Microwave-assisted synthesis of N-sec- and N-tert-alkylated indoles

Article abstract of DOI:10.1055/s-2008-1067005

A synthesis of N-substituted indoles by means of an epoxide-opening, nucleophilic aromatic substitution, and dehydration sequence is reported, which is capable of generating even N-tert alkyl substituted derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067005

1404
PAPER
Microwave-Assisted Synthesis of N-sec- and N-tert-Alkylated Indoles
N-Alkylated
I
ndol
aes rtmut Schirok*
Bayer HealthCare AG, Pharma Research, 42096 Wuppertal, Germany
Fax +49(202)364624; E-mail: hartmut.schirok@bayerhealthcare.com
Received 19 November 2007; revised 11 February 2008
Dedicated to Professor Lutz F. Tietze
amines leading to N-functionalized indoles was disclosed
by Willis.2 N-tert-butylated indoles are furthermore the
outcome of a few indole syntheses of limited synthetic
value, for example, the boron trifluoride mediated reac-
tion of aromatic ketones with tert-butyl isonitrile,14 the
[4+2] cycloaddition of N-tert-butyl vinylpyrroles with di-
enophiles,15 and the addition of tert-butyllithium to quino-
ne imine ketals.16 The copper-mediated cyclization of N-
tert-alkyl-substituted 2-alkynylanilines17 and Doye’s re-
lated indole synthesis via the titanium-catalyzed hy-
droamination of 2-chloro-substituted phenylacetylenes18
yield 2-substituted indoles. Complementary to the latter,
the synthesis of 3-substituted compounds is disclosed
here.
Abstract: A synthesis of N-substituted indoles by means of an ep-
oxide-opening, nucleophilic aromatic substitution, and dehydration
sequence is reported, which is capable of generating even N-tert
alkyl substituted derivatives.
Key words: indoles, cyclizations, microwave heating
Indoles are presumably the most abundant heterocycles in
nature, and the synthesis of the indole framework has been
a major area of focus for more than a century.1 Despite the
outstandingly long tradition of research in this field, only
a single recently reported method has been shown to pro-
vide more general access to N-tert-alkyl-substituted in-
doles.2 Herein the results of our own investigations on an
indole synthesis capable to fill this gap are presented.
Apart from the well-known tritylation of indole3 and in-
tramolecular reactions leading to tricyclic skeletons,4 very
few reports exist on N-tert-alkylated indoles. The reaction
of a 9H-carbazole with tert-butyl alcohol and cyanometh-
ylenetrimethylphosphorane (CMMP) as Mitsunobu re-
agent belongs to these rare examples,5 as well as the
nucleophilic ring opening of 2,2-dimethylaziridines6 and
the (reversible) Michael addition of 6-methoxyindole to
tert-butyl 3-methylcrotonate.7 1-Adamantyl-substituted
indole has been obtained in low yield in the reaction of 1-
bromoadamantane with 3-indolylmagnesium bromide.8
Recently, a new synthesis of 7-azaindoles was reported by
us.19 By treatment of 3-epoxy substituted 2-chloro- or 2-
fluoropyridines with primary amines, the bicyclic hetero-
cycles was isolated by means of an epoxide-opening,
nucleophilic aromatic substitution and dehydration se-
quence. The benefit of microwave-assisted heating and
the broad functional group tolerance of the reaction was
demonstrated.20 Further, it was observed that the velocity
of the reaction largely depends on the steric demands of
the amino component, with a-trisubstituted amines react-
ing slowest. However, the 1-N-tert-substituted 7-azain-
doles were prepared in up to 85% yield.
In an extension of this work, it was questioned if this
method could give general access to N-sec- and N-tert-
alkyl-substituted indoles. Referring back to the original
indole syntheses starting from bromo- and chloroarenes
and simple a-linear amines by Tambute21 and later by
Fleming,22 it was reasoned that the fluoroarenes 2
(Scheme 1) would be best-suited to allow the pivotal ring-
forming intramolecular nucleophilic aromatic substitution
towards 4. The requisite oxiranes 2 could be prepared eas-
ily in a Corey–Chaykovsky epoxide formation23 from aryl
ketones 1.
N-1,1-Dimethylprop-2-enyl (‘reverse prenyl’) indoles
have attracted considerable interest due to their prove-
nance in some uncommon natural products with biologi-
cal activity.9 The direct alkylation of 3-bromoindole with
dimethylpropargyl chloride has been reported in the con-
text of the synthesis of demethylasterriquinone A1.10 The
N-propargylation of N-methoxycarbonyltryptamine was
achieved with the dicobalt hexacarbonyl complex of di-
methyl propargylalcohol.11 The more reliable pathway of
access to N-reverse prenylated indoles comprises the re-
action of the more nucleophilic indolines with the neces-
sity of subsequent aromatization.12 The reaction of indole
with methyl 2-bromopropionate followed by C-alkylation
is another work-around to install a tertiary carbon center
adjacent to the nitrogen.13
The epoxides 2a–g were obtained in 70 to 90% yield from
commercially available ketones (Scheme 1). Compounds
2a and 2b were heated with cyclohexylamine in ethanol to
140 °C in sealed vessels to afford the amino alcohols 3a
and 3b in 91% and 84% yield, respectively (Scheme 2).24
The ring formation and the dehydration step were next in-
vestigated. The intramolecular reaction was performed in
n-butanol, dimethyl sulfoxide or dimethylformamide as
solvent, and microwave heating was used to reach high re-
action temperatures. At 200 °C, only trace amounts of the
desired indoles 5 were detected after 10 minutes reaction
During the preparation of the current publication, the pal-
ladium-catalyzed N-annulation with sterically demanding
SYNTHESIS 2008, No. 9, pp 1404–1414
x
x
.
x
x
.2
0
0
8
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-1067005; Art ID: T17807SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
N-Alkylated Indoles
1405
R
Y
R
Y
X
Y
R
Corey–
Chaykovsky
O
O
2a
2b
2c
2d
2e
2f
H
H
H
H
H
4-F
5-F
Me
Me
Et
i-Pr
Ph
Me
Me
Cl
F
F
F
F
F
F
X
X
a
1
2
2g
R
OH
R
OH
X
X
HN
b
N
Y
R'
R'
3
4
R
X
N
R'
5
Scheme 1 Synthesis of indoles. Reaction mechanism. Reagents and conditions: (a) Me3S+I–, t-BuOK, THF, r.t.; (b) R¢NH2, DMF, mW 240 °C.
time (Table 1). Since spontaneous dehydration and arom-
atization occurs at this temperature as observed in the aza-
indole series,20 the nucleophilic aromatic substitution
must be the rate limiting step. At 240 °C, about 20% in-
dole was formed within 10 minutes, as detected by HPLC
analysis.25 The progress of the reaction was almost inde-
pendent from the nature of the solvent. However, in
DMSO the isolation of the desired products became diffi-
cult after prolonged heating. Best results were obtained in
DMF, even though amine smell clearly indicated the par-
tial thermal decomposition of the solvent. The addition of
diisopropylethylamine did not significantly influence the
outcome of the reaction.
Table 1 Optimization of the Reaction Conditions for the Prepara-
tion of N-Substituted Indoles
Solvent
Temp (°C) Y
Reaction time/Yield (%)a
10 min 30 min 60 min
n-BuOH
DMSO
DMF
200
200
200
F
0
15
<10
23
<10
–
–
–
–
–
F
F
–
–
n-BuOH + ionic liquid 240
F
–
–
Cl
F
–
–
DMSO
DMF
240
240
80
–
–
Cl
F
17
22
18
–
–
In the following, 30 minutes microwave heating at 240 °C
in DMF was used on a routine basis for the reaction with
a-secondary amines such as cyclohexylamine. When nec-
essary, the reaction times were extended to a total of 60 or
90 minutes after intermittent HPLC analysis of the crude
mixtures.
