Reductive N-Arylethylation of Aromatic Amines and N-Heterocycles with Enol Ethers

Article abstract of DOI:10.1055/s-0036-1591859

A convenient method for N-arylethylation of aromatic amines and heterocycles under mild reductive conditions was developed using (2-methoxyvinyl)(hetero)arenes as building blocks and triethylsilane/trifluoroacetic acid as reducing agent. This protocol is compatible with numerous functional groups, and aliphatic amines are inert due to protonation.

Full text of DOI:10.1055/s-0036-1591859

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
K. Vögerl et al.
Paper
Synthesis
Reductive N-Arylethylation of Aromatic Amines and N-Heterocycles
with Enol Ethers
Katharina Vögerl
Duc Nghia Ong
Franz Bracher*
R1
OMe
(Het)Ar
R2/H
R1
0
0
0
0
0-
0
0
3
0-
0
0
9
8-
6
2
9
Et3SiH, TFA
CH2Cl2, 0 °C
N
R2/H
Department of Pharmacy – Center for Drug Research,
Ludwig-Maximilians University Munich, Butenandtstr. 5–13,
81377 Munich, Germany
• yield up to 94%
• high chemoselectivity
• no conversion of
aliphatic amines
N
H
(Het)Ar
Franz.Bracher@cup.uni-muenchen.de
17 examples
Received: 07.10.2017
Accepted after revision: 11.11.2017
Published online: 12.12.2017
ethyl halides to give styrenes is a serious side reaction;3 fur-
ther, the phenylethylated products can undergo base-
mediated fragmentation reactions.4 Moreover, phenylethyl
halides bearing additional substituents on the phenyl ring
are barely commercially available, and their synthesis typi-
cally affords multistep protocols starting, for example, from
substituted styrenes, arylacetic acids, or aromatic alde-
hydes.
Phenylethyl compounds are required for systematic
analysis of structure-activity relationships in the develop-
ment of novel amine-based drugs, and several examples
from literature, for example, in morphine-derived analge-
sics,5 demonstrate the superiority of this particular residue
over benzyl and phenylpropyl groups.
DOI: 10.1055/s-0036-1591859; Art ID: ss-2017-t0648-op
Abstract A convenient method for N-arylethylation of aromatic
amines and heterocycles under mild reductive conditions was devel-
oped using (2-methoxyvinyl)(hetero)arenes as building blocks and tri-
ethylsilane/trifluoroacetic acid as reducing agent. This protocol is com-
patible with numerous functional groups, and aliphatic amines are inert
due to protonation.
Key words arylethylation, triethylsilane, aromatic amines, heterocy-
cles, chemoselectivity
Aliphatic and aromatic amines as well as nitrogen het-
erocycles of various degrees of unsaturation are the most
important functional groups in low-molecular weight
drugs. Consequently, controlled protocols for N-alkylation
reactions of primary and secondary amines and N-hetero-
cycles are of high relevance in drug synthesis. The most
prominent strategies for N-alkylation of amines of suffi-
cient nucleophilicity are direct N-alkylation with alkyl ha-
lides or sulfonates in the presence of an organic or inorgan-
ic auxiliary base, and reductive alkylations using appropri-
ate aldehydes in the presence of a reducing agent, for
example, borohydrides.1 Analogous N-alkylation of less nu-
cleophilic aromatic amines (aniline and derivatives) and N-
heterocycles is less convenient, and typically, prior depro-
tonation with strong bases (e.g., sodium hydride) has to be
performed ahead, in order to enhance reactivity towards al-
kyl halides.2 Nevertheless, methyl, alkyl, and benzyl resi-
dues can be introduced conveniently with this standard
method.
Consequently, alternative N-phenylethylation methods
have been worked out over the years. Reductive N-phenyl-
ethylation of amines with phenylacetaldehyde/NaCNBH36 is
hampered by the intrinsic instability of arylacetaldehydes.
