N-methylation of aromatic amines and N-heterocycles under acidic conditions with the TTT (1,3,5-trioxane-triethylsilane-trifluoroacetic acid) system

Article abstract of DOI:10.1055/s-0034-1381049

A novel reductive N-methylation protocol under acidic conditions with the TTT (1,3,5-trioxane-triethylsilane-trifluoroacetic acid) system is disclosed. This method is highly specific for aromatic amines and several N-heterocycles (indoles and annulated analogues, phenoxazine, phenothiazine), insensitive to steric hindrance, and compatible with a wide range of functional groups. Further the N-methylation step can be combined with an in situ N-Boc deprotection. Compounds in which the nucleophilicity of the NH group is eliminated by protonation under the reaction conditions (aliphatic amines, azaarenes of noteworthy basicity) are inert. In several examples, it was demonstrated that the TTT system is complementary to other N-methylation protocols.

Full text of DOI:10.1055/s-0034-1381049

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3333–3338
paper
3333
T. A. Popp, F. Bracher
Paper
Synthesis
N-Methylation of Aromatic Amines and N-Heterocycles under
Acidic Conditions with the TTT (1,3,5-Trioxane–Triethylsilane–
Trifluoroacetic Acid) System
Tobias A. Popp
Franz Bracher*
O
O
O
, Et3SiH,
Ar
Ar
Me
CF3COOH, CH2Cl2
Department of Pharmacy - Center for Drug Research,
Ludwig-Maximilians University Munich,
Butenandtstr. 5–13, 81377 Munich, Germany
Franz.Bracher@cup.uni-muenchen.de
NH
N
· 24–48 h, r.t., 29–99%
· N-methylation under
acidic conditions
R/H
R/Me
14 examples
· high chemoselectivity
· no conversion of
aliphatic amines
Received: 11.05.2015
Accepted after revision: 22.06.2015
Published online: 07.08.2015
A mild alternative is the reductive N-methylation with
formaldehyde and reducing agents like formic acid
(Eschweiler–Clarke reaction4) and complex hydrides (sodi-
um borohydride,5 sodium cyanoborohydride in combina-
tion with mild Brønsted acids6 or Lewis acids7). This meth-
od avoids the formation of quaternary ammonium salts, but
proceeds significantly slower with aromatic amines.5b Pri-
mary amines give the N,N-dimethyl derivatives directly.6 A
reductive N-methylation of aliphatic and aromatic amines
using paraformaldehyde in strongly acidic media has been
published, but tedious adjustment of reaction conditions
(reducing agent sodium borohydride or sodium cyanoboro-
hydride; solvent mixtures containing acetic acid, trifluoro-
acetic acid, either neat or diluted with THF) was necessary,
depending on the nature of the starting amines.8 The re-
ductive N-methylation of aliphatic and aromatic amines
with formaldehyde can also be performed with decaborane
as reducing agent.9
Selective monomethylation of primary amines can be
achieved by conversion into N-formyl derivatives10 or alkyl
carbamates,11 followed by reduction with lithium alumi-
num hydride. Indoles and related azaheterocycles are N-
methylated upon heating with dimethylformamide dimeth-
yl acetal.12
In continuation of our research on bioactive indole, β-
carboline, and carbazole derivatives,2,13 we required an im-
proved method for selective N-methylation of the pyrrole-
type NH function of these and related heteroarenes. This
new protocol should avoid side reactions that occur under
the commonly used reaction conditions. We were inspired
by a report on the N-alkylation of aromatic amines and het-
eroarenes with acetals of aldehydes and triethylsilane14 or
other silanes15 in the presence of trifluoroacetic acid (TFA).
This method works well for acetals of both aliphatic14 and
aromatic aldehydes,15 but has, to the best of our knowledge,
DOI: 10.1055/s-0034-1381049; Art ID: ss-2015-t0311-op
Abstract A novel reductive N-methylation protocol under acidic con-
ditions with the TTT (1,3,5-trioxane–triethylsilane–trifluoroacetic acid)
system is disclosed. This method is highly specific for aromatic amines
and several N-heterocycles (indoles and annulated analogues, phenox-
azine, phenothiazine), insensitive to steric hindrance, and compatible
with a wide range of functional groups. Further the N-methylation step
can be combined with an in situ N-Boc deprotection. Compounds in
which the nucleophilicity of the NH group is eliminated by protonation
under the reaction conditions (aliphatic amines, azaarenes of notewor-
thy basicity) are inert. In several examples, it was demonstrated that
the TTT system is complementary to other N-methylation protocols.