81
45
80
–
100
80
–
Cl
F
DMF + Hünig’s base 240
Cl
25
82
a Yields determined by HPLC analysis with internal standard.
OH
O
H2N
a
b
+
HN
N
Y
Y
2a: Y = Cl
2b: Y = F
6
3a: Y = Cl, 91%
3b: Y = F, 84%
5a
Scheme 2 Test system for the optimization of the cyclization conditions. Reagents and conditions: (a) EtOH, mW 140 °C, 9 h; (b) See Table 1.
Synthesis 2008, No. 9, 1404–1414 © Thieme Stuttgart · New York

1406
H. Schirok
PAPER
Table 2 Synthesis of N-sec-Alkylated Indoles
Starting Material Product
X
H
R
Reaction time (h) Yield (%)
R
X
2a
5a
Me
0.5
40
N
2b
2c
2g
5a
5b
5c
H
H
F
Me
Et
0.5
1.0
1.5
78
92
64
Me
2b
5d
0.7
64
N
N
2b
5e
0.5
74
R
X
N
2b
5f
H
Me
0.5
70
OH
2d
2e
2g
5g
5h
5i
H
H
F
i-Pr
Ph
0.5
0.5
1.0
70
74
73
Me
R
N
X
2c
2f
5j
H
F
Et
0.5
0.5
73
81
N
Bn
5k
Me
Synthesis 2008, No. 9, 1404–1414 © Thieme Stuttgart · New York

PAPER
N-Alkylated Indoles
1407
Table 2 Synthesis of N-sec-Alkylated Indoles (continued)
Starting Material Product
X
H
R
Reaction time (h) Yield (%)
R
2d
2f
5l
i-Pr
1.5
0.5
57
71
N
X
OBn
5m
F
F
Me
Me
R
N
2f
5n
0.3
74
X
N
H
R
2f
5o
F
Me
0.5
70
N
X
HO
The yields of the isolated indoles varied from 60 to 90% As expected, a-tertiary amines such as tert-butylamine or
(Table 2). Due to the elevated temperature required for the adamantylamine proved to be less reactive. A two-hour
ring formation step, only a limited set of functional groups heating time was required with the oxiranes 2b–e
being compatible with this synthesis was expected. Prima- (Table 3). Only the activated difluoro substituted sub-
ry 5o and secondary alcohols 5f–i proved to be sufficient- strates 2f and 2g reacted in shorter period. The N-adaman-
ly stable under the reaction conditions, and tertiary amines tyl substituted indoles 5p–u were isolated in 70–84%
5j–k were also well tolerated, providing a basic set of yields, and the structure of 5s was confirmed by X-ray dif-
functionalities suited for further derivatizations. Benzyl fraction analysis (Figure 1). The tert-butyl substituted de-
ethers 5l,m and a sterically encumbered secondary amine rivatives 5v–x were obtained in 66–74% yields. Again,
5n did not interfere with the course of the reaction, either.
alcohol functionalities in 5y–aa and tertiary amines 5bb–
ee were tolerated, and the yields reached up to 76% of the
isolated product.
The corresponding formamides were detected as by-
products from reaction of the amine components with the
solvent. Anilines did not react (data not shown).
In summary, a reliable and easy-to-perform method to ac-
cess indoles is presented here, which is valuable especial-
ly for the synthesis of the so far underexplored class of N-
tert-alkylated indoles. One method to prepare the required
oxiranes is the Corey–Chaykovsky epoxide formation.
Despite the high temperatures needed for the ring-closing
nucleophilic aromatic substitution, reasonable functional
group compatibility was demonstrated with alcohols and
amines.
1H NMR and 13C NMR spectra were recorded in DMSO-d6 at r.t. on
Bruker Avance spectrometers operating at 300 MHz, 400 MHz, and
500 MHz for 1H NMR, and at 125 MHz for 13C NMR spectra. Flash
column chromatography was performed on silica gel 60 (0.063–
0.200 mm) purchased from Merck KGaA, Darmstadt, Germany.
Preparative HPLC chromatography was done on a 250 mm ×
30 mm column packed with YMC gel ODS-AQ S-5/15 mM, with
MeCN–H2O as eluent and UV-detection. Solvents for extraction
and chromatography were reagent grade and used as received.
Commercial reagents were used without purification. Petroleum
Figure 1 X-ray diffraction analysis of 5s. ORTEP plot (50%) with
labeling scheme.
Synthesis 2008, No. 9, 1404–1414 © Thieme Stuttgart · New York

1408
H. Schirok
PAPER
Table 3 Synthesis of N-tert-Alkylated Indoles
Starting Material Product
X
H
R
Reaction time (h) Yield (%)
R
X
N
2b
5p
Me
2.0
73
2c
2d
2e
2f
5q
5r
5s
5t
H
Et
2.0
2.0
2.0
1.0
1.0
80
81
71
70
84
H
i-Pr
Ph
H
6-F
5-F
Me
Me
2g
5u
R
2b
5v
H
Me
2.0
66
N
X
2e
2f
5w
5x
H
F
Ph
2.0
1.0
70
74
Me
R
2b
5y
H
Me
2.0
57
N
X
OH
2e
2f
5z
H
F
Ph
2.0
1.0
40
76
5aa
Me
R
2b
2f
5bb
5cc
H
F
Me
Me
2.0
1.0
32a
76
N
X
N
R
N
X
2d
2f
5dd
5ee
H
F
i-Pr
2.0
1.0
68
69
N
Bn
Me
a Plus 12% amino alcohol.
Synthesis 2008, No. 9, 1404–1414 © Thieme Stuttgart · New York

PAPER
N-Alkylated Indoles
1409
ether (PE) refers to the fraction boiling in the range of 40–60 °C. All
microwave irradiation experiments were carried out using the
Emrys optimizer microwave from Biotage. The reactions were per-
formed in Biotage microwave vials (for 0.5–2 mL and 2–5 mL, re-
spectively) sealed with a septum. The power range was up to 300 W
at 2.45 GHz.
HRMS (EI): m/z calcd for C10H11FO [M+]: 166.0794; found:
166.0797.
2-(2-Fluorophenyl)-2-isopropyloxirane (2d)
Yield: 78%; bp 119 °C/21 mbar.
1H NMR (500 MHz, DMSO-d6): d = 0.86 (d, J = 6.9 Hz, 3 H), 0.88
(d, J = 6.9 Hz, 3 H), 1.94 (sept, J = 6.9 Hz, 1 H), 2.74 (d, J = 4.7 Hz,
1 H), 3.04 (d, J = 4.7 Hz, 1H), 7.17–7.22 (m, 2 H), 7.34–7.41 (m, 2
H).
X-ray crystal structure determination was carried out using a dif-
fractometer (Oxford Diffraction, Xcalibur series) equipped with a
CCD area detector (model Ruby), a sealed tube with CuKa radia-
tion, osmic mirrors as monochromator and a Cryojet low tempera-
ture device (T = 100 K). Fullsphere data collection omega and phi
scans. Programs used: Data collection and reduction Crysalis Ver-
sion 1.171.29.2 (Oxford Diffraction 2005). Crystal structure solu-
tion was achieved using direct methods as implemented in
SHELXTL Version 6.10,26 and visualized using XP program. Miss-
ing atoms were subsequently located from difference Fourier syn-
thesis and added to the atom list. Least squares refinement on F2
using all measured intensities was carried out using the program
SHELXTL Version 6.10.26 All nonhydrogen atoms were refined in-
cluding anisotropic displacement parameters.
13C NMR (125 MHz, DMSO-d6): d = 17.7, 17.8 (d, 5JC,F = 0.9 Hz),
33.1, 51.1 (d, 4JC,F = 0.9 Hz), 60.9, 115.3 (d, 2JC,F = 21.7 Hz), 123.9
4
2
(d, JC,F = 3.2 Hz), 126.0 (d, JC,F = 15.0 Hz), 129.8 (d,
3JC,F = 8.3 Hz), 130.3 (d, 3JC,F = 4.4 Hz), 159.9 (d, 1JC,F = 245 Hz).
