Direct preparation of indole hemiaminals through organocatalytic nucleophilic addition of indole to aldehydes

Article abstract of DOI:10.1055/s-0037-1610453

Hemiaminals are common in natural products as well as bioactive compounds. Hemiaminals with an indole moiety are particularly attractive due to the significant bioactivity of indoles. Herein, we reported an efficient organocatalyzed indole N-1 nucleophilic addition of α-oxoaldehydes to deliver various indole hemiaminals in good yields (up to 92percent) and excellent regioselectivities with DABCO or triethylamine as the catalyst. The method is characterized by mild reaction conditions, widely available reagents, and general substrate scope, and it is also applicable to late-stage transformations without affecting the hemiaminal group. In addition, we carried out this reaction in an enantioselective fashion in good yields and high ee values with two general substrates.

Full text of DOI:10.1055/s-0037-1610453

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
N. Zhang et al.
Paper
Synthesis
Direct Preparation of Indole Hemiaminals through Organocatalytic
Nucleophilic Addition of Indole to Aldehydes
Nan Zhanga
Yige Lib
Zhili Chena
Wenling Qin*a
HO
R2
R1
1
R1
O
Organocatalysts
CH2Cl2, r.t., 12 h
NH
+
R2
N
H
O
2
0
0
0
0
0-
0
0
2
5-
6
5
4
5-
7
8
5
3
O
a Chongqing Key Laboratory of Natural Product Synthesis and
Drug Research, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. of China
wenling.qin@cqu.edu.cn
b Applied Chemistry, Department of Chemical Engineering,
Shenyang Institute of Science and Technology, Shenyang
110000, P. R. of China
* yields up to 92%
* readily available catalysts
* applicable in enantioselective fashion
* 26 examples
R1 = alkyl, halogen, cyanide
R2 = OEt, aryl
Received: 23.04.2018
Accepted after revision: 31.05.2018
Published online: 16.07.2018
numerous applications, examples of indole hemiaminal
synthesis have been seldom reported. Existing methods in-
volve the addition of formaldehyde to indole in moderate
yields.6 In another approach reported by the Fukuyama
group in 1998, indole hemiaminals were prepared by re-
duction of an N-acylindole.7 Alternatively, the deprotection
of N-[2-(trimethylsilyl)ethoxy]methylamine or benzy-
loxymethylamine occasionally generates hemiaminals as
byproducts.8 However, a more efficient protocol with wide
substrate scope is still in demand. We envisioned that the
direct nucleophilic addition of indole N-1 to an aldehyde
could be a straightforward approach to prepare indole
hemiaminals. It was documented that the nucleophilic ad-
dition reaction of indole often occurs at the N-1 and C-3 po-
sitions and that the C-3 position of an indole was the most
reactive one. The nucleophilic addition to an aldehyde usu-
ally occurs at the C-3 position of indole. A number of meth-
ods have been developed to give C-3 adducts, including
procedures with Lewis acids catalysts,9a,b catalyst-free,9c
aqueous buffered conditions,9d,e and cinchona-based cata-
lysts.9f While the addition of an aldehyde to the indole N-1
position for forming indole hemiaminals was limited to
formaldehyde. In this study, we aimed to develop an ap-
proach to prepare indole hemiaminals from indoles and a
wide range of α-oxoaldehydes with readily available cata-
lysts. We began our study with 1H-indole (1a) and ethyl
glyoxylate as the model substrates (Table 1). A series of
commercially easily available organic bases such as tri-
ethylamine, diisopropylamine, N,N′-tetramethylguanidine
(TMG), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were
tested at room temperature with diethyl ether as the sol-
vent. Among them, TMG and DBU gave moderate yields for
this transformation (Table 1, entries 3 and 4), whereas tri-
ethylamine and diisopropylamine gave poor yields (Table 1,
entries 1 and 2).
DOI: 10.1055/s-0037-1610453; Art ID: ss-2018-h0280-op
Abstract Hemiaminals are common in natural products as well as bio-
active compounds. Hemiaminals with an indole moiety are particularly
attractive due to the significant bioactivity of indoles. Herein, we re-
ported an efficient organocatalyzed indole N-1 nucleophilic addition of
α-oxoaldehydes to deliver various indole hemiaminals in good yields
(up to 92%) and excellent regioselectivities with DABCO or triethyl-
amine as the catalyst. The method is characterized by mild reaction
conditions, widely available reagents, and general substrate scope, and
it is also applicable to late-stage transformations without affecting the
hemiaminal group. In addition, we carried out this reaction in an enan-
tioselective fashion in good yields and high ee values with two general
substrates.
Key words organocatalysis, indole, hemiaminals, nucleophilic addi-
tion
Hemiaminals widely exist in numerous important natu-
ral products and pharmaceuticals, such as vincamine, vin-
deburnol, eburnaminol, and cladoniamide A. The hemiami-
nal motif is often crucial for their biological activities.1 Be-
sides, hemiaminals also act as versatile building blocks in
organic synthesis, especially the total synthesis of natural
products.2 The preparative methods for hemiaminals are
limited3 due to their lability. It is well known that hemiami-
nals are labile tetrahedral intermediates in the reaction of
an aldehyde carbonyl group with amines to afford Schiff
bases.4 To stabilize the corresponding hemiaminal, the cor-
rect substituent group on nitrogen atom is required. As spe-
cial nitrogen-substituted compounds, indoles are particu-
larly attractive substrates and the resulting indole hemiam-
inals have been reported to possess anti-tumor activity and
may serve as a self-cleavable linker for drug molecules to
improve their bioavailability.5 Despite their high benefits in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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N. Zhang et al.
Paper
Synthesis
Next, we evaluated another commonly used organic
base 1,4-diazabicyclo[2.2.2]octane (DABCO) as the catalyst.
Gratifyingly, the yield increased to 76% under mild reaction
conditions (Table 1, entry 5). The regioselectivity of this re-
action was excellent and the N-1 adduct of indole was
found to be the sole product. After identifying the best cata-
lyst, we started to evaluate the influence of the solvent on
this reaction.
denced by the high yields of 2c–e, 2g,h, 2j,k, 2n,o. Notably,
a C-2 substituted indole also reacted successfully with ethyl
glyoxylate to give the desired product 2p.