Aliphatic and aromatic amines are added to styrenes in an
anti-Markovnikov manner under base or transition-metal
catalysis.7 Base-8 or copper-catalyzed9 addition of styrene
to anilines gives mixtures of mono- and diphenylethylated
products, whereas copper-mediated hydroamination is re-
stricted to electron-deficient styrenes.9
Titanium(III)-catalyzed
hydroamination/hydrosilyla-
tion of phenylacetylene gives mixtures of regioisomers.10
Arylethanols can be used for N-alkylation under ruthenium
catalysis11 and under modified Mitsunobu conditions
(Ph3P/DDQ, one example).12 Mono-phenylethylation of ani-
lines is achieved by copper-promoted cross-coupling with
phenylethylboronic acid.3
Two-step procedures, in which consecutively a C1 build-
ing block and a benzyl residue are attached to the nitrogen
have been published by Katritzky via N-(benzotriazol-1-
yl)methyl13 and (phenylthio)methyl derivatives,14 and by
In contrast, N-phenylethylations are less convenient for
a number of reasons. Under the strongly basic reaction con-
ditions required for prior deprotonation of poorly nucleo-
philic amines and N-heterocycles, β-elimination of phenyl-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
K. Vögerl et al.
Paper
Synthesis
Knochel via N,N-dimethyl(methylene)iminium trifluoroac-
etates.15 However, these protocols require special building
blocks like organozinc reagents.
R1
R2/H
Et3SiH
TFA
R1
N
OMe
Organosilane-acid-mediated reductive alkylations of
amines with (protected) aldehydes have emerged as an at-
tractive alternative to direct N-alkylations via nucleophilic
substitution of alkyl halides and reductive alkylations using
aldehydes in combination with borohydride reagents. A
broad range of anilines have been alkylated using aldehydes
or dimethyl acetals using polymethylhydrosiloxane (PM-
HS)16 or triethylsilane17 combined with trifluoroacetic acid
(TFA). This methodology has been extended to intramolec-
ular N-alkylations giving benzodiazepines, including in situ
deprotection of the N-Boc group.18 This methodology was
further extended to N-methylations using 1,3,5-trioxane as
an easy to handle formaldehyde source.19 All of these proto-
cols allow chemoselective N-alkylations of poorly basic
amines (anilines, indoles, N-heterocycles like carbazoles,
phenothiazines), since aliphatic amines are prevented from
N-alkylation due to complete protonation by the strong
acid (typically trifluoroacetic acid) in the reagent mixture.
To the best of our knowledge, silane/acid-mediated aryleth-
ylation of amines has not been described in the literature
until now.
R2/H
CH2Cl2
0 °C
N
H
1
2–14
Scheme 1 N-Phenethylation of N-containing compounds (aromatic
amines, N-heterocycles) with (E/Z)-(2-methoxyvinyl)benzene (1; 1.5 to
4 equiv) and triethylsilane/trifluoroacetic acid (10 equiv each)
S
N
O
N
N
2
3
4
(1.5 equiv, 2 h, 92%)
(2 equiv, 4 h, 55%)
(2 equiv, 4 h, 54%)
N
N
N
This prompted us to investigate a novel N-arylethylation
protocol. For initial experiments we selected commercially
available (E/Z)-(2-methoxyvinyl)benzene, an enol ether de-
rivative of phenylacetaldehyde with improved stability, as
the source of the phenethyl residue.
5
6
7
(3 equiv, 9 h, 48%)
(4 equiv, 71 h, 80%)
(3 equiv, 8 h, 75%)
O
Me
N
O
Me
Previous applications of the triethylsilane/trifluoroace-
tic acid reagent couple in reductive alkylations using alde-
hydes, acetals16 and 1,3,5-trioxane19 as sources of the alkyl
residue revealed that in this strongly acidic medium ali-
phatic amines are protected by protonation, consequently,
chemoselective N-alkylation of less basic aromatic amines
and N-heterocycles can be accomplished. In a previous in-
vestigation on N-methylations, we already performed a sys-
tematic investigation on the scope and limitations of trieth-
ylsilane/trifluoroacetic acid-mediated reductive alkyla-
tions, and found that besides variously substituted anilines
a broad range of N-heterocycles (3-substituted indoles, car-
bazoles, phenothiazine, phenoxazine) are readily alkylated,
whereas purines, benzimidazole, benzotriazole, acridone,
as well as lactams are not reactive.
N
N
N
9
10
8
(3 equiv, 9 h, 85%)
(3 equiv, 6 h, 55%)
(3 equiv, 5 h, 70%)
O
Cl
Cl
O2N
EtO
NH
NH
NH
Cl
11
12
13
(3 equiv, 5 h, 41%)
(3 equiv, 77 h, 48%)
(2 equiv, 4 h, 52%)
These insights were mostly confirmed in our present in-
vestigations. The substrates were dissolved in dichloro-
methane, treated with excess trifluoroacetic acid (10 equiv)
and triethylsilane (10 equiv), followed by (E/Z)-(2-me-
thoxyvinyl)benzene (1; 1 equiv at once, then, under TLC
monitoring, additional aliquots until full consumption of
the starting amine or stagnation of the reaction). Typically,
about 1.5 to 4 equivalents of the enol ether 1 were needed
for complete conversion (for details, see experimental sec-
tion) (Scheme 1).