HRMS (EI): m/z calcd for C11H13FO [M+]: 180.0950; found:
180.0944.
2-(2-Fluorophenyl)-2-phenyloxirane (2e)
This compound was isolated by column chromatography on silica
gel (eluent: PE–tert-butyl methyl ether 50:1); yield: 75%; oil.
1H NMR (400 MHz, DMSO-d6): d = 3.28 (d, J = 5.1 Hz, 1 H), 3.34
(d, J = 5.1 Hz, 1 H), 7.17–7.37 (m, 7 H), 7.47 (ddt, J = 7.8, 5.7,
1.9 Hz, 1 H), 7.57 (dt, J = 7.4, 1.6 Hz, 1 H).
Epoxides 2 from Ketones 1; General Procedure A
Trimethylsulfonium iodide (12.2 g, 60 mmol) was suspended in
THF (120 mL). The mixture was cooled to 0 °C, and t-BuOK
(6.73 g, 60 mmol) was added. The mixture was warmed to r.t. and
stirred for 5 min. Subsequently, the ketone (50 mmol) was added.
The mixture was stirred at r.t. for 3 h or until complete consumption
of the starting material, detected by HPLC. The precipitate was fil-
tered off, and the filtrate was concentrated in vacuo. The product
was isolated by distillation under reduced pressure.
13C NMR (125 MHz, DMSO-d6): d = 55.6, 58.0 (d, 3JC,F = 0.9 Hz),
2
4
115.6, (d, JC,F = 20.8 Hz), 124.5 (d, JC,F = 3.5 Hz), 125.7, 126.4
2
3
(d, JC,F = 14.8 Hz), 127.9, 128.4, 130.0 (d, JC,F = 3.7 Hz), 130.6
(d, 3JC,F = 8.1 Hz), 139.2, 160.5 (d, 1JC,F = 247 Hz).
HRMS (EI): m/z calcd for C14H11FO [M+]: 214.0794; found:
214.0787.
2-(2,4-Difluorophenyl)-2-methyloxirane (2f)
Yield: 75%; bp 97 °C/22 mbar.
2-(2-Chlorophenyl)-2-methyloxirane (2a)
Yield: 72%; bp 124 °C/37 mbar.
1H NMR (500 MHz, DMSO-d6): d = 2.81 (d, J = 5.0 Hz, 1 H), 2.98
(d, J = 5.0 Hz, 1 H), 7.07 (ddt, J = 8.6, 2.2, 0.4 Hz, 1 H), 7.26 (d,
J = 11.1, 9.2, 2.2 Hz, 1 H), 7.43 (dt, J = 8.6, 6.8 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 1.57 (s, 3 H), 2.77 (d,
J = 5.0 Hz, 1 H), 3.03 (d, J = 5.0 Hz, 1 H), 7.31–7.38 (m, 2 H),
7.42–7.48 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 22.8 (d, 2JC,F = 2.3 Hz), 53.7,
13C NMR (125 MHz, DMSO-d6): d = 22.5, 54.0, 57.3, 127.3, 128.5,
2
2
54.6, 104.0 (d, JC,F = 25.9 Hz), 111.4 (dd, JC,F = 21.2 Hz,
129.1, 129.4, 131.4, 139.3.
2
4
4JC,F = 3.6 Hz), 124.9 (dd, JC,F = 14.9 Hz, JC,F = 3.8 Hz), 129.3
HRMS (EI): m/z calcd for C9H9ClO [M+]: 168.0342; found:
168.0344.
3
3
1
(dd, JC,F = 9.9 Hz, JC,F = 6.0 Hz), 160.1 (dd, JC,F = 248 Hz,
3JC,F = 12.5 Hz), 161.8 (dd, 1JC,F = 246 Hz, 3JC,F = 12.3 Hz).
HRMS (EI): m/z calcd for C9H8F2O [M+]: 170.0543; found:
170.0538.
2-(2-Fluorophenyl)-2-methyloxirane (2b)
Yield: 78%; bp 94 °C/20 mbar.
1H NMR (400 MHz, DMSO-d6): d = 1.58 (s, 3 H), 2.81 (d,
J = 5.1 Hz, 1 H), 2.99 (d, J = 5.1 Hz, 1 H), 7.16–7.23 (m, 2 H),
7.34–7.41 (m, 2 H).
2-(2,5-Difluorophenyl)-2-methyloxirane (2g)
Yield: 74%; bp 94 °C/20 mbar.
1H NMR (500 MHz, DMSO-d6): d = 1.59 (s, 3 H), 2.84 (d,
J = 5.1 Hz, 1 H), 3.00 (d, J = 5.1 Hz, 1 H), 7.15–7.32 (m, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 22.9, 53.8, 54.9, 115.4 (d,
2JC,F = 21.0 Hz), 124.5 (d, 4JC,F = 3.2 Hz), 128.0 (d, 3JC,F = 4.4 Hz),
13C NMR (125 MHz, DMSO-d6): d = 22.3 (d, 4JC,F = 2.8 Hz), 53.9,
2
3
128.4 (d, JC,F = 14.8 Hz), 129.8 (d, JC,F = 8.1 Hz), 160.0 (d,
1JC,F = 245 Hz).
4
2
3
54.6 (d, JC,F = 1.2 Hz), 114.4 (dd, JC,F = 25.2 Hz, JC,F = 4.9 Hz),
116.1 (dd, 2JC,F = 24.2 Hz, 3JC,F = 8.7 Hz), 117.2 (dd,
HRMS (EI): m/z calcd for C9H9FO [M+]: 152.0637; found:
152.0631.
2JC,F = 24.5 Hz, JC,F = 8.8 Hz), 130.3 (dd, JC,F = 17.6 Hz,
3
2
3JC,F = 7.9 Hz), 156.1 (dd, JC,F = 241 Hz, JC,F = 2.3 Hz), 158.0
1
4
(dd, 1JC,F = 240 Hz, 4JC,F = 2.1 Hz).
2-Ethyl-2-(2-fluorophenyl)oxirane (2c)
Yield: 92%; bp 107 °C/20 mbar.
HRMS (EI): m/z calcd for C9H8F2O [M+]: 170.0543; found:
170.0539.
1H NMR (500 MHz, DMSO-d6): d = 0.81 (t, J = 7.6 Hz, 3 H), 1.71–
1.82 (m, 1 H), 1.88–1.99 (m, 1 H), 2.77 (d, J = 5.0 Hz, 1 H), 3.01
(d, J = 5.0 Hz, 1 H), 7.17–7.23 (m, 2 H), 7.31–7.41 (m, 2 H).
Amino Alcohols 3a,b from Epoxides 2a,b; General Procedure B
The oxirane (6.0 mmol) and cyclohexylamine (12.0 mmol) were
dissolved in EtOH (12 mL), and the mixture was heated for 9 h to
140 °C in a microwave oven. Subsequently, the solvent was re-
moved in vacuo, and the residue was purified by column chroma-
tography on silica gel (eluent: CH2Cl2 + 2% Et3N).
13C NMR (125 MHz, DMSO-d6): d = 8.84, 28.6 (d, 5JC,F = 1.8 Hz),
52.3 (d, JC,F = 0.7 Hz), 58.5, 115.3 (d, JC,F = 21.3 Hz), 124.3 (d,
4JC,F = 3.2 Hz), 127.0 (d, 2JC,F = 15.0 Hz), 129.0 (d, 3JC,F = 4.4 Hz),
129.8 (d, 3JC,F = 8.1 Hz), 159.9 (d, 1JC,F = 245 Hz).
