH3OH).
The enantiomers were analyzed by HPLC using Daicel
Chiralpak ID column at 300 nm (n-hexane/i-PrOH = 80/20),
1.0 mL/min; Major enantiomer: tR = 29.7 min, minor
enantiomer: tR = 53.2 min. 91% ee. HRMS (ESI) m/z: [M +
Na]+ Calcd for C20H17NO3SNa 374.0821; Found 374.0830.
(R)-4-((2-hydroxy-3-methoxyphenyl)(phenyl)methyl)-1H-
indol-5-ol (3ab). Compound was isolated as a colorless oil
(21.7 mg, 63% yield) after flash column chromatography on
silica-gel (petroleum ether: EtOAc = 5:1). 1H NMR (500 MHz,
Chloroform-d) δ 8.03 (s, 1H), 7.33 – 7.29 (m, 2H), 7.28 – 7.25
(m, 3H), 7.19 (dd, J = 8.6, 1.0 Hz, 1H), 7.04 (t, J = 2.9 Hz,
1H), 6.88 (dd, J = 6.4, 3.0 Hz, 1H), 6.84 – 6.79 (m, 3H), 6.38
(s, 1H), 6.23 (ddd, J = 3.2, 2.0, 0.9 Hz, 1H), 6.00 (s, 1H), 5.27
(s, 1H), 3.88 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
148.0, 146.5, 143.4, 141.7, 131.3, 128.8, 128.5, 128.4, 127.9,
126.5, 124.3, 122.4, 119.9, 118.9, 113.8, 110.7, 109.2, 101.9,
56.0, 43.5. [α]D30 = +65 (c = 1.0 in CH3OH). The enantiomers
were analyzed by HPLC using Daicel Chiralpak IC column at
300 nm (n-hexane/i-PrOH = 90/10), 1.0 mL/min; Major
enantiomer: tR = 41.3 min, minor enantiomer: tR = 36.7 min.
90% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for C22H19NO3Na
368.1257; Found 368.1260.
30
99.2, 56.0, 43.0. [α]D = +46 (c = 1.0 in CH3OH). The
enantiomers were analyzed by HPLC using Daicel Chiralpak
IC column at 300 nm (n-hexane/i-PrOH = 80/20), 1.0 mL/min;
Major enantiomer: tR = 17.6 min, minor enantiomer: tR = 23.0
min. 97% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for
C28H23NO3Na 444.1570; Found 444.1571.
(R)-5-((2-hydroxy-3-methoxyphenyl)(naphthalen-1-yl)-
methyl)-1H-indol-4-ol (3qa). Compound was isolated as a
colorless oil (35.6 mg, 90% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (600 MHz, CDCl3) δ 8.14 (s, 1H), 8.07 (d, J = 8.4
Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H),
7.44 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.17
(d, J = 7.1 Hz, 1H), 7.08 (dd, J = 3.3, 2.4 Hz, 1H), 6.88 (s,
1H), 6.85 (dd, J = 8.4, 0.9 Hz, 1H), 6.80 (dd, J = 8.1, 1.5 Hz,
1H), 6.75 (t, J = 8.0 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.62 –
6.54 (m, 2H), 5.89 (s, 1H), 5.39 (s, 1H), 3.89 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 146.5, 146.4, 143.1, 139.1, 136.7,
134.1, 132.1, 129.2, 128.6, 127.4, 126.4, 126.1, 125.4, 125.3,
124.7, 124.6, 123.2, 122.7, 119.4, 118.3, 118.0, 109.0, 103.8,
33
98.9, 56.0, 40.1. [α]D = +39 (c = 1.0 in CH3OH). The
enantiomers were analyzed by HPLC using Daicel Chiralpak
IC column at 300 nm (n-hexane/i-PrOH = 80/20), 1.0
mL/min; Major enantiomer: tR = 38.6 min, minor enantiomer:
tR = 55.9 min. 98% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for
C26H21NO3Na 418.1414; Found 418.1421.