Inspired by the good substrate scope of indoles, we then
examined the scope of α-oxoaldehydes in the reaction with
indoles (Scheme 2). We chose a series of substituted benzo-
ylaldehydes to carry out the reaction. Instead of DABCO,
Et3N was used as the reaction catalyst due to its better per-
formance with respect to yield. The substrates with elec-
tron-donating substituents on the benzene ring were suc-
cessfully converted into the desired hemiaminal-containing
products 4a–g in good yields and excellent regioselectivi-
ties.
Table 1 Optimization of Reaction Conditionsa
HO
H
O
O
N
base (20 mol%)
CH2Cl2, 12 h
OEt
N
+
H
OEt
The structure of 4a was confirmed by X-ray crystallog-
raphy. 1-(4-Fluorophenyl)ethane-1,2-dione containing an
electron-withdrawing fluoro substitution group in the para
position was also tolerated under our reaction condition
and the product 4i was observed in high yield and excellent
regioselectivity. Particularly, the naphthoyl-substituted al-
dehyde was then investigated under the standard condi-
tions and the corresponding indole hemiaminal 4h was ob-
tained in 80% yield. 1-(1-Methyl-1H-pyrrol-2-yl)ethane-
1,2-dione was also used as the reaction partner with indole
to deliver the corresponding product 4j in excellent yield
(87%) and regioselectivity. These results indicated that the
nature or position of the substituted groups did not dra-
matically influence the performance of the reaction.
It is well known that the hemiaminal moiety is labile
under various reaction conditions, and it is readily decom-
posed to give aldehyde or ketones. Therefore, it is consid-
ered as a masked carbonyl compound.10 In order to further
demonstrate the synthetic potential of our reaction, a
transformation was performed on 2a to test the tolerance of
the indole hemiaminal moiety under classical reaction con-
ditions. After a typical silyl ether protection of the free hy-
droxy group of 2a to give 5, the ethoxycarbonyl group of 5
was reduced without affecting the stability of the hemiami-
nal to provide alcohol 6 (Scheme 3).
Since the addition of indole N-1 to aldehydes had been
developed as a preparative method for indole hemiaminals,
we envisaged that it should be possible to carry out this
process in an enantioselective fashion. Utilizing recently
developed methodology in our group,11 we used easily ac-
cessible 1,1′-bi-2-naphthol (BINOL)-based polyether or-
ganocatalyst Cat-A and KF as the catalytic system. Gratify-
ingly, the reaction gave chiral 2a′ and 2b′ in good yields and
high ee values (Scheme 4). The further explorations of the
new catalyst and substrate scope is ongoing in our laborato-
ry.
O
1a
2a
Entries
Base (20 mol%)
Temp (°C)
Solvent (1.0 mL) Yield (%)b
1
2
Et3N
25
25
25
25
25
25
25
25
0
Et2O
<5
i-Pr2NH
TMG
Et2O
trace
43
69
76
82
59
60
57
57
48
3
Et2O
4
DBU
Et2O
5
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
Et2O
6
CH2Cl2
THF
7
8
toluene
CH2Cl2
CH2Cl2
CH2Cl2
9
10c
11d
25
25
a Reaction conditions: 1a (0.1 mmol), ethyl glyoxylate (50% in toluene)
(0.15 mmol), base (20 mol%), solvent (1.0 mL), 12 h; unless otherwise stat-
ed
b Isolated yield.
c CH2Cl2 (1.5 mL).
d CH2Cl2 (0.75 mL).
Dichloromethane was demonstrated to be the best sol-
vent compared to diethyl ether, THF, and toluene. Further
screening of reaction conditions including temperature (Ta-
ble 1, entry 9) and the amount of solvent (Table 1, entries
10 and 11) did not improve the results. The best reaction
conditions were identified as DABCO as the catalyst and
CH2Cl2 as the solvent at room temperature for 12 h (Table 1,
entry 6). As shown in Scheme 1, indoles with electron-do-
nating substituents on the indole benzene ring were suc-
cessfully converted into the desired indole hemiaminal
products 2c–e in high yields and excellent regioselectivities.
Indoles with electron-withdrawing groups such as ester,
fluoro, chloro, bromo, and cyano also allowed smooth reac-
tion to afford the corresponding substituted indole hemi-
aminals 2f–o in 78–91% yields. Moreover, disubstituted in-
doles also reacted smoothly to furnish the adducts 2i and 2l
in moderate to high yields. Furthermore, the position of the
substitution had little effect on this transformation, as evi-
In summary, we have developed an efficient method for
the preparation of indole hemiaminals in good yields (up to
92%) and excellent regioselectivities with readily available
DABCO or triethylamine as the catalysts. A series of substi-
tuted indoles with electron-donating groups, electron-
withdrawing groups, and disubstituted groups were well
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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N. Zhang et al.
Paper
Synthesis
HO
N
O
O
DABCO (20 mol%)
CH2Cl2, 12 h
NH
OEt
+
H
OEt
R1
R2
R1
O
R2
2
1
HO
HO
N
HO
N
HO
O
O
O
O
O
N
N
OEt
OEt
OEt
OEt
O
2a, 82% yield
2b, 87% yield
2c, 86% yield
2d, 82% yield
HO
O
HO
N
F
O
HO
N
HO
N
O
O
O
OEt
N
OEt
F
O
OEt
OEt
O
2e, 81% yield
2f, 82% yield
2g, 84% yield
2h, 87% yield
F
HO
Cl
Cl
HO
HO
N
HO
O
O
O
O
OEt
F
N
Cl
Cl
N
N
OEt
OEt
OEt
2i, 91% yield
2j, 86% yield
2k, 90% yield
2l, 78% yield
Br
HO
HO
HO
HO
O
O
O
O
N
NC
N
N
N
OEt
OEt
OEt
OEt
Ph
2p, 58% yield
NC
2m, 84% yield
2n, 85% yield
2o, 89% yield
Scheme 1 Reaction scope of various indoles with ethyl 2-oxoacetate. Reagents and conditions: 1 (0.1 mmol), ethyl glyoxylate (50% in toluene) (0.15
mmol), DABCO (20 mol%), CH2Cl2 (1.0 mL), 25 °C, 12 h (isolated yields are given).