Key words N-methylation, aromatic amines, heterocycles, chemose-
lectivity, triethylsilane, trioxane
N-Methylation of primary, and even more important,
secondary amines is a reaction of very high importance in
natural products and drug synthesis, and numerous meth-
ods have been worked out for this conversion over the de-
cades. Classical methods utilize methyl halides or dimethyl
sulfate in the presence of acid scavengers for N-methylation
of amines, or go through amide anions in the case of poorly
nucleophilic substrates like anilines, pyrroles, azoles, and
annulated analogues. These protocols typically give good
yields, but are hampered by the volatility and toxicity of the
methylation agents.1 Moreover, overalkylation leading to
quaternary ammonium salts or undesired C-alkylations at
acidic positions2 can take place under the required alkaline
reaction conditions. Alternative methods include the use of
the less toxic dimethyl carbonate, but with this reagent un-
desired C-methylations1 as well as N- and C-methoxycarbo-
nylations and formation of symmetrical ureas can occur.3
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3334
T. A. Popp, F. Bracher
Paper
Synthesis
not yet been applied to the introduction of a methyl group.
The organosilane-trifluoroacetic acid mixture is compatible
with a broad range of functional and protective groups.16
1,3,5-Trioxane, the cyclic trimer of formaldehyde, was
selected as precursor of the methyl group for a number of
reasons: first, this compound has a promising acetal-like
structure, further it is (unlike paraformaldehyde) readily
soluble in organic solvents,17 and (in contrast to commonly
used formaldehyde solution) allows working under anhy-
drous conditions.
We intended to investigate a broad panel of aromatic
and aliphatic amines, as well as heterocyclic compounds,
and selected two compounds for an explorative analysis:
the aromatic amine 1,2,3,4-tetrahydroquinoline (1) and its
regioisomer 1,2,3,4-tetrahydroisoquinoline (2) as a second-
ary aliphatic amine. The first experiments clearly indicated
that the aromatic amine 1 readily undergoes N-methylation
to give 1-M with a 1,3,5-trioxane–triethylsilane–trifluoro-
acetic acid (TTT) mixture, whereas the aliphatic amine 2
was recovered unchanged. Reaction conditions for the N-
methylation of 1,2,3,4-tetrahydroquinoline were optimized
systematically, and the following best conditions were
identified: 3 equivalents of 1,3,5-trioxane, 10 equivalents of
triethylsilane in a 1:2 trifluoroacetic acid–dichloromethane
mixture under nitrogen atmosphere, room temperature,
and 24 to 48 hours (TLC control). N-Methylated product 1-
M was obtained in 64% yield after 48 hours; no by-products
were observed, and significant amounts of starting material
were recovered (Scheme 1).
N
N
Me
Me
3-M
(24 h, 89%)
4-M
(48 h, 51%)
O
O
Me
N
OEt
O
Me
Me
N
H
N
Me
5-M
(48 h, 51%)
6-M1
(48 h, 37%)
O
Me
Me
OEt
N
NO2
Me
N
Me
6-M2
(48 h, 57%)
7-M
(48 h, 99%)
Cl
O
Me
N
Cl
N
Me
Me
Cl
9-M
8-M
(48 h, 93%)
(24 h, 99%)
S
1,3,5-trioxane, Et3SiH,
TFA, CH2Cl2
N
N
Me
Me
N
N
48 h, 64%
H
Me
10-M
(24 h, 93%)
11-M
(24 h, 61%)
1-M
1
Scheme 1 N-Methylation of 1,2,3,4-tetrahydroquinoline (1) with the
1,3,5-trioxane–triethylsilane–trifluoroacetic acid (TTT) mixture
NH
O
N
N
Figure 1 shows the outcome of further N-methylation
experiments, in Figure 2 compounds are presented, which
did not undergo N-methylation. The secondary aromatic
amines diphenylamine, N-benzylaniline, and tetracaine
gave the corresponding N-methylated products 3-M, 4-M,
and 5-M in 51–89% yields; once again no side-products
were observed. The primary aromatic amine ethyl 4-ami-
nobenzoate gave 57% of the N,N-dimethyl derivative 6-M2
and 37% of the monomethylated product 6-M1, whereas 4-
nitroaniline was converted into its N,N-dimethyl derivative
7-M in almost quantitative yield, without affecting the nitro
group. Sterically hindered 2,4,6-trichloroaniline was
smoothly converted into the N,N-dimethyl derivative 8-M
(93% yield). Previous synthesis of 8-M required refluxing
the aniline with dimethyl sulfate in toluene, giving only 54%
yield.18
Me
Me
13-M
(48 h, 29%)
14-M
(48 h, 67%)
NH2
N
Me
15-M
(48 h, 30%)
Figure 1 Products obtained by N-methylation with the TTT mixture.