NH
N
14
(3 equiv, 15 h, 20%)
Figure 1 Products obtained by N-phenethylation (required numbers
of equivalents of enol ether 1, reaction times, and yields in parenthe-
ses)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
K. Vögerl et al.
Paper
Synthesis
In fact, the heterocycles phenothiazine, phenoxazine,
carbazole, 1,2,3,4-tetrahydrocarbazole, dibenzazepine as
well as its 10,11-dihydro derivative were conveniently
phenethylated to give products 2–7 (Figure 1) in reasonable
yields (48–92%). Similar results were obtained with second-
ary aromatic amines diphenylamine, tetracaine, and
1,2,3,4-tetrahydroquinoline (products 8–10).
is insensitive to the electron density on the aromatic ring
(see ester and methoxy substituents), and further even
works in the presence of a pyridine ring, which can be pro-
tonated under the reaction conditions (Figure 2).
S
S
N
N
Further, we performed control experiments in which
the enol ether 1 was replaced by alternative sources of the
phenethyl residue. Under identical reaction conditions,
phenylacetaldehyde gave a lower yield (81% instead of 92%)
of product 2, and this product was accompanied by a num-
ber of by-products. With phenylacetaldehyde dimethyl ace-
tal even a slightly higher yield (96%) of 2 was achieved.
In the group of aniline-derived primary amines,
monoalkylation was predominant (products 11–13), and
only trace amounts of dialkylated products were identified.
This is in contrast to the above mentioned reductive N-
methylation with the 1,3,5-trioxane/triethylsilane/trifluo-
roacetic acid (TTT) system,19 where primary aromatic
amines gave mainly N,N-dimethyl derivatives. The expected
chemoselectivity over aliphatic amines was found also
here, for instance, 1,2,3,4-tetrahydroquinoline was readily
phenethylated to give 10, whereas its isomer 1,2,3,4-tetra-
hydroisoquinoline (not shown here) was not at all convert-
ed.
With 1,2,3,4-tetrahydro-β-carboline (product 14) only
phenethylation at the indole nitrogen was observed, but
the obtained yield was very poor and purification was te-
dious (Figure 1). As expected, this protocol was not applica-
ble to 3-unsubstituted indoles. As demonstrated by others
before, 3-unsubstituted indoles undergo reductive alkyla-
tion at C-3 when reacted with acetals20 or aldehydes21 in
the presence of triethylsilane and trifluoroacetic acid. In
fact, reaction of 2-phenylindole with enol ether 1 and tri-
ethylsilane/trifluoroacetic acid gave a product (crude yield
69%), which, on the basis of 1H NMR data,22 consisted main-
ly of known 3-phenethyl-2-phenylindole.
O
O
O
15
16
(3 equiv, 1 h, 81%)
(1.5 equiv, 4 h, 68%)
S
S
N
N
S
N
17
18
(2 equiv, 20 h, 72%)
(1.5 equiv, 3 h, 94%)
Figure 2 Variations of the aromatic ring. The (hetero)arylethyl resi-
dues were introduced into phenothiazine by reductive N-alkylation with
the appropriate 2-methoxyvinyl (hetero)arenes using the standard pro-
tocol (required numbers of equivalents of enol ether, reaction times,
and yields in parentheses).
In conclusion, we have presented here a novel, easy to
perform protocol for the chemoselective N-arylalkylation of
anilines and moderately basic heterocycles. As building
blocks we used (2-methoxyvinyl)(hetero)arenes, which
have a number of advantages over building blocks used for
known arylethylation protocols [poorly available (hete-
ro)arylethyl halides, (hetero)arylacetaldehyde acetals and
(hetero)arylacetylenes, instable (hetero)arylacetaldehydes
and styrenes]. Further, this protocol does not require ex-
pensive or polluting metal catalysts, and is characterized by
high functional group compatibility.
We further investigated the arylethylation with other
(2-methoxyvinyl)(hetero)arenes, since the respective resi-
dues are even harder to introduce, as the required (hete-
ro)arylethyl halides are either not commercially available,
or rather instable, as, for example, the corresponding pyr-
idyl derivatives.