O
OH
H
R3
Et3N (20 mol%)
CH2Cl2
R3
N
+
N
H
O
O
3
4
1a
OH
OH
OH
N
N
N
O
O
O
CCDC:1832241
4a, 92% yield
4b, 83% yield
4c, 81% yield
O
OH
OH
N
OH
N
OH
N
N
O
O
O
O
O
4d, 86% yield
4e, 80% yield
4f, 89% yield
4g, 85% yield
F
OH
OH
OH
N
N
N
N
O
O
O
4h, 80% yield
4i, 83% yield
4j, 87% yield
Scheme 2 Reaction scope of indole with α-oxoaldehydes. Reagents and conditions: 3 (0.1 mmol), 1H-indole (1a; 0.1 mmol), Et3N (20 mol%), CH2Cl2 (1.0
mL), 25 °C, 12 h (isolated yields are given).
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Synthesis
HO
N
TBSO
TBSO
N
O
O
TBS-Cl, Et3N
DMAP, THF
LiAlH4, Et2O
r.t.
N
OEt
OEt
OH
2a
5
6
Scheme 3 Synthetic transformations of an indole hemiaminal
HO
O
HPLC analysis on a Hitachi Chromaster using Daicel Chiralcel AD-H,
4.6 mm i.d. × 250 mm. All reactions were carried out under N2 atmo-
sphere in oven-dried glassware with magnetic stirring. Unless other-
wise stated, all solvents employed in the reactions were distilled from
appropriate drying agents prior to use.
O
∗
Cat-A (10 mol%), KF
NH
OEt
N
+
H
OEt
Et2O, 12 h
O
R4
R4
1
2
2a': R4 = H, 84% yield, 85% ee
2b': R4 = Me, 90% yield, 91% ee
Ethyl 2-Hydroxy-2-(1H-indol-1-yl)acetates 2a–p; General Proce-
dure
A flame-dried Schlenk tube equipped with a magnetic stirring bar
was charged with 1 (0.1 mmol) and DABCO (20 mol%), these were
then dissolved in CH2Cl2 (1.0 mL). Ethyl glyoxylate (50% in toluene)
(0.15 mmol) was injected into the tube at 25 °C. After stirring for 12 h,
the mixture was purified by chromatography (silica gel, PE/EtOAc 5:1)
to afford 2.
Cat-A:
Ph
O
Ph
O
I
I
O
O
OH
HO
I
I
Arylglyoxal Monohydrate 3
To a 50-mL three-neck flask with a condenser was added 1,4-dioxane
(12.5 mL), SeO2 (2.75 g, 0.25 mol), and water (1.5 mL). The mixture
was heated at 50–55 °C and stirred until the solid was dissolved, then
acetophenone (0.25 mol) was added and the mixture was refluxed for
4 h. The solid was removed by filtration, the filtrate was concentrated.
The residue was purified by column chromatography (silica gel, ace-
tone/hexane 1:10) to give 3.
Scheme 4 Enantioselective synthesis of indole hemiaminals
tolerated under our reaction conditions. Moreover, α-oxoal-
dehydes bearing substitution with different natures are also
excellent reaction partners of indole to afford correspond-
ing indole hemiaminals in high yields and excellent N-1 re-
gioselectivity. The prominent features of this transforma-
tion include mild reaction conditions, general substrate
scope, good functional group tolerance, and readily avail-
able starting materials. Moreover, the further transforma-
tion of the product without affecting the hemiaminal group
makes this method extremely attractive. Furthermore, we
have achieved an organocatalytic enantioselective reaction
for the preparation of chiral indole hemiaminals in good
yields and high ee values. Further exploration of this enan-
tioselective reaction is currently underway in our group.
1-Aryl-2-hydroxy-2-(1H-indol-1-yl)ethan-1-ones 4a–j; General
Procedure
A flame-dried Schlenk tube equipped with a magnetic stirring bar,
was charged with 3 (0.1 mmol) and 1a (0.1 mmol), these were then
dissolved in CH2Cl2 (1.0 mL). Et3N (20 mol%) was injected into the
tube at 25 °C. After stirring for 12 h, the mixture was purified by
chromatography (silica gel, PE/CH2Cl2/EtOAc 3:1:0.2) to afford 4.
Ethyl 2-Hydroxy-2-(1H-indol-1-yl)acetate (2a)
Colorless oil; yield: 17.9 mg (82%).
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 7.6 Hz, 1 H), 7.38 (d, J = 8.0
Hz, 1 H), 7.19 (t, J = 7.4 Hz, 1 H), 7.15–7.05 (m, 2 H), 6.51 (s, 1 H), 6.03
(d, J = 5.9 Hz, 1 H), 4.42 (d, J = 6.1 Hz, 1 H), 4.18 (dp, J = 24.7, 7.3 Hz, 2
H), 1.12 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.58, 135.34, 129.19, 125.31,
122.32, 121.06, 120.47, 109.77, 103.65, 76.40, 63.03, 13.79.
HRMS (ESI): m/z [M + Na]+ calcd for C12H13NNaO3: 242.0787; found:
242.0788.
All reagents were obtained from Adamas, Aladin, Accela, or Acros and
used without further purification unless otherwise noted. The prod-
ucts were purified by column chromatography with Huanghai Silica
Gel 50–75 μm, ultrapure silica gel. 1H and 13C NMR spectra were re-
corded on an Agilent 400MR DD2 (400 MHz) or Agilent 600MR DD2
(600 MHz) spectrometer. Chemical shifts are reported referenced to
TMS or the residual solvent peak was used as an internal reference;
1H (TMS δ = 0.00), 13C (CDCl3 δ = 77.00). HRMS were performed on a
Bruker solarix 7.0T. X-ray crystallography analysis of single crystals
was performed on an Agilent SuperNova-CCD X-Ray diffractometer.