The introduced methyl groups are highlighted in bold, and reaction
times and yields are given in parentheses. Both compounds 6-M1 and
6-M2 were obtained upon conversion of ethyl 4-aminobenzoate.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3333–3338

3335
T. A. Popp, F. Bracher
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Synthesis
Surprisingly, no conversion was achieved with both the
O
1-oxo-1,2,3,4-tetrahydro-β-carboline 1622 and harmane
(17). We assume that in these examples the nucleophilicity
of the pyrrole nitrogen is strongly diminished by cationic
groups (protonated lactam carbonyl group, protonated pyr-
idine ring) in direct conjugation to the nitrogen atom. We
investigated another lactam substrate 18,23 but once again
only recovered the starting material. The same outcome
was observed for theophylline (19), not even traces of N-
methylation product caffeine were found. Finally, other
azaaromatic compounds were investigated, but no conver-
sion of benzimidazole (20), 2-chlorobenzimidazole (21), 4-
iodopyrazole (22), and benzotriazole (23) was observed.
Our attempts to extend this method to the N-ethylation
of aromatic amines failed. Reaction of 1,2,3,4-tetrahydro-
quinoline (1) and paraldehyde (2,4,6-trimethyl-1,3,5-triox-
ane), the cyclic trimer of acetaldehyde, with triethylsilane
in trifluoroacetic acid–dichloromethane gave a complex
mixture of unidentifiable products.
Since trifluoroacetic acid is a major component of the
TTT reagent mixture, we investigated whether the above
mentioned N-methylation procedure can be combined with
other trifluoroacetic acid-mediated reactions. N-Boc groups
are cleanly cleaved by this acid; further, triethylsilane is
known as a beneficial scavenger for tert-butyl cations in
deprotections of tert-butyl esters and tert-butoxycarbonyl
residues.20b,24 Accordingly, N-Boc-carbazole (11-Boc)25 was
treated with the TTT mixture, and in fact N-methylcarba-
zole (11-M) was obtained in 49% yield in a one-pot depro-
tection–methylation sequence (Scheme 2).
NH
NH
N
N
H
H
O
12
16
2
EtO
O
O
H
Me
O
N
N
N
N
H
NH
N
N
Me
O
17
18
19
H
I
H
N
N
R
N
NH
N
N
N
20 R = H
21 R = Cl
22
23
Figure 2 Compounds that did not undergo any conversion with the
TTT system
In the series of heterocyclic substrates, phenoxazine and
phenothiazine gave excellent yields of 9-M and 10-M, and
N-methylcarbazole (11-M) was formed in 61% yield. In con-
trast, acridone (12) did not undergo any reaction.
Next, indole-based compounds bearing additional func-
tional groups were investigated. The N-methylated product
13-M was obtained from 1-oxo-1,2,3,4-tetrahydrocarba-
zole in 29% yield, the only other substance in the reaction
mixture was the starting material. This outcome is in strong
contrast to attempts to perform the same conversion in a
classical manner (sodium hydride, iodomethane), which
gave only the 2,2,9-trimethyl derivative.2 In accordance
with the previous insights, 1,2,3,4-tetrahydro-β-carboline
gave the N9-methylated product 14-M19 in 67% yield, with
no indication of a methylation of the secondary aliphatic
amino group. In an analogous manner, exclusively the N1-
methylated derivative 15-M (30% yield) was obtained from
tryptamine. Most likely, in both cases the aliphatic amino
groups are fully protonated in the strongly acidic reagent
mixture,15a and thence protected from electrophilic attack
by a reactive cationic intermediate generated from 1,3,5-
trioxane.
This shows impressively that our TTT method is com-
plementary to the standard reductive N-methylation proto-
col (aqueous formaldehyde, sodium cyanoborohydride),
which gives clean conversions of 2 into 2-methyl-1,2,3,4-
tetrahydroisoquinoline19 and of tryptamine to N′,N′-di-
methyltryptamine.10 The results obtained with tryptamine
are noteworthy, since we observed neither a reduction to
Pictet–Spengler-type cyclization
tetrahydro-β-carboline), as
demonstrated for related arylethylamines, when treated
1,3,5-trioxane, Et3SiH,
TFA, CH2Cl2
N
N
48 h, 49%
Me
O
Ot-Bu
11-Boc
11-M
Scheme 2 One-pot deprotection–methylation of N-Boc-carbazole
(11-Boc)
In conclusion, we have worked out a novel reductive N-
methylation protocol under acidic conditions with the TTT
(1,3,5-trioxane–triethylsilane–trifluoroacetic acid) system.
This method is highly specific for aromatic amines and sev-
eral N-heterocycles (indoles and annulated analogues, phe-
noxazine, phenothiazine), insensitive to steric hindrance,
and compatible with a wide range of functional groups.