4
2
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1410
H. Schirok
PAPER
2-(2-Chlorophenyl)-1-(cyclohexylamino)propan-2-ol (3a)
1H NMR (400 MHz, DMSO-d6): d = 0.85–1.19 (m, 5 H), 1.45–1.52
(m, 2 H), 1.54 (s, 3 H), 1.55–1.77 (m, 4 H), 2.20 (tt, J = 10.0, 3.7 Hz,
1 H), 2.91 (d, J = 11.7 Hz, 1 H), 3.19 (d, J = 11.7 Hz, 1 H), 5.25 (br
s, 1 H), 7.22 (dt, J = 7.6, 1.8 Hz, 1 H), 7.30 (dt, J = 7.6, 1.3 Hz, 1
H), 7.34 (dd, J = 7.6, 1.3 Hz, 1 H), 7.81 (dd, J = 7.6, 1.8 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 24.3, 24.4, 25.7, 25.8, 33.1,
33.2, 54.3, 56.2, 73.2, 126.7, 128.2, 128.7, 129.9, 130.7, 144.6.
HRMS (EI): m/z calcd for C15H22ClNO + [H+] [M+ + H]: 268.1460;
found: 268.1463.
1-Cyclohexyl-5-fluoro-3-methyl-1H-indole (5c)
Purified by preparative HPLC to yield an oil.
1H NMR (400 MHz, DMSO-d6): d = 1.24 (qt, J = 12.9, 3.6 Hz, 1
H), 1.48 (qt, J = 12.9, 3.0 Hz, 2 H), 1.62–1.74 (m, 3 H), 1.79–1.87
(m, 2 H), 1.88–1.95 (m, 2 H), 2.21 (s, 3 H), 4.26 (tt, J = 11.7, 3.6 Hz,
1 H), 6.93 (ddd, J = 9.7, 8.9, 2.4 Hz, 1 H), 7.21 (dd, J = 10.0,
2.4 Hz, 1 H), 7.31 (s, 1 H), 7.47 (dd, J = 8.9, 4.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 9.48, 25.0, 25.3, 33.0, 54.0,
2
2
103.1 (d, JC,F = 22.7 Hz), 108.7 (d, JC,F = 25.9 Hz), 109.0 (d,
4JC,F = 4.6 Hz), 110.5 (d, JC,F = 9.7 Hz), 124.5, 128.1 (d,
3
3JC,F = 9.5 Hz), 132.1, 156.6 (d, 1JC,F = 231 Hz).
1-(Cyclohexylamino)-2-(2-fluorophenyl)propan-2-ol (3b)
1H NMR (400 MHz, DMSO-d6): d = 0.85–0.99 (m, 2 H), 1.00–1.20
(m, 3 H), 1.34 (br s, 1 H), 1.44 (s, 3 H), 1.45–1.52 (m, 1 H), 1.55–
1.64 (m, 2 H), 1.65–1.77 (m, 2 H), 2.21 (tt, J = 10.0, 3.7 Hz, 1 H),
2.78 (d, J = 10.6 Hz, 1 H), 2.89 (d, J = 10.6 Hz, 1 H), 5.14 (br s, 1
H), 7.07 (dd, J = 12.2, 8.1 Hz, 1 H), 7.14 (ddd, J = 7.6, 7.5, 0.9 Hz,
1 H), 7.22–7.29 (m, 1 H), 7.60 (ddd, J = 8.1, 7.6, 1.7 Hz, 1 H).
HRMS (EI): m/z calcd for C15H18FN [M+]: 231.1423; found:
231.1428.
1-Cyclopentyl-3-methyl-1H-indole (5d)
Purified by preparative HPLC to yield an oil.
1H NMR (500 MHz, DMSO-d6): d = 1.64–1.87 (m, 6 H), 2.07–2.15
(m, 2 H), 2.24 (s, 3 H), 4.82 (tt, J = 7.0, 7.0 Hz, 1 H), 6.97–7.01 (m,
1 H), 7.08–7.12 (m, 1 H), 7.20 (s, 1 H), 7.43 (d, J = 8.2 Hz, 1 H),
7.46 (d, J = 7.9 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 9.57, 23.7, 32.1, 55.8, 109.0,
109.8, 118.2, 118.5, 120.8, 122.7, 128.3, 136.1.
HRMS (EI): m/z calcd for C14H17N [M+]: 199.1361; found:
199.1361.
13C NMR (125 MHz, DMSO-d6): d = 24.4, 25.8, 26.6 (d,
4
4JC,F = 3.9 Hz), 33.1, 55.9 (d, JC,F = 4.2 Hz), 56.3, 71.9 (d,
3JC,F = 4.6 Hz), 115.5 (d, 2JC,F = 23.8 Hz), 123.8 (d, 4JC,F = 3.0 Hz),
3
3
128.1 (d, JC,F = 4.9 Hz), 128.4 (d, JC,F = 8.6 Hz), 134.7 (d,
2JC,F = 12.9 Hz), 159.0 (d, 1JC,F = 243 Hz).
HRMS (EI): m/z calcd for C15H22FNO + [H+] [M+ + H]: 252.1759;
found: 252.1758.
1-(2,3-Dihydro-1H-inden-2-yl)-3-methyl-1H-indole (5e)
Purified by flash chromatography (CH2Cl2); mp 94 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.19 (s, 3 H), 3.19 (dd,
J = 16.1, 6.1 Hz, 2 H), 3.45 (dd, J = 16.1, 7.7 Hz, 2 H), 5.38 (tt,
J = 7.7, 6.1 Hz, 1 H), 7.00–7.04 (m, 1 H), 7.07 (s, 1 H), 7.10–7.15
(m, 1 H), 7.19–7.32 (m, 4 H), 7.46–7.49 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 9.52, 39.1, 55.1, 109.2, 109.8,
118.5, 118.6, 121.1, 122.8, 124.5, 126.8, 128.4, 135.8, 140.8.
HRMS (EI): m/z calcd for C18H17N [M+]: 247.1361; found:
Indoles 5 from Epoxides 2 and Amines; General Procedure C
An oxirane (1.0 mmol) and a primary amine (2.0 mmol) were dis-
solved in DMF (1.0 mL), and the mixture was heated in a micro-
wave oven for the time indicated in Table 2 or 3 to 240 °C. Very
lipophilic indoles may be extracted with pentane (5 × 5 mL) from
the mixture. Otherwise, EtOAc (20 mL) was added, and the mixture
was washed with H2O (20 mL). The organic layer was dried
(Na2SO4), the solvent was evaporated, and the residue was purified
by flash column chromatography on silica gel or by preparative
HPLC.
247.1361.
1-Cyclohexyl-3-methyl-1H-indole (5a)
Purified by preparative HPLC; mp 68 °C.
trans-4-(3-Methyl-1H-indol-1-yl)cyclohexanol (5f)
Purified by preparative HPLC; mp 136 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.25 (qt, J = 12.9, 3.6 Hz, 1
H), 1.49 (qt, J = 12.9, 3.2 Hz, 2 H), 1.64–1.76 (m, 3 H), 1.80–1.87
(m, 2H), 1.89–1.96 (m, 2H), 2.24 (s, 3 H), 4.26 (tt, J = 11.7, 3.8 Hz,
1 H), 6.96–7.01 (m, 1 H), 7.09 (ddd, J = 7.9, 7.5, 0.6 Hz, 1 H), 7.22
(s, 1 H), 7.42–7.45 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 9.56, 25.1, 25.3, 33.0, 53.8,
108.8, 109.5, 118.1, 118.5, 120.7, 122.5, 128.0, 135.4.
1H NMR (400 MHz, DMSO-d6): d = 1.38–1.51 (m, 2 H), 1.73–1.84
(m, 2 H), 1.85–1.98 (m, 4 H), 2.23 (s, 3 H), 3.49–3.59 (m, 1 H), 4.26
(tt, J = 11.6, 3.9 Hz, 1 H), 4.67 (d, J = 4.4 Hz, 1 H), 6.98 (dd,
J = 7.7, 7.4 Hz, 1 H), 7.09 (dd, J = 8.2, 7.7 Hz, 1 H), 7.20 (s, 1 H),
7.43–7.47 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 9.57, 30.8, 34.4, 53.2, 68.2,
108.9, 109.6, 118.2, 118.5, 120.8, 122.5, 128.1, 135.6.