Melting points were measured using SGWX-4A Microscopic melting
point meter and are uncorrected. No melting points were reported for
amorphous solids. Enantiomeric excesses (ee) were determined by
2a′
HPLC analysis (Chiralcel AD-H, hexane/i-PrOH = 80:20, flow rate = 1.0
mL/min, λ = 254 nm): tR = 6.571 (major), 7.808 min (minor); yield:
84%; 85% ee.
Ethyl 2-Hydroxy-2-(3-methyl-1H-indol-1-yl)acetate (2b)
Yellow oil; yield: 20.3 mg (87%).
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N. Zhang et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 7.7 Hz, 1 H), 7.27 (d, J = 8.1
Hz, 1 H), 7.12 (t, J = 7.6 Hz, 1 H), 7.05 (t, J = 7.4 Hz, 1 H), 6.78 (s, 1 H),
5.93 (d, J = 6.3 Hz, 1 H), 4.26–4.02 (m, 3 H), 2.20 (s, 3 H), 1.08 (t, J = 6.8
Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C14H15NNaO5: 300.0842; found:
300.0841.
Ethyl 2-(5-Fluoro-1H-indol-1-yl)-2-hydroxyacetate (2g)
13C NMR (100 MHz, CDCl3): δ = 169.82, 135.82, 129.70, 122.53,
Light yellow oil; yield: 19.9 mg (84%).
122.33, 119.92, 119.15, 112.98, 109.54, 76.10, 62.98, 13.85, 9.51.
HRMS (ESI): m/z [M + Na]+ calcd for C13H15NNaO3: 256.0944; found:
256.0943.
1H NMR (400 MHz, CDCl3): δ = 7.28 (dd, J = 8.9, 4.2 Hz, 1 H), 7.23 (d, J =
9.3 Hz, 1 H), 7.12 (d, J = 2.9 Hz, 1 H), 6.92 (t, J = 8.7 Hz, 1 H), 6.46 (d, J =
3.0 Hz, 1 H), 5.98 (s, 1 H), 4.64 (s, 1 H), 4.29–4.08 (m, 2 H), 1.11 (t, J =
7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.17, 159.26, 156.92, 131.70,
129.63, 129.53, 127.19, 110.64, 110.55, 110.29, 105.90, 105.67,
103.35, 103.31, 76.66, 62.91, 13.58.
2b′
HPLC analysis (Chiralcel AD-H, hexane/i-PrOH = 80:20, flow rate = 1.0
mL/min, λ = 254 nm): tR = 6.518 (major), 7.957 min (minor); yield:
90%; 91% ee.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12FNNaO3: 260.0693; found:
260.0692.
Ethyl 2-Hydroxy-2-(4-methoxy-1H-indol-1-yl)acetate (2c)
Colorless oil; yield: 21.4 mg (86%).
Ethyl 2-(6-Fluoro-1H-indol-1-yl)-2-hydroxyacetate (2h)
1H NMR (400 MHz, CDCl3): δ = 6.97 (t, J = 7.9 Hz, 1 H), 6.87 (d, J = 8.2
Hz, 2 H), 6.51 (s, 1 H), 6.38 (d, J = 7.7 Hz, 1 H), 5.84 (d, J = 5.9 Hz, 1 H),
4.63 (d, J = 6.4 Hz, 1 H), 4.06–3.92 (m, 2 H), 3.74 (s, 3 H), 0.95 (t, J = 7.1
Hz, 3 H).
Colorless oil; yield: 20.6 mg (87%).
1H NMR (400 MHz, CDCl3): δ = 7.48 (dd, J = 8.6, 5.4 Hz, 1 H), 7.10 (d, J =
9.9 Hz, 1 H), 7.06 (d, J = 3.3 Hz, 1 H), 6.89 (td, J = 9.4, 2.0 Hz, 1 H), 6.47
(d, J = 3.1 Hz, 1 H), 5.95 (d, J = 6.5 Hz, 1 H), 4.62 (d, J = 6.5 Hz, 1 H), 4.18
(qt, J = 14.3, 5.3 Hz, 2 H), 1.12 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.24, 153.11, 136.63, 123.81,
123.08, 119.45, 103.12, 100.61, 100.32, 76.45, 62.69, 55.04, 13.58.
HRMS (ESI): m/z [M + Na]+ calcd for C13H15NNaO4: 272.0893; found:
272.0892.
13C NMR (100 MHz, CDCl3): δ = 169.29, 161.06, 158.69, 135.37,
125.81, 125.78, 125.56, 121.67, 109.25, 109.01, 103.64, 96.79, 96.52,
76.55, 63.14, 13.7.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12FNNaO3: 260.0693; found:
260.0692.
Ethyl 2-Hydroxy-2-(5-methoxy-1H-indol-1-yl)acetate (2d)
Light yellow oil; yield: 20.4 mg (82%).
1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 8.7 Hz, 1 H), 7.05 (d, J = 10.1
Hz, 2 H), 6.83 (d, J = 8.8 Hz, 1 H), 6.43 (s, 1 H), 5.97 (d, J = 5.2 Hz, 1 H),
4.59 (d, J = 6.1 Hz, 1 H), 4.19 (tt, J = 17.0, 9.1 Hz, 2 H), 3.78 (s, 3 H), 1.12
(t, J = 6.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.41, 154.45, 130.41, 129.72,
126.08, 112.23, 110.55, 103.19, 102.89, 76.64, 62.87, 55.63, 13.75.
Ethyl 2-(5,6-Difluoro-1H-indol-1-yl)-2-hydroxyacetate (2i)
Yellow oil; yield: 23.2 mg (91%).
1H NMR (400 MHz, CDCl3): δ = 7.31 (dd, J = 10.6, 7.7 Hz, 1 H), 7.21 (dd,
J = 10.9, 6.7 Hz, 1 H), 7.12 (d, J = 3.4 Hz, 1 H), 6.45 (d, J = 3.4 Hz, 1 H),
5.96 (d, J = 6.2 Hz, 1 H), 4.68 (d, J = 6.3 Hz, 1 H), 4.32–4.13 (m, 2 H),
1.15 (t, J = 7.1 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C13H15NNaO4: 272.0893; found:
272.0892.