This protocol should favorably complement existing
methods for N-arylalkylation of amines and heterocycles,
especially in the field of medicinal chemistry.
For this purpose we performed N-arylalkylations of
phenothiazine to give products 15–18 using appropriate
enol ethers bearing 4-(methoxycarbonyl)phenyl,23 4-me-
thoxyphenyl,24 3-pyridyl,25 and 2-thienyl26 residues. These
building blocks are readily available (as mixtures of E and Z
isomers) in high yields from the corresponding (hetero)aro-
matic aldehydes via Wittig olefination with methoxymeth-
yl(triphenylphosphonium) chloride following established
protocols. All of these reactions proceeded in high yields
(68–81%), demonstrating that this protocol is compatible
with functional groups like esters (in 15) and ethers (in 16),
Melting points were determined with a Büchi Melting Point B-540
(Büchi, Flawil, Switzerland) and are uncorrected. IR spectra were re-
corded with either PerkinElmer FT-IR Spectrometer Paragon 1000
(PerkinElmer, Waltham, USA) or Jasco FT/IR-410 (Jasco Inc., Easton,
USA) as a thin film on a NaCl plate or KBr disc. 1H and 13C NMR spectra
were recorded with either Avance III HD 400 MHz Bruker BioSpin or
Avance III HD 500 MHz Bruker BioSpin spectrometers (Bruker Bio-
Spin, Billerica, USA). Chemical shifts are given in parts per million
(ppm). J values are given in hertz (Hz). Standard abbreviations are
used to denote multiplicities. Signal assignments were carried out
based on 1H, 13C, HMBC, HMQC, and COSY spectra. For the numbering
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
K. Vögerl et al.
Paper
Synthesis
of C-atoms, see Supporting Information. EI mass spectra were record-
ed at an ionization energy of 70 eV with a Finnigan MAT 95 spectrom-
eter (ThermoFisher Scientific, Waltham, USA). ESI mass spectra were
recorded on a Thermo Finnigan LTQ FT at 4 kV (ThermoFisher Scien-
tific, Waltham, USA). Purification by flash column chromatography
(FCC) was performed using Silica Gel 60 (Merck, Darmstadt, Germa-
ny). All reactions were monitored by TLC using precoated plastic
sheets POLYGRAM from Macherey-Nagel (Düren, Germany). Com-
pounds on TLC plates were detected under UV light at 254 nm. HPLC
purity analysis was performed 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 soft-
ware (Agilent, Santa Clara, USA). A G1315A DAD detector was set to
210 nm for detection. The HPLC methods used are listed in the
Supporting Information (Methods a–f).
10-Phenethyl-10H-phenoxazine (3)
Prepared from phenoxazine (183 mg, 1.00 mmol) and enol ether 1 (2
equiv) in CH2Cl2 (3.0 mL); reaction time: 4 h, extraction with EtOAc (2
× 60 mL). FCC [Rf = 0.4 (hexanes–EtOAc, 19:1)] gave the pure com-
pound 3 as a pale beige solid; yield: 157 mg (0.55 mmol, 55%); mp
71–73 °C; purity (HPLC, method a): 99%; tR = 1.6 min.
IR (KBr): 3062, 3026, 2959, 2924, 2900, 2866, 1629, 1592, 1492, 1383,
1327, 1312, 1275, 1133, 1066, 907, 848, 737, 704, 517 cm–1
.
1H NMR (CD2Cl2, 400 MHz): δ = 7.39–7.31 (m, 4 H, 2′′-H, 3′′-H, 5′′-H,
6′′-H), 7.29–7.24 (m, 1 H, 4′′-H), 6.84 (ddd, J = 8.0, 7.1, 1.9 Hz, 2 H, 2-H,
8-H), 6.67 (td, J = 7.5, 1.3 Hz, 2 H, 3-H, 7-H), 6.65–6.59 (m, 4 H, 1-H, 4-
H, 6-H, 9-H), 3.77–3.70 (m, 2 H, 1′-H), 2.99–2.92 (m, 2 H, 2′-H).
13C NMR (CD2Cl2, 101 MHz): δ = 145.5 (C-4a, C-5a), 139.3 (C-1′′),
133.6 (C-9a, C-10a), 129.3 (C-2′′, C-6′′/C-3′′, C-5′′), 129.2 (C-3′′, C-
5′′/C-2′′, C-6′′), 127.1 (C-4′′), 124.3 (C-2, C-8), 121.4 (C-3, C-7), 115.8
(C-4, C-6), 112.0 (C-1, C-9), 46.2 (C-1′), 31.7 (C-2′).