HRMS (EI): m/z calcd for C15H19N [M+]: 213.1517; found:
213.1517.
HRMS (EI): m/z calcd for C15H19NO [M+]: 229.1467; found:
229.1467.
1-Cyclohexyl-3-ethyl-1H-indole (5b)
Purified by flash chromatography (cyclohexane) to yield an oil.
trans-4-(3-Isopropyl-1H-indol-1-yl)cyclohexanol (5g)
Purified by preparative HPLC; mp 96 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.19–1.32 (m, 1 H), 1.25 (t,
J = 7.5 Hz, 3 H), 1.42–1.55 (m, 2 H), 1.66–1.78 (m, 3 H), 1.80–1.88
(m, 2 H), 1.89–1.97 (m, 2 H), 2.69 (q, J = 7.5 Hz, 2 H), 4.26 (tt,
J = 11.7, 3.7 Hz, 1 H), 6.97 (dd, J = 7.8, 7.1 Hz, 1 H), 7.09 (dd,
J = 8.1, 7.1 Hz, 1 H), 7.21 (s, 1 H), 7.44 (d, J = 8.1 Hz, 1 H), 7.49
(d, J = 7.8 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.6, 17.9, 25.1, 25.4, 32.9,
53.8, 109.6, 116.0, 118.1, 118.6, 120.7, 121.3, 127.2, 135.5.
HRMS (EI): m/z calcd for C16H21N [M+]: 227.1674; found:
227.1673.
1H NMR (400 MHz, DMSO-d6): d = 1.29 (d, J = 6.9 Hz, 6 H),
1.38–1.50 (m, 2 H), 1.75–1.98 (m, 6 H), 3.11 (sept, J = 6.9 Hz, 1 H),
3.55 (dtt, J = 10.8, 4.4, 4.2 Hz, 1 H), 4.27 (tt, J = 11.4, 4.2 Hz, 1 H),
4.67 (d, J = 4.4 Hz, 1 H), 6.97 (ddd, J = 7.8, 7.3, 0.3 Hz, 1 H), 7.08
(ddd, J = 8.1, 7.3, 0.8 Hz, 1 H), 7.17 (s, 1 H), 7.45 (dd, J = 8.1,
0.3 Hz, 1 H), 7.53 (dd, J = 7.8, 0.8 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 23.4, 25.0, 30.7, 34.4, 53.2,
68.2, 109.7, 118.1, 118.9, 119.9, 120.7, 121.3, 126.5, 135.9.
HRMS (EI): m/z calcd for C17H23NO [M+]: 257.1780; found:
257.1778.
Synthesis 2008, No. 9, 1404–1414 © Thieme Stuttgart · New York

PAPER
N-Alkylated Indoles
1411
trans-4-(3-Phenyl-1H-indol-1-yl)cyclohexanol (5h)
Purified by flash chromatography (PE–EtOAc, 1:1); mp 129 °C.
4.40 (d, J = 12.2 Hz, 1 H), 4.44 (d, J = 12.2 Hz, 1 H), 4.49–4.57 (m,
1 H), 6.97 (ddd, J = 7.8, 7.1, 0.5 Hz, 1 H), 7.07 (ddd, J = 8.1, 7.1,
1.0 Hz, 1 H), 7.15–7.19 (m, 3 H), 7.21–7.30 (m, 3 H), 7.45 (dd,
J = 8.1, 0.5 Hz, 1 H), 7.55 (dd, J = 7.8, 1.0 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 10.5, 23.4, 24.4, 25.0, 56.2,
71.8, 71.9, 109.8, 118.0, 118.8, 120.6, 120.7, 121.6, 126.4, 127.2,
127.3, 128.1, 137.1, 138.3.
1H NMR (500 MHz, DMSO-d6): d = 1.43–1.55 (m, 2 H), 1.86–2.02
(m, 6 H), 3.53–3.63 (m, 1 H), 4.35–4.45 (m, 1 H), 4.71 (d,
J = 4.2 Hz, 1 H), 7.11 (t, J = 7.6 Hz, 1 H), 7.19 (t, J = 7.9 Hz, 1 H),
7.22 (t, J = 7.6 Hz, 1 H), 7.42 (t, J = 7.9 Hz, 1 H), 7.61 (d,
J = 8.0 Hz, 1 H), 7.67 (t, J = 7.9 Hz, 2 H), 7.81 (s, 1 H), 7.86 (d,
J = 8.0 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 30.7, 34.4, 53.5, 68.1, 110.4,
115.2, 119.2, 119.8, 121.3, 123.3, 125.2, 125.3, 126.5, 128.7, 135.6,
136.3.
HRMS (EI): m/z calcd for C22H27NO [M+]: 321.2093; found:
321.2098.
1-{1-[(Benzyloxy)methyl]propyl}-6-fluoro-3-methyl-1H-indole
(5m)
HRMS (EI): m/z calcd for C20H21NO [M+]: 291.1623; found:
Purified by preparative HPLC to yield an oil.
291.1619.
1H NMR (400 MHz, DMSO-d6): d = 0.69 (t, J = 7.3 Hz, 3 H), 1.74–
1.93 (m, 2 H), 2.24 (s, 3 H), 3.68 (dd, J = 10.2, 5.1 Hz, 1 H), 3.72
(dd, J = 10.2, 6.7 Hz, 1 H), 4.39 (d, J = 12.2 Hz, 1 H), 4.45 (d,
J = 12.2 Hz, 1 H), 4.46–4.54 (m, 1 H), 6.83 (ddd, J = 9.4, 8.9,
2.0 Hz, 1 H), 7.14–7.17 (m, 2 H), 7.22 (s, 1 H), 7.22–7.31 (m, 3 H),
7.34 (dd, J = 11.0, 2.2 Hz, 1 H), 7.44 (dd, J = 8.6, 5.6 Hz, 1 H).
trans-4-(5-Fluoro-3-methyl-1H-indol-1-yl)cyclohexanol (5i)
Purified by preparative HPLC; mp 109 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.39–1.50 (m, 2 H), 1.71–1.83
(m, 2 H), 1.84–1.96 (m, 4 H), 2.20 (s, 3 H), 3.53 (tq, J = 10.7,
4.3 Hz, 1 H), 4.26 (tt, J = 11.6, 3.8 Hz, 1 H), 4.68 (d, J = 4.3 Hz, 1
H), 6.93 (ddd, J = 9.7, 8.8, 2.4 Hz, 1 H), 7.20 (dd, J = 9.8, 2.4 Hz, 1
H), 7.28 (s, 1 H), 7.48 (dd, J = 8.8, 4.4 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 9.6, 10.4, 24.3, 56.3, 71.89,
2
2
71.91, 96.1 (d, JC,F = 26.6 Hz), 106.5 (d, JC,F = 24.5 Hz), 109.7,
3
4
119.3 (d, JC,F = 10.4 Hz), 123.4 (d, JC,F = 3.5 Hz), 124.7, 127.3,
127.4, 128.2, 137.0 (d, JC,F = 12.5 Hz), 138.2, 159.0 (d,
13C NMR (125 MHz, DMSO-d6): d = 9.5, 30.8, 34.4, 53.4, 68.2,
3
2
2
103.2 (d, JC,F = 22.7 Hz), 108.7 (d, JC,F = 25.9 Hz), 109.1 (d,
1JC,F = 234 Hz).
4JC,F = 4.9 Hz), 110.6 (d, JC,F = 9.7 Hz), 124.5, 128.2 (d,
3
3JC,F = 9.7 Hz), 132.3, 156.7 (d, 1JC,F = 231 Hz).