13C NMR (100 MHz, CDCl3): δ = 169.16, 149.19, 149.04, 148.04,
147.89, 146.79, 146.63, 145.66, 145.51, 130.40, 126.88, 124.44,
107.60, 103.57, 98.48, 76.86, 63.31, 13.73.
HRMS (ESI): m/z [M + Na]+ calcd for C12H11F2NNaO3: 278.0599; found:
Ethyl 2-Hydroxy-2-(6-methoxy-1H-indol-1-yl)acetate (2e)
278.0598.
Brown oil; yield: 20.2 mg (81%).
1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.6 Hz, 1 H), 7.00 (d, J = 3.3
Hz, 1 H), 6.91 (s, 1 H), 6.81 (dd, J = 8.6, 2.0 Hz, 1 H), 6.47 (d, J = 3.3 Hz,
1 H), 6.03 (d, J = 6.9 Hz, 1 H), 4.37–4.18 (m, 3 H), 3.84 (s, 3 H), 1.20 (t,
J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.44, 156.49, 136.12, 124.20,
123.27, 121.50, 110.27, 103.47, 93.71, 76.42, 62.91, 55.53, 13.79.
Ethyl 2-(5-Chloro-1H-indol-1-yl)-2-hydroxyacetate (2j)
White solid; yield: 21.7 mg (86%); mp 63–64 °C.
1H NMR (400 MHz, CDCl3): δ = 7.55 (s, 1 H), 7.28 (d, J = 8.7 Hz, 1 H),
7.17–7.06 (m, 2 H), 6.45 (s, 1 H), 5.98 (s, 1 H), 4.52 (s, 1 H), 4.27–4.08
(m, 2 H), 1.13 (t, J = 6.9 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C13H15NNaO4: 272.0893; found:
13C NMR (100 MHz, CDCl3): δ = 169.18, 133.57, 130.21, 126.78,
272.0892.
126.07, 122.49, 120.38, 110.88, 103.09, 76.55, 63.10, 13.70.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12ClNNaO3: 276.0397; found:
276.0398.
Ethyl 2-(4-Acetoxy-1H-indol-1-yl)-2-hydroxyacetate (2f)
Colorless oil; yield: 22.7 mg (82%).
1H NMR (400 MHz, CDCl3): δ = 7.28 (d, J = 8.3 Hz, 1 H), 7.17 (t, J = 8.0
Hz, 1 H), 7.10 (d, J = 3.2 Hz, 1 H), 6.89 (d, J = 7.7 Hz, 1 H), 6.42 (d, J = 3.0
Hz, 1 H), 6.02 (d, J = 4.6 Hz, 1 H), 4.68 (d, J = 4.0 Hz, 1 H), 4.26–4.09 (m,
2 H), 2.34 (s, 3 H), 1.15 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.37, 169.05, 143.48, 137.02,
125.70, 122.47, 122.30, 112.57, 107.94, 100.05, 76.58, 62.90, 20.81,
13.70.
Ethyl 2-(6-Chloro-1H-indol-1-yl)-2-hydroxyacetate (2k)
White solid; yield: 22.7 mg (90%); mp 59–60 °C.
1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 8.4 Hz, 1 H), 7.42 (s, 1 H),
7.10 (dd, J = 12.1, 2.3 Hz, 2 H), 6.49 (d, J = 3.2 Hz, 1 H), 5.99 (d, J = 6.5
Hz, 1 H), 4.46 (d, J = 6.6 Hz, 1 H), 4.34–4.12 (m, 2 H), 1.16 (t, J = 7.1 Hz,
3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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13C NMR (100 MHz, CDCl3): δ = 169.33, 135.71, 128.34, 127.74,
126.01, 121.89, 121.24, 110.02, 103.77, 76.46, 63.32, 13.81.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12ClNNaO3: 276.0397; found:
276.0398.
13C NMR (100 MHz, CD3OD): δ = 175.21, 139.09, 137.72, 133.71,
129.92, 129.73, 129.20, 128.06, 123.03, 120.75, 120.52, 112.15,
110.40, 67.71, 62.27, 14.39.
HRMS (ESI): m/z [M + Na]+ calcd for C18H17NNaO3: 318.1100; found:
318.1085.
Ethyl 2-(5,6-Dichloro-1H-indol-1-yl)-2-hydroxyacetate (2l)
2-Hydroxy-2-(1H-indol-1-yl)-1-phenylethan-1-one (4a)
Colorless oil; yield: 22.4 mg (78%).
White solid; yield: 23.1 mg (92%); mp 107–108 °C.
1H NMR (400 MHz, CDCl3): δ = 7.66 (s, 1 H), 7.53 (s, 1 H), 7.13 (d, J =
3.3 Hz, 1 H), 6.45 (d, J = 3.2 Hz, 1 H), 5.99 (d, J = 6.4 Hz, 1 H), 4.54 (d, J =
6.5 Hz, 1 H), 4.33–4.18 (m, 2 H), 1.18 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.01, 134.02, 128.80, 127.32,
126.17, 124.52, 121.88, 111.59, 103.15, 76.65, 63.36, 13.78.
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 7.9 Hz, 2 H), 7.58 (d, J = 7.8
Hz, 1 H), 7.54 (d, J = 8.3 Hz, 1 H), 7.47 (t, J = 7.3 Hz, 1 H), 7.29 (t, J = 8.1
Hz, 3 H), 7.15 (t, J = 7.5 Hz, 1 H), 6.94 (d, J = 2.9 Hz, 1 H), 6.84 (d, J = 7.3
Hz, 1 H), 6.48 (d, J = 2.9 Hz, 1 H), 5.13 (d, J = 7.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 193.94, 135.49, 134.74, 132.25,
129.29, 128.90, 128.76, 124.97, 122.74, 121.26, 120.71, 109.37,
104.57, 76.80.
HRMS (ESI): m/z [M + Na]+ calcd for C12H11Cl2NNaO3: 310.0008;
found: 310.0007.
HRMS (ESI): m/z [M + Na]+ calcd for C16H13NNaO2: 274.0838; found:
274.0837.
Ethyl 2-(6-Bromo-1H-indol-1-yl)-2-hydroxyacetate (2m)
White solid; yield: 24.9 mg (84%); mp 73–74 °C.