(E/Z)-(2-Methoxyvinyl)benzene (1) was purchased from Sigma-
Aldrich.
MS (ESI): m/z = 288 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H18NO+: 288.1383; found:
N-(Hetero)arylethylation of Aromatic Amines and N-Heterocycles;
General Procedure
288.1384.
The N-containing substrate (1.0 mmol) was dissolved in CH2Cl2 under
N2 atmosphere at 0 °C. Then TFA (0.74 mL, 9.7 mmol), Et3SiH (1.6 mL,
10 mmol), and (E/Z)-(2-methoxyvinyl)benzene (1; 0.13 mL, 1.0
mmol) (or 1.0 mmol of another enol ether, as outlined in the respec-
tive protocols) was added. Progress of the reaction was monitored by
TLC (every 2–3 h), and additional aliquots (0.5 or 1–3 equiv) of the
enol ether were added until full consumption of the starting N-con-
taining substrate or stagnation of the reaction. Then aq 2 N NaOH (20
mL) was added carefully and the mixture was extracted with the indi-
cated solvent. The combined organic layers were dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash column
chromatography (FCC) using the indicated eluent.
9-Phenethyl-9H-carbazole (4)
Prepared from carbazole (167 mg, 1.00 mmol) and enol ether 1 (2
equiv) in CH2Cl2 (3.0 mL); reaction time: 4 h, extraction with EtOAc (2
× 60 mL). FCC [Rf = 0.3 (hexanes–EtOAc, 19:1)] gave the pure com-
pound 44 as a white solid; yield: 145 mg (0.53 mmol, 54%); mp 105–
108 °C; purity (HPLC, method a): 95%; tR = 1.3 min.
IR (KBr): 3049, 3027, 2929, 2878, 2855, 1595, 1484, 1452, 1350, 1326,
1236, 1185, 1152, 1127, 1063, 998, 749, 726, 703, 542 cm–1
.
1H NMR (CD2Cl2, 400 MHz): δ = 8.10 (ddd, J = 7.8, 1.2, 0.8 Hz, 2 H, 4-H,
5-H), 7.44 (ddd, J = 8.2, 7.0, 1.2 Hz, 2 H, 2-H, 7-H), 7.37 (dt, J = 8.2, 0.9
Hz, 2 H, 1-H, 8-H), 7.29–7.17 (m, 7 H, 3-H, 6-H, 2′′-H, 3′′-H, 4′′-H, 5′′-
H, 6′′-H), 4.57–4.51 (m, 2 H, 1′-H), 3.17–3.11 (m, 2 H, 2′-H).
13C NMR (CD2Cl2, 101 MHz): δ = 140.8 (C-8a, C-9a), 139.4 (C-1′′),
129.4 (C-2′′, C-6′′), 129.1 (C-3′′, C-5′′), 127.1 (C-4′′), 126.1 (C-2, C-7),
123.3 (C-4a, C-4b), 120.7 (C-4, C-5), 119.4 (C-3, C-6), 109.2 (C-1, C-8),
45.4 (C-1′), 35.6 (C-2′).
10-Phenethyl-10H-phenothiazine (2)
Prepared from phenothiazine (199 mg, 1.00 mmol) and enol ether 1
(1.5 equiv) in CH2Cl2 (3.0 mL); reaction time: 2 h, extraction with
EtOAc (2 × 70 mL). FCC [Rf = 0.3 (hexanes–EtOAc, 19:1)] gave the pure
compound 227 as a white solid; yield: 280 mg (0.92 mmol, 92%); mp
72–73 °C; purity (HPLC, method a): >99%; tR = 1.6 min.
MS (EI): m/z (%) = 271 ([M•]+, 28), 180 (100), 152 (14), 91 (5).
HRMS (EI): m/z [M•]+ calcd for C20H17N•+: 271.1356; found: 271.1357.
9-Phenethyl-2,3,4,9-tetrahydro-1H-carbazole (5)
IR (KBr): 3059, 3024, 2988, 2933, 2872, 2858, 1589, 1487, 1458, 1335,
1286, 1244, 1174, 1106, 1042, 749, 727, 702, 629, 507 cm–1
.