(R)-5-((2-hydroxy-3-methoxyphenyl)(naphthalen-2-yl)-
methyl)-1H-indol-4-ol (3ra). Compound was isolated as a
colorless oil (30.0 mg, 76% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (600 MHz, CDCl3) δ 8.15 (s, 1H), 7.85 – 7.77 (m,
2H), 7.74 – 7.70 (m, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.47 – 7.40
(m, 3H), 7.12 (t, J = 2.8 Hz, 1H), 6.93 (dd, J = 8.4, 1.0 Hz,
1H), 6.84 – 6.79 (m, 3H), 6.72 (dd, J = 5.6, 3.7 Hz, 1H), 6.61
(ddd, J = 3.2, 2.1, 0.9 Hz, 1H), 6.35 (s, 1H), 5.96 (s, 1H), 5.65
(R)-4-((2-hydroxy-3-methoxyphenyl)(m-tolyl)methyl)-1H-
indol-5-ol (3bb). Compound was isolated as a colorless oil
(28.0 mg, 78% yield) after flash column chromatography on
ACS Paragon Plus Environment

The Journal of Organic Chemistry
silica-gel (petroleum ether: EtOAc = 5:1). 1H NMR (500 MHz,
(R)-6-((2-hydroxy-3-methoxyphenyl)(2-(trifluoromethyl)-
Page 10 of 12
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CDCl3) δ 8.04 (s, 1H), 7.22 – 7.15 (m, 2H), 7.11 – 7.03 (m,
4H), 6.87 (dd, J = 5.9, 3.5 Hz, 1H), 6.83 – 6.79 (m, 3H), 6.34
(s, 1H), 6.30 – 6.26 (m, 1H), 5.98 (s, 1H), 5.23 (s, 1H), 3.88 (s,
3H), 2.28 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 148.1,
146.4, 143.34, 141.6, 138.3, 131.2, 129.5, 128.5, 128.5, 128.0,
127.5, 125.6, 124.3, 122.4, 119.9, 118.9, 113.8, 110.6, 109.2,
101.7, 77.3, 56.0, 43.6, 21.5. [α]D30 = +71 (c = 1.0 in CH3OH).
The enantiomers were analyzed by HPLC using Daicel
Chiralpak ID column at 324 nm (n-hexane/i-PrOH = 80/20),
1.0 mL/min; Major enantiomer: tR = 14.6 min, minor
enantiomer: tR = 27.7 min. 93% ee. HRMS (ESI) m/z: [M +
Na]+ Calcd for C23H21NO3Na 382.1414; Found 382.1415.
(R)-4-((4-chlorophenyl)(2-hydroxy-3-methoxyphenyl)-
phenyl)methyl)-1H-indol-7-ol (3cc). Compound was isolated
as a colorless oil (32.2 mg, 78% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 4:1).
1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 7.73 (dd, J = 7.8,
1.6 Hz, 1H), 7.48 – 7.43 (m, 1H), 7.39 – 7.32 (m, 2H), 7.19 –
7.08 (m, 2H), 6.82 (dd, J = 8.1, 1.6 Hz, 1H), 6.78 (t, J = 7.9
Hz, 1H), 6.56 (d, J = 8.3 Hz, 1H), 6.53 (s, 1H), 6.49 – 6.43 (m,
2H), 5.90 (s, 1H), 5.69 (s, 1H), 3.86 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 146.6, 143.2, 141.3, 139.1, 131.9, 131.6,
128.9, 128.7 (q, J = 29.7 Hz), 128.4, 127.0, 126.6, 126.3 (q, J
= 6.1 Hz), 124.6 (q, J = 274.6 Hz), 124.3, 121.8, 121.5, 120.6,
119.3, 112.8, 109.5, 102.6, 56.0, 40.2. [α]D30 = +39 (c = 1.0 in
CH3OH). The enantiomers were analyzed by HPLC using
Daicel Chiralpak ID column at 292 nm (n-hexane/i-PrOH =
80/20), 1.0 mL/min; Major enantiomer: tR = 17.1 min, minor
enantiomer: tR = 14.3 min. 88% ee. HRMS (ESI) m/z: [M +
Na]+ Calcd for C23H18F3NO3Na 436.1131; Found 436.1134.
(R)-3-((2-hydroxy-3-methoxyphenyl)(phenyl)methyl)-9H-
carbazol-4-ol (3ae). Compound was isolated as a colorless oil
(29.6 mg, 75% yield) after flash column chromatography on
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methyl)-1H-indol-5-ol (3cb). Compound was isolated as
colorless oil (28.4 mg, 75% yield) after flash column
chromatography on silica-gel (petroleum ether: EtOAc = 5:1).