HRMS (EI): m/z calcd for C20H22FNO [M+]: 311.1685; found:
311.1685.
HRMS (EI): m/z calcd for C15H18FNO [M+]: 247.1372; found:
247.1367.
6-Fluoro-3-methyl-1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-
indole (5n)
Purified by preparative HPLC; mp 58 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.11 (s, 6 H), 1.31 (s, 6 H),
1.59 (tt, J = 12.3 Hz, 2 H), 1.77 (dd, J = 12.3, 3.3 Hz, 2 H), 2.23 (s,
3H), 3.50 (br s under H2O, 1 H), 4.67 (tt, J = 12.3, 3.3 Hz, 1 H),
6.85 (ddd, J = 9.6, 8.6, 2.0 Hz, 1 H), 7.22 (s, 1 H), 7.40 (dd,
J = 10.8, 2.0 Hz, 1 H), 7.45 (dd, J = 8.6, 5.6 Hz, 1 H).
1-(1-Benzylpiperidin-4-yl)-3-ethyl-1H-indole (5j)
Purified by preparative HPLC to yield an oil.
1H NMR (400 MHz, DMSO-d6): d = 1.25 (t, J = 7.5 Hz, 3 H), 1.85–
1.92 (m, 2 H), 1.92–2.01 (m, 2 H), 2.20 (dt, J = 11.0, 1.4 Hz, 2 H),
2.69 (q, J = 7.5 Hz, 2 H), 2.91–2.98 (m, 2 H), 3.54 (s, 2 H), 4.29 (tt,
J = 11.5, 4.4 Hz, 1 H), 6.98 (t, J = 7.4 Hz, 1 H), 7.09 (t, J = 7.4 Hz,
1 H), 7.23–7.30 (m, 2 H), 7.33–7.36 (m, 4 H), 7.45 (d, J = 8.3 Hz, 1
H), 7.49 (d, J = 7.8 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.6, 17.9, 32.0, 52.4, 62.0,
109.6, 116.2, 118.2, 118.6, 120.8, 121.3, 126.9, 127.3, 128.2, 128.8,
135.7, 138.5.
13C NMR (125 MHz, DMSO-d6): d = 9.51, 28.3, 34.5, 44.2, 48.1,
2
2
50.8, 96.0 (d, JC,F = 26.1 Hz), 106.6 (d, JC,F = 24.5 Hz), 109.5,
119.6 (d, 3JC,F = 10.4 Hz), 123.0 (d, 4JC,F = 3.5 Hz), 124.9, 135.4 (d,
3JC,F = 12.5 Hz), 158.9 (d, 1JC,F = 234 Hz).
HRMS (EI): m/z calcd for C18H25FN2 [M+]: 288.2002; found:
288.1999.
HRMS (EI): m/z calcd for C22H26N2 [M+]: 318.2096; found:
318.2093.
2-(6-Fluoro-3-methyl-1H-indol-1-yl)-2-phenylethanol (5o)
Purified by preparative HPLC.
1-(1-Benzylpiperidin-4-yl)-6-fluoro-3-methyl-1H-indole (5k)
Purified by preparative HPLC to yield an oil.
1H NMR (400 MHz, DMSO-d6): d = 2.26 (s, 3 H), 4.03 (ddd,
J = 11.3, 5.2, 5.1 Hz, 1 H), 4.20 (ddd, J = 11.3, 8.4, 6.0 Hz, 1 H),
5.18 (dd, J = 6.0, 5.2 Hz, 1 H), 5.56 (dd, J = 8.4, 5.1 Hz, 1 H), 6.82
(ddd, J = 10.3, 8.0, 2.2 Hz, 1 H), 7.20–7.32 (m, 6 H), 7.44 (dd,
J = 8.7, 5.7 Hz, 1 H), 7.46 (s, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 1.83–1.98 (m, 4 H), 2.20 (dt,
J = 11.6, 2.3 Hz, 2 H), 2.22 (s, 3 H), 2.90–2.96 (m, 2 H), 3.54 (s, 2
H), 4.25 (tt, J = 10.9, 5.0 Hz, 1 H), 6.83 (ddd, J = 9.6, 8.6, 1.8 Hz, 1
H), 7.23–7.29 (m, 1 H), 7.27 (s, 1 H), 7.32–7.37 (m, 5 H), 7.43 (dd,
J = 8.6, 5.6 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 9.57, 60.7, 62.9, 96.3 (d,
13C NMR (125 MHz, DMSO-d6): d = 9.5, 32.0, 52.2, 52.4, 62.0,
3
2JC,F = 26.4 Hz), 106.7 (d, JC,F = 24.3 Hz), 109.5, 119.4 (d,
2
2
96.0 (d, JC,F = 26.4 Hz), 106.6 (d, JC,F = 24.5), 109.5, 119.5 (d,
4
4JC,F = 10.4 Hz), 124.2 (d, JC,F = 3.5 Hz), 125.0, 126.9, 127.5,
3JC,F = 10.4 Hz), 123.0 (d, JC,F = 3.5 Hz), 124.8, 126.9, 128.2,
4
128.4, 136.5 (d, 3JC,F = 12.5 Hz), 139.4, 158.9 (d, 1JC,F = 234 Hz).
128.8, 135.5 (d, 3JC,F = 12.5 Hz), 138.4, 159.0 (d, 1JC,F = 234.0 Hz).
HRMS (EI): m/z calcd for C17H16FNO [M+]: 269.1216; found:
269.1214.
HRMS (EI): m/z calcd for C21H23FN2 [M+]: 322.1845; found:
322.1845.
1-(Adamantan-1-yl)-3-methyl-1H-indole (5p)
Purified by flash chromatography (PE–CH2Cl2, 5:1); mp 214–
217 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.71–1.85 (m, 6 H), 2.20 (br s,
3 H), 2.22 (s, 3 H), 2.28 (s, 6 H), 6.96–7.00 (m, 1 H), 7.03–7.07 (m,
1 H), 7.22 (s, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1
H).
1-{1-[(Benzyloxy)methyl]propyl}-3-isopropyl-1H-indole (5l)
Purified by flash chromatography (cyclohexane–tert-butyl methyl
ether, 4:1) to yield an oil.
1H NMR (400 MHz, DMSO-d6): d = 0.70 (t, J = 7.3 Hz, 3 H), 1.30
(d, J = 6.8 Hz, 6 H), 1.78–1.97 (m, 2 H), 3.14 (sept, J = 6.8 Hz, 1
H), 3.70 (dd, J = 10.2, 4.9 Hz, 1 H), 3.76 (dd, J = 10.2, 6.7 Hz, 1 H),
Synthesis 2008, No. 9, 1404–1414 © Thieme Stuttgart · New York

1412
H. Schirok
PAPER
13C NMR (125 MHz, DMSO-d6): d = 9.5, 29.3, 35.7, 41.6, 55.8,
107.6, 113.5, 117.8, 118.8, 120.2, 122.6, 129.8, 134.2.
HRMS (EI): m/z calcd for C19H22FN [M+]: 283.1736; found:
283.1732.
HRMS (EI): m/z calcd for C19H23N [M+]: 265.1830; found:
265.1824.
1-tert-Butyl-3-methyl-1H-indole (5v)
Purified by preparative HPLC to yield an oil.
1-(Adamantan-1-yl)-3-ethyl-1H-indole (5q)
Purified by flash chromatography (PE–CH2Cl2, 5:1); mp 162 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.25 (t, J = 7.5 Hz, 3 H), 1.72–
1.77 (m, 3 H), 1.79–1.85 (m, 3 H), 2.21 (s, 3 H), 2.28 (s, 6 H), 2.68
(q, J = 7.5 Hz, 2 H), 6.95–6.99 (m, 1 H), 7.03–7.08 (m, 1 H), 7.20
(s, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 1.64 (s, 9 H), 2.23 (d,
J = 1.0 Hz, 3 H), 6.99 (ddd, J = 7.6, 7.2, 0.3 Hz, 1 H), 7.08 (ddd,
J = 8.1, 7.2, 1.0 Hz, 1 H), 7.19 (q, J = 1.0 Hz, 1 H), 7.47 (d,
J = 7.6 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 9.42, 29.4, 55.1, 107.5, 113.0,
117.8, 118.7, 120.4, 123.6, 129.9, 134.6.