1H NMR (CD2Cl2, 500 MHz): δ = 7.33–7.22 (m, 5 H, 2′′-H, 3′′-H, 4′′-H,
5′′-H, 6′′-H), 7.19 (ddd, J = 8.1, 7.3, 1.5 Hz, 2 H, 2-H, 8-H), 7.15 (dd, J =
7.6, 1.5 Hz, 2 H, 4-H, 6-H), 6.97 (dd, J = 8.3, 1.2 Hz, 2 H, 1-H, 9-H), 6.94
(td, J = 7.5, 1.2 Hz, 2 H, 3-H, 7-H), 4.12–4.07 (m, 2 H, 1′-H), 3.12–3.06
(m, 2 H, 2′-H).
13C NMR (CD2Cl2, 126 MHz): δ = 145.7 (C-9a, C-10a), 139.8 (C-1′′),
129.3 (C-2′′, C-6′′), 129.0 (C-3′′, C-5′′), 127.9 (C-4, C-6), 127.9 (C-2, C-
8), 126.9 (C-4′′), 125.7 (C-4a, C-5a), 123.1 (C-3, C-7), 116.2 (C-1, C-9),
49.4 (C-1′), 33.9 (C-2′).
Prepared from 2,3,4,9-tetrahydro-1H-carbazole (172 mg, 1.00 mmol)
and enol ether 1 (3 equiv) in CH2Cl2 (1.5 mL); reaction time: 9 h, ex-
traction with CH2Cl2 (3 × 20 mL). FCC [Rf = 0.2 (hexanes–CH2Cl2, 98:2)]
gave the pure compound 528 as a pale yellow oil; yield: 131 mg (0.48
mmol, 48%); purity (HPLC, method b): 98%; tR = 3.9 min.
IR (film): 3084, 3053, 3026, 2929, 2877, 2851, 2837, 1613, 1496,
1467, 1426, 1372, 1357, 1316, 1238, 1177, 1012, 737, 700 cm–1
.
1H NMR (CD2Cl2, 400 MHz): δ = 7.45 (dt, J = 7.8, 1.0 Hz, 1 H, 5-H),
7.33–7.18 (m, 4 H, 8-H, 3′′-H, 4′′-H, 5′′-H), 7.12 (ddd, J = 8.2, 7.0, 1.3
Hz, 1 H, 7-H), 7.08–7.01 (m, 3 H, 6-H, 2′′-H, 6′′-H), 4.25–4.20 (m, 2 H,
1′-H), 3.03–2.96 (m, 2 H, 2′-H), 2.74–2.65 (m, 2 H, 4-H), 2.41–2.37 (m,
2 H, 1-H), 1.87–1.75 (m, 4 H, 2-H, 3-H).
13C NMR (CD2Cl2, 101 MHz): δ = 139.6 (C-1′′), 136.4 (C-8a), 136.2 (C-
9a), 129.5 (C-2′′, C-6′′), 129.0 (C-3′′, C-5′′), 128.3 (C-4b), 127.0 (C-4′′),
120.8 (C-7), 119.0 (C-6), 118.2 (C-5), 109.6 (C-4a), 109.2 (C-8), 45.2
(C-1′), 37.0 (C-2′), 23.9 (C-2/C-3), 23.8 (C-3/C-2), 22.5 (C-1), 21.6 (C-
4).
MS (ESI): m/z = 320, 304 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H18NS+: 304.1155; found:
304.1155.
Control experiments with other sources of the phenethyl residue un-
der otherwise identical reaction conditions: With phenylacetalde-
hyde 245 mg (0.81 mmol, 81%) of 2 were obtained, with phenylacet-
aldehyde dimethyl acetal 291 mg (0.96 mmol, 96%).
MS (ESI): m/z = 276 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
K. Vögerl et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C20H22N+: 276.1747; found:
MS (ESI): m/z = 274 [M + H]+.
276.1747.
HRMS (ESI): m/z [M + H]+ calcd for C20H20N+: 274.1590; found:
5-Phenethyl-5H-dibenz[b,f]azepine (6)
274.1591.
Prepared from 5H-dibenz[b,f]azepine (199 mg, 1.03 mmol) and enol
ether 1 (4 equiv) in CH2Cl2 (3.5 mL); reaction time: 71 h, extraction
with CH2Cl2 (2 × 80 mL). FCC [Rf = 0.2 (hexanes–EtOAc, 19:1)] gave the
pure compound 6 as a reddish-brown oil; yield: 245 mg (0.82 mmol,
80%); purity (HPLC, method a): 97%; tR = 1.6 min.