Further, the N-methylation step can be combined with an
in situ N-Boc deprotection. Compounds in which the nucle-
ophilicity of the NH group is eliminated by protonation un-
der the reaction conditions (aliphatic amines, azaarenes of
noteworthy basicity) are inert. In contrast to established re-
ductive N-methylation protocols utilizing formaldehyde
and complex hydrides in neutral or acidic solution,5–9 this
system shows no tendency for methylation of aliphatic
the indoline20 nor
(which would result in
a
a
with 1,3,5-trioxane and acid.21
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T. A. Popp, F. Bracher
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Synthesis
amines. In several examples, the TTT system is demonstrat-
ed as complementary to other N-methylation protocols,
hence, we are confident that it will be a versatile tool for
chemoselective N-methylations in the future.
N-Methyl-N-phenylaniline (3-M)
Prepared from diphenylamine. Standard protocol workup after 24 h
and purification by FCC [Rf = 0.5 (hexanes–EtOAc, 10:1)] gave the pure
compound as a colorless oil; yield: 0.35 g (1.9 mmol, 89%); purity
(HPLC): >99%; tR = 3.7 min.
IR (film): 3060, 3035, 2939, 2878, 1591, 1496, 1342, 1252, 1131 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.22 (m, 4 H), 7.03–6.98 (m, 4 H),
6.96–6.91 (m, 2 H), 3.29 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 149.1, 129.3, 121.4, 120.5, 40.3.
MS (EI+): m/z (%) = 77.1 (32), 104.1 (17), 168.1 (11), 183.2 (100, [M]+).
HRMS (EI+): m/z [M]+ calcd for C13H13N: 183.1048; found: 183.1036.
Melting points were determined with a Büchi Melting Point B-540
(Büchi, Flawil, Switzerland) and are uncorrected. IR spectra were re-
corded with a Perkin Elmer FT-IR Spectrometer Paragon 1000 (Perkin
Elmer, Waltham, USA) as a thin film on a NaCl plate or KBr discs. 1H
and 13C NMR spectra were recorded with either Avance III HD 400
MHz Bruker BioSpin or Avance III HD 500 MHz Bruker BioSpin spec-
trometers (Bruker Biospin, Billerica, USA). Chemical shifts are given in
ppm. EI mass spectra were recorded at an ionization energy of 70 eV
either with a JMS GCmate II Jeol or a JEOL JMS-700 MStation (Joel,
Peabody, USA). ESI mass spectra were recorded on a Thermo Finnigan
LTQ FT at 4 kV (ThermoFisher Scientific, Waltham, USA). Purification
by flash column chromatography (FCC) was performed using Silica
Gel 60 (Merck, Darmstadt, Germany). HPLC purity analysis was per-
formed on an Agilent 1100 Series apparatus with a G1311A Quat-
Pump, a G1329A ALS autosampler, a G1316A ColComp column oven,
and Agilent ChemStation Rev. B04.02 as software (Agilent, Santa
Clara, USA). A G1315A DAD detector was set to 210 nm for detection.
Agilent Poroshell 120 EC-C18 (3.0 × 100 mm; 2.7 μm) was used as
column and a mixture of 80% MeCN, 19.8% H2O, and 0.2% THF as mo-
bile phase. Flow was 0.8 mL/min and column temperature 50 °C. In-
jection volume was 5 or 10 μL of a dilution of 100 μg/mL (sample in
mobile phase).
N-Benzyl-N-methylaniline (4-M)
Prepared from N-benzylaniline. Standard protocol workup after 48 h
and purification by FCC [Rf = 0.6 (hexanes–EtOAc, 10:1)] gave the pure
compound as a yellow oil; yield: 0.19 g (1.0 mmol, 51%); purity
(HPLC): 96%; tR = 4.6 min.
IR (film): 3061, 3026, 2894, 1599, 1506, 1451, 1354 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.33–7.27 (m, 2 H), 7.25–7.18 (m, 5 H),
6.77–6.72 (m, 2 H), 6.72–6.68 (m, 1 H), 4.51 (s, 2 H), 2.99 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 149.9, 139.1, 129.3, 128.7, 127.0,
126.8, 116.6, 112.5, 56.7, 38.6.
MS (EI+): m/z (%) = 91.0 (100), 120.1 (59), 197.1 (71, [M]+).
HRMS (EI+): m/z [M]+ calcd for C14H15N: 197.1204; found: 197.1198.
2-(Dimethylamino)ethyl 4-(N-Butyl-N-methylamino)benzoate
(5-M)
N-Methylation of Aromatic Amines and N-Heterocycles; General
Procedure
Prepared from 2-(dimethylamino)ethyl 4-(N-butylamino)benzoate
(tetracaine). Standard protocol workup after 48 h and purification by
FCC [Rf = 0.2 (CH2Cl2 + 10% MeOH)] gave the pure compound as a col-
The N-containing substrate (1 mmol) and trioxane (270 mg, 3 mmol)
were dissolved in CH2Cl2 (1.5 mL) under N2 atmosphere. To this solu-
tion were added TFA (0.75 mL) and Et3SiH (1.45 mL, 10 mmol). The
reaction was monitored by TLC (eluent: see below). After 24 or 48 h
(in case of incomplete conversion, after 24 h), aq 2 N NaOH (20 mL)
solution was carefully added and the mixture was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried (MgSO4)
and concentrated in vacuo and the residue was purified by flash col-
umn chromatography (FCC).
orless oil; yield: 0.27 g (1.0 mmol, 51%); purity (HPLC): >99%; tR
=
3.6 min.