13C NMR (125 MHz, DMSO-d6): d = 14.6, 17.8, 29.3, 35.8, 41.6,
55.9, 113.7, 114.8, 117.9, 118.9, 120.3, 121.4, 129.0, 134.4.
HRMS (EI): m/z calcd for C13H17N [M+]: 187.1361; found:
187.1361.
HRMS (EI): m/z calcd for C20H25N [M+]: 279.1987; found:
279.1986.
1-tert-Butyl-3-phenyl-1H-indole (5w)
Purified by trituration with EtOAc and MeOH; mp 91 °C.
1-(Adamantan-1-yl)-3-isopropyl-1H-indole (5r)
Purified by flash chromatography (PE–CH2Cl2, 5:1); mp 121 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.29 (d, J = 6.8 Hz, 6 H),
1.71–1.86 (m, 6 H), 2.21 (s, 3 H), 2.28 (s, 6 H), 3.11 (sept,
J = 6.8 Hz, 1 H), 6.94–6.99 (m, 1 H), 7.02–7.07 (m, 1 H), 7.15 (s, 1
H), 7.5 (d, J = 7.7 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 1.73 (s, 9 H), 7.08–7.20 (m, 2
H), 7.23 (t, J = 7.3 Hz, 1 H), 7.43 (t, J = 7.3 Hz, 2 H), 7.67 (d,
J = 7.3 Hz, 2 H), 7.69 (s, 1 H), 7.79 (d, J = 8.6 Hz, 1 H), 7.86 (d,
J = 7.8 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 29.3, 55.9, 113.8, 114.1,
119.3, 119.4, 121.0, 124.3, 125.3, 126.8, 127.0, 128.7, 135.3, 135.5.
13C NMR (125 MHz, DMSO-d6): d = 23.3, 24.8, 29.3, 35.7, 41.5,
55.9, 113.7, 117.7, 119.2, 119.8, 119.9, 120.1, 128.3, 134.5.
HRMS (EI): m/z calcd for C18H19N [M+]: 249.1517; found:
249.1517.
HRMS (EI): m/z calcd for C21H27N [M+]: 293.2144; found:
293.2144.
1-tert-Butyl-6-fluoro-3-methyl-1H-indole (5x)
Purified by preparative HPLC to yield an oil.
1-(Adamantan-1-yl)-3-phenyl-1H-indole (5s)
Purified by trituration with MeOH; mp 170–172 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.62 (s, 9 H), 2.21 (d,
J = 0.7 Hz, 3 H), 6.85 (ddd, J = 9.8, 8.5, 2.0 Hz, 1 H), 7.20 (q,
J = 0.7 Hz, 1 H), 7.43 (dd, J = 11.6, 2.0 Hz, 1 H), 7.45 (dd, J = 8.5,
6.0 Hz, 1 H).
1H NMR (500 MHz, DMSO-d6): d = 1.74–1.89 (m, 6 H), 2.25 (br s,
3 H), 2.36–2.39 (m, 6 H), 7.07–7.18 (m, 2 H), 7.23 (t, J = 7.3 Hz, 1
H), 7.42 (t, J = 7.7 Hz, 2 H), 7.64–7.67 (m, 2 H), 7.71 (s, 1 H), 7.87
(t, J = 7.5 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 29.3, 35.7, 41.4, 56.6, 114.2,
114.3, 119.4, 119.5, 120.8, 123.3, 125.3, 126.8, 127.0, 128.7, 134.9,
135.6.
13C NMR (125 MHz, DMSO-d6): d = 9.37, 29.2, 55.3, 99.2 (d,
2
2JC,F = 27.0 Hz), 106.2 (d, JC,F = 24.5 Hz), 108.0, 119.5 (d,
4
3JC,F = 10.4 Hz), 124.3 (d, JC,F = 3.7 Hz), 126.6, 134.2 (d,
3JC,F = 12.0 Hz), 158.2 (d, 1JC,F = 233 Hz).
HRMS (EI): m/z calcd for C13H16FN [M+]: 205.1267; found:
205.1266.
HRMS (EI): m/z calcd for C24H25N [M+]: 327.1987; found:
327.1987.
2-Methyl-2-(3-methyl-1H-indol-1-yl)propan-1-ol (5y)
Purified by preparative HPLC; mp 99 °C.
1-(Adamantan-1-yl)-6-fluoro-3-methyl-1H-indole (5t)
Purified by trituration with EtOAc and MeOH; mp 217 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.58 (s, 6 H), 2.22 (s, 3 H),
3.76 (d, J = 5.6 Hz, 2 H), 4.99 (t, J = 5.6 Hz, 1 H), 6.95–7.00 (m, 1
H), 7.02–7.07 (m, 1 H), 7.19 (s, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.58
(d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 9.4, 24.8, 59.2, 67.2, 107.4,
113.0, 117.8, 118.6, 120.3, 124.8, 129.8, 134.8.
1H NMR (500 MHz, DMSO-d6): d = 1.69–1.86 (m, 6 H), 2.18–2.25
(m, 12 H), 6.85 (ddd, J = 9.0, 8.6, 2.0 Hz, 1 H), 7.23 (s, 1 H), 7.45
(dd, J = 8.6, 5.9 Hz, 1 H), 7.51 (dd, J = 11.7, 2.0 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 9.43, 29.3, 35.6, 41.3, 56.1,
99.7 (d, 2JC,F = 26.8 Hz), 106.3 (d, 2JC,F = 24.3 Hz), 108.1, 119.6 (d,
4
3JC,F = 10.4 Hz), 123.3 (d, JC,F = 3.5 Hz), 126.6, 133.7 (d,
HRMS (EI): m/z calcd for C13H17NO [M+]: 203.1310; found:
203.1304.
3JC,F = 12.3 Hz), 158.0 (d, 1JC,F = 233 Hz).
HRMS (EI): m/z calcd for C19H22FN [M+]: 283.1736; found:
283.1732.
2-Methyl-2-(3-phenyl-1H-indol-1-yl)propan-1-ol (5z)
Purified by preparative HPLC to yield an oil.
1-(Adamantan-1-yl)-5-fluoro-3-methyl-1H-indole (5u)
Purified by trituration with EtOH and MeOH; mp 168 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.70–1.85 (m, 6 H), 2.18–2.25
(m, 12 H), 6.88 (ddd, J = 9.3, 9.2, 2.7 Hz, 1 H), 7.21 (dd, J = 9.8,
2.7 Hz, 1 H), 7.30 (s, 1 H), 7.73 (dd, J = 9.3, 4.4 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 1.67 (s, 6 H), 3.86 (d,
J = 5.6 Hz, 2 H), 5.10 (t, J = 5.6 Hz, 1 H), 7.08–7.17 (m, 2 H), 7.23
(t, J = 7.3 Hz, 1 H), 7.43 (t, J = 7.7 Hz, 2 H), 7.65 (d, J = 7.7 Hz, 2
H), 7.68 (s, 1 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.85 (d, J = 7.3 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 24.7, 60.0, 67.1, 113.8, 114.0,
119.2, 119.4, 120.9, 125.3, 125.6, 126.8, 127.0, 128.8, 135.5, 135.6.
13C NMR (125 MHz, DMSO-d6): d = 9.36, 29.2, 35.6, 41.6, 55.9,
2
4
103.3 (d, JC,F = 22.2 Hz), 107.9 (d, JC,F = 4.6 Hz), 108.1 (d,
HRMS (EI): m/z calcd for C18H19NO [M+]: 265.1467; found:
265.1461.