2-(Dimethylamino)ethyl 4-[N-Butyl-N-(phenethyl)amino]benzo-
ate (9)
Prepared from 2-(dimethylamino)ethyl 4-(butylamino)benzoate (tet-
racaine; 265 mg, 1.00 mmol) and enol ether 1 (3 equiv) in CH2Cl2 (1.0
mL); reaction time: 9 h, extraction with CH2Cl2 (3 × 20 mL). FCC [Rf =
0.3 (CH2Cl2–MeOH, 19:1)] gave the pure compound 9 as a pale yellow
oil; yield: 315 mg (0.85 mmol, 85%); purity (HPLC, method f): >99%; tR
= 3.1 min.
IR (film): 3060, 3023, 2926, 2844, 1593, 1484, 1459, 1436, 1322,
1232, 1179, 1116, 1030, 939, 907, 788, 767, 699 cm–1
.
1H NMR (CD2Cl2, 400 MHz): δ = 7.29 (ddd, J = 8.2, 7.2, 1.7 Hz, 2 H, 3-H,
7-H), 7.29–7.24 (m, 2 H, 3′′-H, 5′′-H), 7.23–7.14 (m, 3 H, 2′′-H, 4′′-H,
6′′-H), 7.09 (dd, J = 7.5, 1.8 Hz, 2 H, 1-H, 9-H), 7.08 (dd, J = 8.1, 0.9 Hz,
2 H, 4-H, 6-H), 7.01 (td, J = 7.3, 1.1 Hz, 2 H, 2-H, 8-H), 6.73 (s, 2 H, 10-
H, 11-H), 3.97–3.92 (m, 2 H, 1′-H), 2.87–2.81 (m, 2 H, 2′-H).
13C NMR (CD2Cl2, 101 MHz): δ = 151.4 (C-4a, C-5a), 140.6 (C-1′′),
134.5 (C-9a, C-11a), 132.6 (C-10, C-11), 129.7 (C-1, C-9), 129.5 (C-2′′,
C-6′′), 129.4 (C-3, C-7), 128.8 (C-3′′, C-5′′), 126.6 (C-4′′), 123.9 (C-2, C-
8), 120.9 (C-4, C-6), 53.0 (C-1′), 34.8 (C-2′).
IR (film): 3085, 3061, 3027, 2956, 2871, 2820, 2769, 1703, 1606,
1523, 1455, 1402, 1365, 1277, 1183, 1112, 828, 768, 700 cm–1
.
1H NMR (CD2Cl2, 400 MHz): δ = 7.89–7.83 (m, 2 H, 2′-H, 6′-H), 7.34–
7.28 (m, 2 H, 3′′′-H, 5′′′-H), 7.26–7.20 (m, 3 H, 2′′′-H, 4′′′-H, 6′′′-H),
6.70–6.64 (m, 2 H, 3′-H, 5′-H), 4.32 (t, J = 5.8 Hz, 2 H, 1′′′′′-H), 3.60–
3.54 (m, 2 H, 1′′-H), 3.30–3.23 (m, 2 H, 1′′′′-H), 2.92–2.86 (m, 2 H, 2′′-
H), 2.65 (t, J = 5.8 Hz, 2 H, 2′′′′′-H), 2.30 (s, 6 H, 2 × CH3), 1.62–1.49 (m,
2 H, 2′′′′-H), 1.34 (m, 2 H, 3′′′′-H), 0.94 (t, J = 7.3 Hz, 3 H, 4′′′′-H).
MS (ESI): m/z = 298 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H20N+: 298.1590; found:
13C NMR (CD2Cl2, 101 MHz): δ = 167.1 (C-1), 151.7 (C-4′), 139.9 (C-
1′′′), 131.9 (C-2′, C-6′), 129.3 (C-2′′′, C-6′′′), 129.1 (C-3′′′, C-5′′′), 126.9
(C-4′′′), 117.0 (C-1′), 111.0 (C-3′, C-5′), 62.7 (C-1′′′′′), 58.6 (C-2′′′′′), 53.3
(C-1′′), 51.4 (C-1′′′′), 46.1 (2 × CH3), 33.9 (C-2′′), 29.8 (C-2′′′′), 20.8 (C-
3′′′′), 14.3 (C-4′′′′).
298.1590.