IR (film): 2956, 2873, 2770, 1703, 1607, 1525, 1278, 1184, 1111 cm–1
.
1H NMR (500 MHz, CD2Cl2): δ = 7.76–7.73 (m, 2 H), 6.54–6.51 (m, 2
H), 4.21 (t, J = 5.9 Hz, 2 H), 3.28–3.24 (m, 2 H), 2.88 (s, 3 H), 2.54 (t,
J = 5.8 Hz, 2 H), 2.19 (s, 6 H), 1.50–1.43 (m, 2 H), 1.29–1.20 (m, 2 H),
0.85 (t, J = 7.3 Hz, 3 H).
13C NMR (126 MHz, CD2Cl2): δ = 167.1, 153.0, 131.7, 117.0, 110.9,
62.7, 58.6, 52.6, 46.1, 38.7, 29.5, 20.8, 14.3.
1-Methyl-1,2,3,4-tetrahydroquinoline (1-M)
Prepared from 1,2,3,4-tetrahydroquinoline. Standard protocol work-
up after 48 h and purification by FCC [Rf = 0.5 (hexanes–EtOAc, 20:1)]
gave the pure compound as a colorless oil; yield: 0.32 g (2.2 mmol,
64%); purity (HPLC): >99%; tR = 2.7 min.
MS (EI+): m/z (%) = 58.1 (100), 164.1 (53), 207.1 (38), 278.2 (0.2, [M]+).
HRMS (EI+): m/z [M]+ calcd for C16H26N2O2: 278.1994; found:
278.1997.
IR (film): 3065, 2927, 2862, 1602, 1507, 1321, 1208 cm–1
.
Ethyl 4-(N-Methylamino)benzoate (6-M1) and Ethyl 4-(N,N-Di-
methylamino)benzoate (6-M2)
1H NMR (500 MHz, CDCl3): δ = 7.15–7.11 (m, 1 H), 7.02–6.99 (m, 1 H),
6.68–6.63 (m, 2 H), 3.28–3.25 (m, 2 H), 2.93 (s, 3 H), 2.82 (t, J = 6.5 Hz,
2 H), 2.07–2.00 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 146.9, 128.9, 127.1, 123.0, 116.3,
111.1, 51.4, 39.2, 27.9, 22.6.
MS (EI+): m/z (%) = 91.1 (21), 131.1 (23), 146.1 (100, [M – H]+), 147.1
(87, [M]+).
HRMS (EI+): m/z [M]+ calcd for C10H13N: 147.1048; found: 147.1031.
Prepared from ethyl 4-aminobenzoate (benzocaine). Standard proto-
col workup after 48 h and purification by FCC [Rf = 0.5 and 0.3 (hex-
anes–EtOAc, 5:1)] gave ethyl 4-(methylamino)benzoate (6-M1) and
ethyl 4-(dimethylamino)benzoate (6-M2) as white solids.
6-M1
Yield: 0.13 g (0.7 mmol, 37%); mp 62.4–62.7 °C; purity (HPLC): >99%;
tR = 1.8 min.
IR (KBr): 3383, 2962, 2936, 2903, 1680, 1602, 1538, 1276, 1174, 835
cm–1
.
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T. A. Popp, F. Bracher
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Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.90–7.86 (m, 2 H), 6.57–6.53 (m, 2 H),
13C NMR (126 MHz, CDCl3): δ = 145.7, 135.1, 123.9, 121.0, 115.4,
4.31 (q, J = 7.1 Hz, 2 H), 4.19 (s, 1 H), 2.88 (s, 3 H), 1.36 (t, J = 7.1 Hz, 3
111.5, 31.0.
H).
MS (EI+): m/z (%) = 127.1 (6), 182.1 (100), 197.1 (63, [M]+).
HRMS (EI+): m/z [M]+ calcd for C13H11NO: 197.0841; found: 197.0831.
13C NMR (126 MHz, CDCl3): δ = 167.0, 152.9, 131.6, 118.7, 111.2, 60.3,
30.3, 14.6.
MS (EI+): m/z (%) = 106.1 (10), 134.1 (100), 151.1 (19), 179.1 (68,
10-Methyl-10H-phenothiazine (10-M)
[M]+).