2JC,F = 25.4 Hz), 114.4 (d, JC,F = 9.5 Hz), 124.7, 130.2 (d,
3
3JC,F = 9.5 Hz), 130.8, 156.2 (d, 1JC,F = 232 Hz).
Synthesis 2008, No. 9, 1404–1414 © Thieme Stuttgart · New York

PAPER
N-Alkylated Indoles
1413
2-(6-Fluoro-3-methyl-1H-indol-1-yl)-2-methylpropan-1-ol
(5aa)
J = 9.1, 9.0, 2.0 Hz, 1 H), 7.21–7.27 (m, 1 H), 7.28–7.34 (m, 5 H),
7.41 (dd, J = 11.7, 2.0 Hz, 1 H), 7.46 (dd, J = 9.0, 6.0 Hz, 1 H).
Purified by preparative HPLC; mp 69 °C.
13C NMR (125 MHz, DMSO-d6): d = 9.45, 24.8, 36.3, 49.5, 56.4,
1H NMR (500 MHz, DMSO-d6): d = 1.56 (s, 6 H), 2.20 (s, 3 H),
3.73 (d, J = 5.6 Hz, 2 H), 5.01 (t, J = 5.6 Hz, 1 H), 6.84 (ddd,
J = 9.2, 8.6, 2.2 Hz, 1 H), 7.20 (s, 1 H), 7.40 (dd, J = 11.5, 2.1 Hz,
1 H), 7.43 (dd, J = 8.6, 5.6 Hz, 1 H).
62.0, 99.4 (d, JC,F = 27.0 Hz), 106.3 (d, JC,F = 24.5 Hz), 108.5,
2
2
3
119.5 (d, JC,F = 10.4 Hz), 124.3 (br), 126.7, 126.9, 128.1, 128.8,
134.1 (d, 3JC,F = 12.0 Hz), 138.5, 158.1 (d, 1JC,F = 233 Hz).
HRMS (EI): m/z calcd for C22H25FN2 [M+]: 336.2002; found:
336.1991.
13C NMR (125 MHz, DMSO-d6): d = 9.37, 24.6, 59.4, 67.1, 99.3 (d,
2
2JC,F = 27.0 Hz), 106.1 (d, JC,F = 24.5 Hz), 107.8, 119.3 (d,
4
3JC,F = 10.6 Hz), 125.5 (d, JC,F = 3.7 Hz), 126.5, 134.5 (d,
3JC,F = 12.3 Hz), 158.1 (d, 1JC,F = 232.3 Hz).
Acknowledgment
HRMS (EI): m/z calcd for C13H16FNO [M+]: 221.1216; found:
221.1216.
I am grateful to Dr. P. Schmitt, C. Streich, and D. Bauer for recor-
ding NMR spectra. In addition, I thank H. Musche, S. Brauner, M.
Stoltefuß, and G. Wiefel-Hübschmann for HRMS measurements.
Dr. H.-C. Weiß determined the crystal structure of compound.
3-Methyl-1-(1,1-dimethyl-2-pyrrolidin-1-ylethyl)-1H-indole
(5bb)
Purified by preparative HPLC.
References
1H NMR (400 MHz, DMSO-d6): d = 1.41–1.48 (m, 4 H), 1.65 (s, 6
H), 2.02–2.09 (m, 4 H), 2.50 (s, 3 H), 2.98 (s, 2 H), 6.95–6.99 (m, 1
H), 7.03–7.07 (m, 1 H), 7.15 (s, 1 H), 7.45 (d, J = 7.7 Hz, 1 H), 7.63
(d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 9.5, 23.3, 26.9, 54.7, 58.9,
63.2, 107.7, 113.3, 117.8, 118.6, 120.2, 124.5, 129.7, 135.0.
(1) For recent reviews, see: (a) Joule, J. A. In Science of
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(2) Fletcher, A. J.; Bax, M. N.; Willis, M. C. Chem. Commun.
HRMS (EI): m/z calcd for C17H24N2 [M+]: 256.1939; found:
256.1938.
2007, 4764.
(3) (a) Funakubo, E.; Hirotani, T. Ber. Dtsch. Chem. Ges. 1936,
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6-Fluoro-3-methyl-1-(1,1-dimethyl-2-pyrrolidin-1-ylethyl)-1H-
indole (5cc)
Purified by preparative HPLC; mp 73 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.41–1.50 (m, 4 H), 1.63 (s, 6
H), 2.02–2.09 (m, 4 H), 2.22 (d, J = 0.7 Hz, 3 H), 2.95 (s, 2 H), 6.84
(ddd, J = 9.1, 9.0, 1.9 Hz, 1 H), 7.17 (q, J = 0.7 Hz, 1 H), 7.41–7.47
(m, 2 H).
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13C NMR (125 MHz, DMSO-d6): d = 9.40, 23.3, 26.7, 54.6, 59.2,
2
2
63.1, 99.5 (d, JC,F = 27.0 Hz), 106.2 (d, JC,F = 24.3 Hz), 108.1,
119.4 (d, 3JC,F = 10.6 Hz), 125.1 (d, 4JC,F = 3.5 Hz), 126.5, 134.6 (d,
3JC,F = 12.3 Hz), 158.0 (d, 1JC,F = 233 Hz).
HRMS (EI): m/z calcd for C17H23FN2 [M+]: 274.1845; found:
274.1838.
(5) Bombrun, A.; Casi, G. Tetrahedron Lett. 2002, 43, 2187.
(6) Assithianakis, P.; Onistschenko, A.; Stamm, H. Arch.
Pharm. (Weinheim, Germany) 1987, 320, 604.
1-(1-Benzyl-4-methylpiperidin-4-yl)-3-(1-methylethyl)-1H-
indole (5dd)
Purified by flash chromatography (cyclohexane–tert-butyl methyl
ether, 1:1) to an oil.
(7) Bond, R. F.; Boeyens, J. C. A.; Holzapfel, C. W.; Steyn, P.
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1H NMR (400 MHz, DMSO-d6): d = 1.29 (d, J = 6.8 Hz, 6 H), 1.54
(s, 3 H), 2.06–2.14 (m, 2 H), 2.35–2.50 (m, 6 H), 3.12 (sept,
J = 6.8 Hz, 1 H), 3.47 (s, 2 H), 6.97 (dd, J = 8.1, 6.6 Hz, 1 H), 7.05
(dd, J = 8.6, 6.8, 0.6 Hz, 1 H), 7.20 (s, 1 H), 7.21–7.28 (m, 1 H),
7.29–7.34 (m, 4 H), 7.56 (d, J = 7.6 Hz, 1 H), 7.61 (d, J = 8.6 Hz, 1
H).
13C NMR (125 MHz, DMSO-d6): d = 23.4, 24.8, 36.5, 49.5, 56.2,
62.0, 113.3, 117.9, 119.1, 120.2, 120.4, 121.0, 126.9, 128.1, 128.4,
128.7, 134.8, 138.5.
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HRMS (EI): m/z calcd for C24H30N2 + [M+ + H]: 347.2482; found:
(10) Pirrung, M. C.; Li, Z.; Park, K.; Zhu, J. J. Org. Chem. 2002,
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347.2484.
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1-(1-Benzyl-4-methylpiperidin-4-yl)-6-fluoro-3-methyl-1H-
indole (5ee)
Purified by preparative HPLC to yield an oil.
1H NMR (400 MHz, DMSO-d6): d = 1.49 (s, 3 H), 2.03–2.11 (m, 2
H), 2.22 (s, 3 H), 2.32–2.48 (m, 6 H), 3.45 (s, 2 H), 6.86 (ddd,
Synthesis 2008, No. 9, 1404–1414 © Thieme Stuttgart · New York

1414
H. Schirok
PAPER
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assisted opening of epoxides in medicinal chemistry is given
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Synthesis 2008, No. 9, 1404–1414 © Thieme Stuttgart · New York