1H NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 7.27 – 7.23 (m,
2H), 7.18 (dd, J = 2.5, 0.9 Hz, 2H), 7.17 – 7.16 (m, 1H), 7.03
(t, J = 2.9 Hz, 1H), 6.85 (dd, J = 6.6, 2.9 Hz, 1H), 6.83 – 6.79
(m, 3H), 6.33 (s, 1H), 6.14 (ddd, J = 3.2, 2.1, 0.9 Hz, 1H),
6.09 (s, 1H), 5.42 (d, J = 32.1 Hz, 1H), 3.87 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 147.7, 146.5, 143.3, 140.4, 132.0,
131.4, 130.2, 128.4, 128.2, 127.7, 124.4, 122.2, 120.0, 118.6,
113.7, 110.8, 109.3, 101.9, 56.0, 42.8. [α]D30 = +77 (c = 1.0 in
CH3OH). The enantiomers were analyzed by HPLC using
Daicel Chiralpak ID column at 320 nm (n-hexane/i-PrOH =
80/20), 1.0 mL/min; Major enantiomer: tR = 12.8 min, minor
enantiomer: tR = 20.2 min. 92% ee. HRMS (ESI) m/z: [M +
Na]+ Calcd for C22H18ClNO3Na 402.0867; Found 402.0869.
(R)-6-((2-hydroxy-3-methoxyphenyl)(phenyl)methyl)-1H-
indol-7-ol (3ac). Compound was isolated as colorless oil (30.7
mg, 89% yield) after flash column chromatography on silica-
1
silica-gel (petroleum ether: EtOAc = 5:1). H NMR (500
MHz, CDCl3) δ 8.30 (d, J = 7.8 Hz, 1H), 7.97 (s, 1H), 7.39 –
7.32 (m, 4H), 7.32 – 7.27 (m, 3H), 7.23 (ddd, J = 8.1, 6.8, 1.3
Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H),
6.85 – 6.78 (m, 2H), 6.74 (dd, J = 7.5, 1.8 Hz, 1H), 6.21 (s,
1H), 6.04 (s, 2H), 3.88 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 150.1, 146.5, 143.0, 142.2, 140.2, 139.2, 129.3,
128.6, 128.4, 127.9, 126.5, 124.9, 122.9, 122.7, 122.2, 119.9,
30
119.4, 119.3, 112.7, 109.9, 109.1, 102.9, 56.0, 43.5. [α]D
=
+29 (c = 1.0 in CH3OH). The enantiomers were analyzed by
HPLC using Daicel Chiralpak ID column at 300 nm (n-
hexane/i-PrOH = 80/20), 1.0 mL/min; Major enantiomer: tR =
20.1 min, minor enantiomer: tR = 23.2 min. 96% ee. HRMS
(ESI) m/z: [M + Na]+ Calcd for C26H21NO3Na 418.1414;
Found 418.1415.
1
gel (petroleum ether: EtOAc = 4:1). H NMR (500 MHz,
CDCl3) δ 8.42 (s, 1H), 7.36 – 7.29 (m, 2H), 7.27 (dd, J = 8.0,
2.2 Hz, 3H), 7.20 – 7.09 (m, 2H), 6.85 – 6.78 (m, 2H), 6.77 –
6.71 (m, 2H), 6.49 (t, J = 2.6 Hz, 1H), 6.14 (s, 1H), 6.06 (s,
1H), 5.88 (s, 1H), 3.89 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 146.4, 142.8, 142.2, 139.8, 129.2, 128.9, 128.5,
128.3, 127.1, 126.4, 124.0, 122.3, 122.0, 121.0, 120.1, 113.1,
109.0, 102.6, 56.0, 43.6. [α]D30 = +13 (c = 1.0 in CH3OH). The
enantiomers were analyzed by HPLC using Daicel Chiralpak
ID column at 292 nm (n-hexane/i-PrOH = 80/20), 1.0 mL/min;
Major enantiomer: tR = 18.7 min, minor enantiomer: tR = 21.5
min. 86% ee. HRMS (ESI) m/z: [M + Na]+ Calcd for
C22H19NO3Na 368.1257; Found 368.1258.