1H NMR (400 MHz, CDCl3): δ = 7.59 (s, 1 H), 7.45 (d, J = 8.4 Hz, 1 H),
7.28–7.20 (m, 1 H), 7.08 (d, J = 3.3 Hz, 1 H), 6.50 (d, J = 3.2 Hz, 1 H),
6.00 (s, 1 H), 4.42 (s, 1 H), 4.24 (qdd, J = 14.2, 8.9, 5.3 Hz, 2 H), 1.17 (t,
J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.32, 136.13, 128.07, 125.90,
123.84, 122.27, 115.98, 112.97, 103.83, 76.45, 63.35, 13.85.
2-Hydroxy-2-(1H-indol-1-yl)-1-(p-tolyl)ethan-1-one (4b)
White solid; yield: 22.0 mg (83%); mp 108–109 °C.
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.2 Hz, 2 H), 7.57 (dd, J =
15.2, 8.1 Hz, 2 H), 7.28 (t, J = 7.7 Hz, 1 H), 7.15 (dd, J = 15.4, 7.7 Hz, 3
H), 6.95 (d, J = 3.3 Hz, 1 H), 6.84 (d, J = 7.3 Hz, 1 H), 6.50 (d, J = 3.2 Hz,
1 H), 5.14 (d, J = 7.3 Hz, 1 H), 2.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 193.49, 146.23, 135.58, 129.78,
129.73, 129.34, 128.99, 125.00, 122.75, 121.30, 120.70, 109.40,
104.52, 76.74, 21.77.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12BrNNaO3: 319.9892; found:
319.9893.
Ethyl 2-(4-Cyano-1H-indol-1-yl)-2-hydroxyacetate (2n)
HRMS (ESI): m/z [M + Na]+ calcd for C17H15NNaO2: 288.0995; found:
288.0993.
Colorless oil; yield: 20.7 mg (85%).
1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.3 Hz, 1 H), 7.42 (d, J = 7.4
Hz, 1 H), 7.38 (d, J = 3.0 Hz, 1 H), 7.20 (t, J = 7.9 Hz, 1 H), 6.68 (d, J = 2.8
Hz, 1 H), 6.18 (s, 1 H), 5.03 (s, 1 H), 4.23 (qd, J = 10.7, 5.2 Hz, 2 H), 1.16
(t, J = 7.1 Hz, 3 H).
2-Hydroxy-2-(1H-indol-1-yl)-1-(o-tolyl)ethan-1-one (4c)
White solid; yield: 21.5 mg (81%); mp 113–114 °C.
1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 7.9 Hz, 1 H), 7.49 (dd, J =
10.9, 8.6 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.24 (t, J = 7.7 Hz, 1 H), 7.19
(d, J = 7.6 Hz, 1 H), 7.13 (t, J = 7.5 Hz, 1 H), 7.05 (t, J = 7.6 Hz, 1 H), 6.95
(d, J = 3.3 Hz, 1 H), 6.82 (d, J = 7.3 Hz, 1 H), 6.47 (d, J = 3.2 Hz, 1 H), 5.21
(d, J = 7.3 Hz, 1 H), 2.57 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.61, 134.82, 130.37, 128.31,
125.62, 121.81, 118.20, 114.96, 102.91, 101.98, 76.78, 63.07, 13.70.
HRMS (ESI): m/z [M + Na]+ calcd for C13H12N2NaO3: 267.0740; found:
267.0741.
13C NMR (100 MHz, CDCl3): δ = 196.15, 141.05, 135.42, 133.30,
132.47, 131.59, 129.20, 129.04, 125.89, 124.93, 122.54, 121.14,
120.55, 109.50, 104.29, 77.32, 21.85.
HRMS (ESI): m/z [M + Na]+ calcd for C17H15NNaO2: 288.0995; found:
288.0993.
Ethyl 2-(5-Cyano-1H-indol-1-yl)-2-hydroxyacetate (2o)
Colorless oil; yield: 21.7 mg (89%).
1H NMR (400 MHz, CDCl3): δ = 7.88 (s, 1 H), 7.51 (d, J = 8.5 Hz, 1 H),
7.37 (d, J = 8.6 Hz, 1 H), 7.35–7.29 (m, 1 H), 6.60 (d, J = 2.5 Hz, 1 H),
6.17 (d, J = 6.0 Hz, 1 H), 4.96 (d, J = 5.9 Hz, 1 H), 4.24 (tdd, J = 17.5, 10.4,
7.3 Hz, 2 H), 1.17 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.47, 136.78, 128.74, 127.77,
126.25, 124.85, 120.17, 110.89, 103.86, 102.95, 76.63, 62.92, 13.65.
1-(3,4-Dimethylphenyl)-2-hydroxy-2-(1H-indol-1-yl)ethan-1-one
(4d)
White solid; yield: 24.0 mg (86%), mp 115–116 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C13H12N2NaO3: 267.0740; found:
267.0741.
1H NMR (400 MHz, CDCl3): δ = 7.67 (s, 1 H), 7.55 (dd, J = 11.9, 8.2 Hz, 2
H), 7.48 (d, J = 7.1 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.13 (t, J = 7.5 Hz, 1
H), 6.99 (d, J = 7.9 Hz, 1 H), 6.94 (d, J = 3.3 Hz, 1 H), 6.82 (d, J = 7.4 Hz,
1 H), 6.46 (d, J = 3.2 Hz, 1 H), 5.24 (d, J = 7.4 Hz, 1 H), 2.15 (s, 3 H), 2.13
(s, 3 H).
Ethyl 2-Hydroxy-2-(2-phenyl-1H-indol-1-yl)acetate (2p)
White solid; yield: 17.0 mg (58%); mp 176–177 °C.
1H NMR (400 MHz, CD3OD): δ = 7.72 (dd, J = 7.8, 3.0 Hz, 3 H), 7.48 (t,
J = 7.5 Hz, 2 H), 7.39 (d, 2 H), 7.12 (t, J = 7.5 Hz, 1 H), 7.02 (t, J = 7.5 Hz,
1 H), 5.51 (s, 1 H), 4.83 (s, 2 H), 4.21–4.01 (m, 2 H), 1.09 (t, J = 7.1 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 193.58, 145.02, 137.44, 135.40,
130.06, 129.93, 129.84, 129.20, 126.49, 124.97, 122.60, 121.17,
120.54, 109.37, 104.34, 76.58, 20.08, 19.60.