Prepared from 10H-phenothiazine. Standard protocol workup after
24 h and purification by FCC [Rf = 0.6 (hexanes–EtOAc, 20:1)] gave the
pure compound as a white solid; yield: 0.41 g (1.9 mmol, 95%); mp
100.5–101.7 °C; purity (HPLC): 99%; tR = 4.0 min.
HRMS (EI+): m/z [M]+ calcd for C10H13NO2: 179.0946; found:
179.0947.
IR (KBr): 3058, 2968, 2888, 1592, 1568, 1457, 1331, 1258, 1137 cm–1
.
6-M2
Yield: 0.21 g (1.1 mmol, 57%); mp 61.4–62.3 °C; purity (HPLC): >99%;
tR = 2.6 min.
1H NMR (500 MHz, CDCl3): δ = 7.21–7.14 (m, 4 H), 6.97–6.92 (m, 2 H),
6.82 (dd, J = 8.1, 1.1 Hz, 2 H), 3.38 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 145.9, 127.5, 127.3, 123.5, 122.6,
IR (KBr): 2982, 2903, 2820, 1695, 1611, 1365, 1283, 1186, 1106 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.93–7.89 (m, 2 H), 6.64–6.60 (m, 2 H),
4.31 (q, J = 7.1 Hz, 2 H), 3.00 (s, 6 H), 1.36 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 167.0, 153.2, 131.2, 117.3, 110.7, 60.1,
114.2, 35.4.
MS (EI+): m/z (%) = 198.1 (73), 213.1 (100, [M]+).
HRMS (EI+): m/z [M]+ calcd for C13H11NS: 213.0612; found: 213.0601.
40.0, 14.5.
MS (EI+): m/z (%) = 148.1 (100), 164.1 (41), 193.2 (68, [M]+).
HRMS (EI+): m/z [M]+ calcd for C11H15NO2: 193.1103; found:
9-Methyl-9H-carbazole (11-M)
Prepared from 9H-carbazole. Standard protocol workup after 24 h
and purification by FCC [Rf = 0.3 (hexanes–EtOAc, 20:1)] gave the pure
compound as a white solid; yield: 0.21 g (1.2 mmol, 61%). Starting
from N-Boc-carbazole (11-Boc), the same solid product was obtained
in slightly lower yield (0.17 g, 1.0 mmol, 49%); mp 84.4–85.3 °C; puri-
ty (HPLC): 97%; tR = 3.9 min.
IR (KBr): 3433, 3049, 2926, 1598, 1467, 1323, 1246 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J = 8.0 Hz, 2 H), 7.45–7.40 (m, 2
H), 7.30 (d, J = 8.2 Hz, 2 H), 7.22–7.18 (m, 2 H), 3.70 (s, 3 H).
193.1088.
N,N-Dimethyl-4-nitroaniline (7-M)
Prepared from 4-nitroaniline. Standard protocol workup after 48 h
and purification by FCC [Rf = 0.3 (hexanes–EtOAc, 5:1)] gave the pure
compound as a yellow solid; yield: 0.31 g (1.9 mmol, 99%); mp 162.1–
162.9 °C; purity (HPLC): >96%; tR = 2.0 min.
.
IR (KBr): 3424, 2924, 1735, 1601, 1582, 1485, 1457, 1310, 1116 cm–1
.
1H NMR (500 MHz, CD2Cl2): δ = 8.12–8.05 (m, 2 H), 6.65–6.60 (m, 2
13C NMR (126 MHz, CDCl3): δ = 141.1, 125.7, 122.8, 120.4, 118.9,
H), 3.09 (s, 6 H).
108.5, 29.0.
13C NMR (126 MHz, CD2Cl2): δ = 154.7, 137.1, 126.3, 110.6, 40.5.
MS (EI+): m/z (%) = 152.1 (20), 166.1 (9), 181.1 (100, [M]+).
MS (EI+): m/z (%) = 105.0 (18), 119.0 (26), 136.1 (28)
HRMS (EI+): m/z [M]+ calcd for C13H11N: 181.0891; found: 181.0884.
166.1 (100, [M]+).
HRMS (EI+): m/z [M]+ calcd for C8H10N2O2: 166.0742; found:
9-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (13-M)
166.0738.
Prepared from 2,3,4,9-tetrahydro-1H-carbazol-1-one. Standard pro-
tocol workup after 48 h and purification by FCC [Rf = 0.3 (hexanes–
EtOAc, 10:1)] gave the pure compound as a yellow solid; yield: 0.11 g
(0.6 mmol, 29%); mp 95.1–97.3 °C; purity (HPLC): 98%; tR = 2.5 min.
N,N-Dimethyl-2,4,6-trichloroaniline (8-M)
Prepared from 2,4,6-trichloroaniline. Standard protocol workup after
48 h and purification by FCC [Rf = 0.7 (hexanes)] gave the pure com-
pound as a colorless oil; yield: 0.40 g (1.8 mmol, 93%); purity (HPLC):
>99%; tR = 10.4 min.