(R)-6-((2-ethylphenyl)(2-hydroxy-3-methoxyphenyl)-methyl)-
1H-indol-7-ol (3bc). Compound was isolated as colorless oil
(24.2 mg, 65% yield) after flash column chromatography on
silica-gel (petroleum ether: EtOAc = 4:1). 1H NMR (500 MHz,
CDCl3) 8.40 (s, 1H), 7.29 – 7.23 (m, 3H), 7.16 – 7.10 (m, 3H),
7.04 – 7.01 (m, 1H), 6.83 – 6.76 (m, 2H), 6.59 – 6.54 (m, 2H),
6.48 (dd, J = 3.1, 2.1 Hz, 1H), 6.25 (s, 1H), 5.90 (s, 1H), 5.34
(s, 1H), 3.89 (s, 3H), 2.62 (qd, J = 7.4, 4.8 Hz, 2H), 1.16 (t, J
= 7.5 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.5,
143.2, 142.9, 139.9, 139.6, 128.8, 128.7, 128.7, 128.6, 127.0,
127.0, 125.9, 124.0, 122.5, 121.9, 120.7, 119.6, 112.9, 109.2,
102.6, 56.0, 40.7, 25.4, 14.6. [α]D30 = +30 (c = 1.0 in CH3OH).
The enantiomers were analyzed by HPLC using Daicel
Chiralpak ID column at 288 nm (n-hexane/i-PrOH = 80/20),
1.0 mL/min; Major enantiomer: tR = 16.5 min, minor
enantiomer: tR = 13.9 min. 92% ee. HRMS (ESI) m/z: [M +
Na]+ Calcd for C24H23NO3Na 396.1570; Found 396.1572.
Procedure for Preparation of compound 4.9a Compound
3aa (34.5 mg, 0.1 mmol) and 4-dimethylaminopyridine (73.4
mg, 0.6 mmol, 6.0 eq) were placed in a 10 mL round
bottomed flask. Then, the flask was purged with N2 and
CH2Cl2 (4 mL) was added. After 5 minutes, N-Phenyl-
bis(trifluoromethanesulfonimide) (142.8 mg, 0.4 mmol, 4.0 eq)
was added and the mixture was stirred at room temperature.
The reaction was monitored by thin layer chromatography
eluting with CH2Cl2. When the starting material was
consumed, H2O was added (5 mL) and the mixture was
extracted with EtOAc (3 x 15 mL). The combined organic
phases was concentrated in vacuo and purified by the flash
column chromatography on silica-gel (CH2Cl2) to afford the
compound 4 (77% yield ).
(R)-5-((3-methoxy-2-(((trifluoromethyl)sulfonyl)oxy)phen-
yl)(phenyl)methyl)-1H-indol-4-yl trifluoromethanesulfonate (4)
Compound was isolated as white foamy solid (46.9 mg, 77%
yield) after flash column chromatography on silica-gel
(CH2Cl2 as eluent), mp 62-65 oC. 1H NMR (600 MHz, CDCl3)
δ 8.36 (s, 1H), 7.31 (td, J = 8.0, 7.5, 2.0 Hz, 2H), 7.29 – 7.25
(m, 1H), 7.24 – 7.17 (m, 3H), 7.15 – 7.08 (m, 2H), 6.96 (dd, J
= 8.3, 1.6 Hz, 1H), 6.75 (dd, J = 8.5, 1.9 Hz, 1H), 6.71 (d, J =
2.9 Hz, 1H), 6.55 (dd, J = 8.0, 1.6 Hz, 1H), 6.39 (s, 1H), 3.90
(s, 3H). 13C{1H} (151 MHz, CDCl3) δ 151.2, 141.4, 139.0,
137.4, 137.2, 137.0, 129.3, 128.3, 128.0, 126.9, 126.2, 125.4,
124.7, 121.9, 118.7 (q, J = 321.0 Hz), 118.6 (q, J = 320.0 Hz),
30
111.7, 111.2, 100.3, 56.1 43.7. [α]D = +71 (c = 1.0 in
CH3OH). The enantiomers were analyzed by HPLC using
ACS Paragon Plus Environment

Page 11 of 12
The Journal of Organic Chemistry
Crafts Alkylation of Indoles with γ-Hydroxy-γ-lactams. Adv. Synth.