HRMS (ESI): m/z [M + Na]+ calcd for C18H17NNaO2: 302.1151; found:
302.1150.
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Synthesis
2-Hydroxy-2-(1H-indol-1-yl)-1-(4-isopropylphenyl)ethan-1-one
(4e)
1H NMR (400 MHz, CDCl3): δ = 7.92–7.80 (m, 2 H), 7.61 (d, J = 7.9 Hz, 1
H), 7.54 (d, J = 8.3 Hz, 1 H), 7.30 (t, J = 7.7 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 1
H), 7.02 (t, J = 8.5 Hz, 2 H), 6.95 (d, J = 3.1 Hz, 1 H), 6.83 (d, J = 7.2 Hz, 1
H), 6.53 (d, J = 3.0 Hz, 1 H), 5.11 (d, J = 7.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 192.38, 167.66, 165.09, 135.31,
131.65, 131.55, 129.22, 128.60, 128.58, 124.90, 122.81, 121.31,
120.78, 116.33, 116.11, 109.26, 104.67, 76.76.
Orange oil; yield: 23.4 mg (80%).
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.2 Hz, 2 H), 7.56 (dd, J =
13.7, 8.1 Hz, 2 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.15 (d, J = 7.5 Hz, 1 H), 7.11
(d, J = 8.3 Hz, 2 H), 6.94 (d, J = 3.2 Hz, 1 H), 6.82 (d, J = 7.4 Hz, 1 H), 6.47
(d, J = 3.2 Hz, 1 H), 5.26 (d, J = 7.4 Hz, 1 H), 2.80 (hept, J = 6.8 Hz, 1 H),
1.13 (d, J = 2.5 Hz, 3 H), 1.11 (d, J = 2.5 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C16H12FNNaO2: 292.0744; found:
13C NMR (100 MHz, CDCl3): δ = 193.31, 156.60, 135.44, 129.92,
129.20, 129.09, 127.06, 124.99, 122.65, 121.19, 120.61, 109.36,
104.38, 76.56, 34.18, 23.27.
292.0743.
2-Hydroxy-2-(1H-indol-1-yl)-1-(1-methyl-1H-pyrrol-2-yl)ethan-1-
one (4j)
HRMS (ESI): m/z [M + Na]+ calcd for C19H19NNaO2: 316.1308; found:
White solid; yield: 22.0 mg (87%); mp 112–113 °C.
316.1306.
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 7.8 Hz, 1 H), 7.51 (d, J = 8.3
Hz, 1 H), 7.23 (t, J = 7.6 Hz, 1 H), 7.12 (t, J = 7.4 Hz, 1 H), 7.05 (d, J = 3.3
Hz, 1 H), 6.73 (s, 1 H), 6.64 (d, J = 4.1 Hz, 1 H), 6.60 (d, J = 7.1 Hz, 1 H),
6.49 (d, J = 3.2 Hz, 1 H), 5.90 (dd, J = 4.2, 2.4 Hz, 1 H), 5.38 (d, J = 7.1 Hz,
1 H), 3.90 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 182.52, 135.33, 133.40, 129.12,
126.42, 125.18, 122.39, 121.10, 121.06, 120.30, 109.53, 109.48,
103.85, 76.68, 37.64.
2-Hydroxy-2-(1H-indol-1-yl)-1-(3-methoxyphenyl)ethan-1-one
(4f)
Orange oil; yield: 25.0 mg (89%).
1H NMR (400 MHz, CDCl3): δ = 7.58 (dd, J = 16.2, 8.1 Hz, 2 H), 7.37 (d,
J = 7.7 Hz, 1 H), 7.34 (d, J = 2.1 Hz, 1 H), 7.28 (t, J = 7.5 Hz, 1 H), 7.24–
7.12 (m, 2 H), 7.04 (dd, J = 8.2, 2.0 Hz, 1 H), 6.96 (d, J = 3.3 Hz, 1 H),
6.84 (d, J = 7.3 Hz, 1 H), 6.51 (d, J = 3.2 Hz, 1 H), 5.16 (d, J = 7.3 Hz, 1 H),
3.63 (s, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C15H14N2NaO2: 277.0947; found:
13C NMR (100 MHz, CDCl3): δ = 193.77, 159.72, 135.46, 133.33,
129.98, 129.26, 124.88, 122.81, 121.80, 121.33, 120.74, 112.50,
109.26, 104.67, 76.84, 55.25.
277.0946.
Ethyl 2-(tert-Butyldimethylsiloxy)-2-(1H-indol-1-yl)acetate (5)
HRMS (ESI): m/z [M + Na]+ calcd for C17H15NNaO3: 304.0944; found:
304.0943.
A solution of 2a (2 g, 9.12 mmol), tert-butylchlorodimethylsilane
(1.84 g, 12.22 mmol), Et3N (3.2 mL, 23.35 mmol), and DMAP (111.4
mg, 0.91 mmol) in anhyd THF (15 mL) was stirred under a dry N2 at-
mosphere for 12 h, at the end of which time NH4Cl was added. The
mixture was extracted with EtOAc (3 × 25 mL). The combined organ-
ics were washed with brine (40 mL), dried (Na2SO4), and filtered. Re-
moval of solvent by rotary evaporation and purification by flash col-
umn chromatography (silica gel, PE/EtOAc, 40:1) afforded 5 (2.33 g,
77%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 7.8 Hz, 1 H), 7.51 (d, J = 8.2
Hz, 1 H), 7.34 (d, J = 3.3 Hz, 1 H), 7.24 (t, J = 7.2 Hz, 1 H), 7.16 (t, J = 7.4
Hz, 1 H), 6.58 (d, J = 3.3 Hz, 1 H), 6.17 (s, 1 H), 4.20 (qq, J = 10.8, 7.1 Hz,
2 H), 1.22 (t, J = 7.1 Hz, 3 H), 0.92 (s, 9 H), 0.15 (s, 3 H), –0.07 (s, 3 H).
2-Hydroxy-2-(1H-indol-1-yl)-1-(4-methoxyphenyl)ethan-1-one
(4g)
Pink solid; yield: 24.0 mg (85%); mp 111–112 °C.