IR (KBr): 3428, 2927, 2838, 1643, 1408, 1230, 935, 760 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.62 (d, J = 8.1 Hz, 1 H), 7.39–7.35 (m, 1
H), 7.30 (d, J = 8.5 Hz, 1 H), 7.14–7.10 (m, 1 H), 4.03 (s, 3 H), 2.97 (t,
J = 6.1 Hz, 2 H), 2.63–2.59 (m, 2 H), 2.21–2.15 (m, 2 H).
IR (film): 3054, 2986, 1421, 1265, 739, 705 cm–1
.
1H NMR (500 MHz, CD2Cl2): δ = 7.30–7.28 (m, 2 H), 2.85 (s, 6 H).
13C NMR (126 MHz, CD2Cl2): δ = 145.8, 136.3, 130.4, 129.2, 42.2.
MS (EI+): m/z (%) = 223.0 (49, [M]+), 222.0 (100, [M – H]+).
13C NMR (126 MHz, CDCl3): δ = 192.3, 139.7, 130.4, 129.2, 126.7,
124.7, 121.3, 120.0, 110.3, 40.1, 31.6, 24.8, 21.9.
MS (EI+): m/z (%) = 128.0 (20), 143.1 (63), 170.1 (40), 199.1 (100,
[M]+).
HRMS (EI+): m/z [M]+ calcd for C8H8Cl3N: 222.9722; found: 222.9722.
HRMS (EI+): m/z [M]+ calcd for C13H13NO: 199.0997; found: 199.0988.
10-Methyl-10H-phenoxazine (9-M)
9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (14-M)
Prepared from 10H-phenoxazine. Standard protocol workup after 24
h and purification by FCC [Rf = 0.6 (hexanes–EtOAc, 20:1)] gave the
pure compound as a white to pale violet solid; yield: 0.37 g
(1.9 mmol, 99%); mp 26.5–27.1 °C; purity (HPLC): >99%; tR = 3.4 min.
IR (KBr): 3063, 2882, 1592, 1486, 1362, 1268, 1217 cm–1
1H NMR (500 MHz, CDCl3): δ = 6.90–6.84 (m, 2 H), 6.75–6.70 (m, 4 H),
6.54 (d, J = 7.9 Hz, 2 H), 3.05 (s, 3 H).
Prepared from 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. Standard
protocol workup after 48 h and purification by FCC [Rf = 0.3 (CH2Cl2 +
10% MeOH)] gave the pure compound as a yellow oil; yield: 0.24 g
(1.3 mmol, 67%); purity (HPLC): 95%; tR = 2.6 min.
.
IR (film): 3306, 3049, 2918, 2838, 1615, 1471, 1380, 1183, 739 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3333–3338

3338
T. A. Popp, F. Bracher
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.48 (dt, J = 7.8, 1.0 Hz, 1 H), 7.25 (dt,
J = 8.2, 1.0 Hz, 1 H), 7.17 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 7.08 (ddd,
J = 8.0, 7.0, 1.1 Hz, 1 H), 4.01 (t, J = 1.7 Hz, 2 H), 3.56 (s, 3 H), 3.15 (t,
J = 5.7 Hz, 2 H), 2.79–2.72 (m, 2 H), 1.80 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 136.8, 134.4, 127.2, 121.0, 118.9,
117.9, 108.7, 107.7, 44.0, 42.5, 29.3, 22.7.
(4) Clarke, H. T.; Gillespie, H. B.; Weisshaus, S. Z. J. Am. Chem. Soc.
1933, 55, 4571.
(5) (a) Sondengam, B. L.; Hémo, J. H.; Charles, G. Tetrahedron Lett.
1973, 14, 261. (b) Bhattacharyya, S. Synth. Commun. 1995, 25,
2061.
(6) Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673.
(7) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J. Org. Chem.
1985, 50, 1927.
(8) Gribble, G. W.; Nutaitis, C. F. Synthesis 1987, 709.
(9) Jung, Y. J.; Bae, J. W.; Yoon, C.-O. M.; Yoo, B. W.; Yoon, C. M.
Synth. Commun. 2001, 31, 3417.
MS (EI+): m/z (%) = 142.1 (11), 157.1 (100), 186.1 (36, [M]+).
HRMS (EI+): m/z [M]+ calcd for C12H14N2: 186.1157; found: 186.1152.
2-(1-Methyl-1H-indol-3-yl)ethan-1-amine (15-M)
(10) Castro, J. L.; Baker, R.; Guiblin, A. R.; Hobbs, S. C.; Jenkins, M. R.;
Russel, M. G. N.; Beer, M. S.; Stanton, J. A.; Scholey, K.;
Hargreaves, R. J.; Graham, M. I.; Matassa, V. G. J. Med. Chem.
1994, 37, 3023.