Catal. 2013, 355, 836; (b) Hatano, M.; Mochizuki, T.; Nishikawa, K.;
Ishihara, K. Enantioselective aza-Friedel−Crafts Reaction of Indoles
Daicel Chiralpak AD-H column at 254 nm (n-hexane/i-PrOH
1
2
3
4
5
6
7
8
= 97/3), 1.0 mL/min; Major enantiomer: tR = 20.5 min, minor
enantiomer: tR = 23.2 min. 95% ee. HRMS (ESI) m/z: [M +
Na]+ Calcd for C24H17F6NO7S2Na 632.0243; Found 632.0241.
with
Ketimines
Catalyzed
by
Chiral
Potassium
Binaphthyldisulfonates. ACS Catal. 2017, 8, 349; (c) Qi, L. W.; Mao,
J. H.; Zhang, J.; Tan, B. Organocatalytic Asymmetric Arylation of
Indoles Enabled by Azo Groups. Nat Chem. 2018, 10, 58; (d) Ibáñez,
I.; Kaneko, M.; Kamei, Y.; Tsutsumi, R.; Yamanaka, M.; Akiyama, T.
Enantioselective Friedel-Crafts Alkylation Reaction of Indoles with
α‑Trifluoromethylated β‑Nitrostyrenes Catalyzed by Chiral BINOL
Metal Phosphate. ACS Catal. 2019, 9, 6903; (e) Staleva, P.;
Hernández, J. G.; Bolm, C. Mechanochemical Copper-Catalyzed
Asymmetric Michael-Type Friedel-Crafts AlkylationofIndoles with
Arylidene Malonates. Chemistry. 2019, 25, 9202.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
9
Experimental procedures and characterization details (PDF)
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Accession Codes
(4) (a) Zeng, M.; Kang, Q.; He, Q.-L.; You, S.-L. Highly
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β,γ-Unsaturated α-Keto Esters by Chiral Brønsted Acids Adv. Synth.
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Q. Q.; Liu, X. P.; Li, Y.; Deng, Q. H.; Chen, J. R.; Xiao, W. J. Highly
Enantioselective Friedel-Crafts Alkylation/N-Hemiacetalization
Cascade Reaction with Indoles. Angew. Chem. Int. Ed. 2013, 52,
3250; (c) Zhang, Y.; Liu, X.; Zhao, X.; Zhang, J.; Zhou, L.; Lin, L.;
Feng, X. Enantioselective Friedel-Crafts Alkylation for Synthesis of
2-Substituted Indole Derivatives. Chem. Commun. 2013, 49, 11311;
(d) Bi, B.; Lou, Q. X.; Ding, Y. Y.; Chen, S. W.; Zhang, S. S.; Hu, W.
H.; Zhao, J. L. Chiral Phosphoric Acid Catalyzed Highly
Enantioselective Friedel-Crafts Alkylation Reaction of C3-
Substituted Indoles to β,γ-Unsaturated α‑Ketimino Esters. Org. Lett.
2015, 17, 540; (e) Weng, J.-Q.; Fan, R.-J.; Deng, Q.-M.; Liu, R.-R.;
Gao, J.-R.; Jia, Y.-X. Enantioselective Friedel-Crafts Alkylation
Reactions of 3‑Substituted Indoles with Electron-Deficient Alkenes.
J. Org. Chem. 2016, 81, 3023; (f) Wu, J.-L.; Wang, J.-Y.; Wu, P.;
Mei, G.-J.; Shi, F. Catalytic Asymmetric C2-Nucleophilic
Substitutions of C3-Substituted Indoles with ortho-Hydroxybenzyl
Alcohols. Org. Chem. Front. 2017, 4, 2465; (g) Zhou, Z.; Li, Y.;
Gong, L.; Meggers, E. Enantioselective 2‑Alkylation of 3‑Substituted
Indoles with Dual Chiral Lewis Acid/Hydrogen-Bond-Mediated
Catalyst. Org. Lett. 2017, 19, 222; (h) Huang, B.-B.; Wu, L.; Liu, R.-
R.; Xing, L.-L.; Liang, R.-X.; Jia, Y.-X. Enantioselective Friedel-
CCDC 1936470 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif,
or
by
emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: wangyifeng@zjut.edu.cn
*E-mail: chrc@zjut.edu.cn
ORCID
Yi-Feng Wang: 0000-0001-6585-4515
Dan-Qian Xu: 0000-0003-0152-0860
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The research was supported by The National Key Research and
Development Program of China (2017YFB0307200), National
Natural Science Foundation of China (21402176), Natural
Science Foundation of Zhejiang Province (LY14B020003).
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