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 8.9 Hz, 2 H), 7.48 (dd, J =
15.7, 8.1 Hz, 2 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 6.86
(d, J = 3.3 Hz, 1 H), 6.71 (d, J = 7.3 Hz, 1 H), 6.66 (d, J = 8.9 Hz, 2 H), 6.40
(d, J = 3.2 Hz, 1 H), 5.18 (d, J = 7.3 Hz, 1 H), 3.62 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 192.05, 164.74, 135.46, 131.35,
129.20, 125.01, 124.97, 122.66, 121.23, 120.62, 114.23, 109.33,
104.36, 76.45, 55.43.
13C NMR (100 MHz, CDCl3): δ = 168.01, 135.16, 129.10, 125.64,
121.99, 120.94, 120.21, 110.24, 103.21, 78.13, 61.73, 25.44, 18.07,
13.98, –5.32, –5.44.
HRMS (ESI): m/z [M + Na]+ calcd for C17H15NNaO3: 304.0944; found:
304.0943.
HRMS (ESI): m/z [M + Na]+ calcd for C18H27NNaO3Si: 356.1652; found:
356.1651.
2-Hydroxy-2-(1H-indol-1-yl)-1-(naphthalen-2-yl)ethan-1-one
(4h)
White solid; yield: 24.0 mg (80%); mp 99–100 °C.
2-(tert-Butyldimethylsiloxy)-2-(1H-indol-1-yl)ethan-1-ol (6)
1H NMR (400 MHz, CDCl3): δ = 8.32 (s, 1 H), 7.86 (dd, J = 8.7, 1.5 Hz, 1
H), 7.73 (d, J = 8.7 Hz, 2 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.60 (dd, J = 16.5,
8.1 Hz, 2 H), 7.52 (t, J = 7.2 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.31 (t, J =
7.6 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.01 (d, J = 3.3 Hz, 1 H), 6.98 (d, J =
7.1 Hz, 1 H), 6.49 (d, J = 3.2 Hz, 1 H), 5.25 (d, J = 7.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 193.85, 136.12, 135.50, 132.05,
131.32, 129.86, 129.44, 129.38, 129.30, 128.91, 127.67, 127.04,
124.98, 123.55, 122.81, 121.35, 120.74, 109.37, 104.67, 76.89.
To a cooled suspension of LiAlH4 (114 mg, 3.0 mmol) in dry Et2O (13
mL) was added dropwise a solution of 5 (1.0 g, 3.0 mmol) in dry Et2O
(2 mL) slowly under an argon atmosphere. The mixture was stirred
for 30 min at this temperature. Sat. aq potassium sodium tartrate (10
mL) was added to the mixture and it was extracted with Et2O (3 × 10
mL). The combined organic layer was washed with water and brine,
dried (Na2SO4), and concentrated in vacuo. The residual oil was puri-
fied by column chromatography (silica gel, PE/EtOAc, 20:1) to afford 6
(813 mg, 93%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 7.8 Hz, 1 H), 7.51 (d, J = 8.2
Hz, 1 H), 7.28–7.23 (m, 2 H), 7.17 (t, J = 7.4 Hz, 1 H), 6.57 (d, J = 3.2 Hz,
1 H), 5.88 (t, J = 6.0 Hz, 1 H), 3.85 (ddt, J = 17.2, 11.4, 6.3 Hz, 2 H), 1.99
(s, 1 H), 0.93 (s, 9 H), 0.11 (s, 3 H), –0.17 (s, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C20H15NNaO2: 324.0995; found:
324.0993.
1-(4-Fluorophenyl)-2-hydroxy-2-(1H-indol-1-yl)ethan-1-one (4i)
Red oil; yield: 22.3 mg (83%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Synthesis
13C NMR (100 MHz, CDCl3): δ = 134.98, 129.00, 124.75, 121.72,
121.01, 119.92, 110.25, 102.60, 80.75, 65.83, 25.54, 17.92, –5.35,
–5.57.
HRMS (ESI): m/z [M + Na]+ calcd for C16H25NNaO2Si: 314.1546; found:
314.1545.
(d) Ingrassia, L.; Mulliez, M. Synthesis 1999, 1731. (e) Bach, J.;
Blachère, C.; Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Price, P. D.;
Sanganee, H. J.; Smith, A. D. Org. Biomol. Chem. 2003, 1, 2001.
(4) Iwasawa, T.; Hooley, R. J.; Rebek, J. Jr. Science (Washington, D. C.)
2007, 317, 493.
(5) (a) Liou, J.-P.; Wu, C.-Y.; Hsieh, H.-P.; Chang, C.-Y.; Chen, C.-M.;
Kuo, C.-C.; Chang, J.-Y. J. Med. Chem. 2007, 50, 4548.
(b) Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Crogan-
Grundy, C.; Labreque, D.; Bubenick, M.; Attardo, G.; Denis, R.;
Lamothe, S.; Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S. X.
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Funding Information
This study was supported by the Scientific Research Foundation of
China (Grant No: 21772018).
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Acknowledgment
We are grateful to Mr. Xiangnan Gong (Analytical and Testing Center
of Chongqing University) for X-ray crystallographic analysis. We
would like to thank Prof. Hailong Yan (Chongqing University) for help-
ful discussions.
(7) Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T. Tetrahedron
Lett. 1998, 39, 71.
Supporting Information
(8) (a) Evans, G. B.; Furneaux, R. H.; Hutchison, T. L.; Kezar, H. S.;
Morris, P. E. Jr.; Schramm, V. L.; Tyler, P. C. J. Org. Chem. 2001,
66, 5723. (b) Delgado, A.; Clardy, J. J. Org. Chem. 1993, 58, 2862.
(c) Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2005,
127, 5970. (d) Dhanak, D.; Reese, C. B. J. Chem. Soc., Perkin Trans.
1 1986, 2181.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610453.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H