Prepared from 2-(1H-indol-3-yl)ethan-1-amine (tryptamine). Stan-
dard protocol workup after 48 h and purification by FCC [Rf = 0.1
(CH2Cl2 + 10% MeOH)] gave the pure compound as a colorless oil;
yield: 0.10 g (0.6 mmol, 30%); purity (HPLC): 96%; tR = 3.0 min.
(11) (a) Horner, J. K.; Skinner, W. A. Can. J. Chem. 1966, 44, 315.
(b) Ram, S.; Ehrenkaufer, R. E. Tetrahedron Lett. 1985, 26, 5367.
(12) (a) Stanovnik, B.; Tisler, M.; Hribar, A.; Barlin, G. B.; Brown, D. J.
Austr. J. Chem. 1981, 34, 1729. (b) Middleton, R. W.; Monney, H.;
Parrick, J. Synthesis 1984, 740.
(13) (a) Pohl, B.; Luchterhandt, T.; Bracher, F. Synth. Commun. 2007,
37, 1273. (b) Fedorov, O.; Huber, K.; Eisenreich, A.;
Filippakopoulos, P.; King, O.; Bullock, A. N.; Fabro, D.; Trappe, J.;
Rauch, U.; Bracher, F.; Knapp, S. Chem. Biol. 2011, 18, 67.
(c) Huber, K.; Brault, L.; Fedorov, O.; Gasser, C.; Filippakopoulos,
P.; Bullock, A. N.; Fabbro, D.; Trappe, J.; Schwaller, J.; Knapp, S.;
Bracher, F. J. Med. Chem. 2012, 55, 403. (d) Strödke, B.; Gehring,
A. P.; Bracher, F. Arch. Pharm. Chem. Life Sci. 2015, 348, 125.
(14) Righi, M.; Bedini, A.; Piersanti, G.; Romagnoli, F.; Spadoni, G.
J. Org. Chem. 2011, 76, 704.
IR (film): 3347, 3050, 2926, 1578, 1473, 1328, 739 cm–1
.
1H NMR (500 MHz, CD2Cl2): δ = 7.55 (d, J = 7.9 Hz, 1 H), 7.26 (d, J = 8.2
Hz, 1 H), 7.17 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 7.04 (ddd, J = 7.9, 6.9, 1.1
Hz, 1 H), 6.89 (s, 1 H), 3.69 (s, 3 H), 3.13 (s, 2 H), 2.97 (t, J = 6.8 Hz, 2
H), 2.89 (t, J = 6.8 Hz, 2 H).
13C NMR (126 MHz, CD2Cl2): δ = 137.6, 128.2, 127.5, 121.8, 119.1,
119.0, 111.9, 109.6, 42.4, 32.8, 28.5.
MS (ESI+): m/z (%) = 158.1 (100), 175.1 (78, [M + H]+).
HRMS (ESI+): m/z [M + H]+ calcd for C11H15N2: 175.1230; found:
175.1231.
Acknowledgment
(15) (a) Patel, J. P.; Li, A.-H.; Dong, H.; Korlipara, V. L.; Mulvihill, M. J.
Tetrahedron Lett. 2009, 50, 5975. (b) Park, E. S.; Lee, J. H.; Kim, S.
J.; Yoon, C. M. Synth. Commun. 2003, 33, 3387.
We thank Andrea Lopéz Goméz, Lorenz Isert, Michael Tully, and Minh
Ngoc Diep Huynh for valuable technical support.
(16) Righi, M.; Topi, F.; Bartolucci, S.; Bedini, A.; Piersanti, G.;
Spadoni, G. J. Org. Chem. 2012, 77, 6351.
(17) Sokol, H.; Heights, H. US Patent 2465489 A, 1949; Chem. Abstr.
1949, 43, 5809i.
(18) Pews, R. G.; Hunter, J. E.; Wehmeyer, R. M. Tetrahedron 1993, 49,
4809.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1381049.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(19) Butler, K. V.; Kalin, J.; Brochier, C.; Vistoli, G.; Langley, B.;
Kozikowski, A. P. J. Am. Chem. Soc. 2010, 132, 10842.
(20) (a) Lanzilotti, A. E.; Littell, R.; Fanshawe, W. J.; McKenzie, T. C.;
Lovell, F. M. J. Org. Chem. 1979, 44, 4809. (b) Pearson, D. A.;
Blanchette, M.; Baker, M. L.; Guindon, C. A. Tetrahedron Lett.
1989, 30, 2739.
(21) Chen, M. Z.; Micalizio, G. C. Org. Lett. 2009, 11, 4982.
(22) Bracher, F.; Hildebrand, D. Liebigs Ann. Chem. 1992, 1315.
(23) Bracher, F.; Hildebrand, D. Arch. Pharm. (Weinheim) 1992, 325,
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3333–3338