5-Phenethyl-10,11-dihydro-5H-dibenz[b,f]azepine (7)
Prepared from 10,11-dihydro-5H-dibenz[b,f]azepine (195 mg, 1.00
mmol) and enol ether 1 (3 equiv) in CH2Cl2 (3.0 mL); reaction time: 8
h, extraction with CH2Cl2 (2 × 80 mL). FCC [Rf = 0.3 (hexanes–EtOAc,
19:1)] gave the pure compound 7 as a pale yellow oil; yield: 225 mg
(0.75 mmol, 75%); purity (HPLC, method a): >99%; tR = 2.0 min.
MS (ESI): m/z = 369 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C23H33N2O2+: 369.2537; found:
369.2533.
1-Phenethyl-1,2,3,4-tetrahydroquinoline (10)
IR (film): 3061, 3025, 2918, 2839, 1596, 1487, 1469, 1455, 1332,
Prepared from 1,2,3,4-tetrahydroquinoline (136 mg, 1.02 mmol) and
enol ether 1 (3 equiv) in CH2Cl2 1.5 mL (reaction time): 6 h, extraction
with CH2Cl2 (3 × 20 mL). FCC [Rf = 0.1 (hexanes–CH2Cl2, 9:1)] gave the
pure compound 1030 as a colorless oil; yield: 133 mg (0.56 mmol,
55%); purity (HPLC, method a): 99%; tR = 1.4 min.
1249, 1229, 1125, 1111, 1030, 916, 763, 747, 699 cm–1
.
1H NMR (CD2Cl2, 400 MHz): δ = 7.28–7.21 (m, 2 H, 3′′-H, 5′′-H), 7.21–
7.16 (m, 1 H, 4′′-H), 7.15–7.12 (m, 4 H, 3-H, 4-H, 6-H, 7-H), 7.12–7.05
(m, 4 H, 1-H, 9-H, 2′′-H, 6′′-H), 6.95–6.89 (m, 2 H, 2-H, 8-H), 4.04–3.95
(m, 2 H, 1′-H), 2.97 (s, 4 H, 10-H, 11-H), 2.90–2.82 (m, 2 H, 2′-H).
13C NMR (CD2Cl2, 101 MHz): δ = 148.8 (C-4a, C-5a), 140.6 (C-1′′),
135.0 (C-9a, C-11a), 130.3 (C-1, C-9), 129.3 (C-2′′, C-6′′), 128.8 (C-3′′,
C-5′′), 126.9 (C-3, C-7), 126.6 (C-4′′), 123.0 (C-2, C-8), 120.5 (C-4, C-6),
52.8 (C-1′), 34.9 (C-2′), 32.4 (C-10, C-11).
IR (film): 3062, 3025, 2930, 2884, 2842, 1601, 1505, 1455, 1346,
1304, 1201, 1115, 1061, 994, 743, 699 cm–1
.
1H NMR (CD2Cl2, 400 MHz): δ = 7.35–7.29 (m, 2 H, 3′′-H, 5′′-H), 7.28–
7.20 (m, 3 H, 2′′-H, 4′′-H, 6′′-H), 7.04 (ddd, J = 8.2, 7.3, 1.8 Hz, 1 H, 7-
H), 6.93 (ddd, J = 7.4, 1.9, 1.0 Hz, 1 H, 5-H), 6.65 (dd, J = 8.2, 1.0 Hz, 1 H,
8-H), 6.54 (td, J = 7.3, 1.1 Hz, 1 H, 6-H), 3.52–3.46 (m, 2 H, 1′-H), 3.25–
3.20 (m, 2 H, 2-H), 2.90–2.84 (m, 2 H, 2′-H), 2.76–2.70 (m, 2 H, 4-H),
1.96–1.85 (m, 2 H, 3-H).
13C NMR (CD2Cl2, 101 MHz): δ = 145.5 (C-8a), 140.7 (C-1′′), 129.6 (C-
5), 129.4 (C-2′′, C-6′′), 129.0 (C-3′′, C-5′′), 127.6 (C-7), 126.6 (C-4′′),
123.0 (C-4a), 115.9 (C-6), 110.9 (C-8), 53.9 (C-1′), 50.1 (C-2), 32.9 (C-
2′), 28.7 (C-4), 22.8 (C-3).
MS (ESI): m/z = 300 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H22N+: 300.1747; found:
300.1747.
N-Phenethyl-N-phenylaniline (8)
Prepared from diphenylamine (169 mg, 1.00 mmol) and enol ether 1
(3 equiv) in CH2Cl2 (1.5 mL); reaction time: 5 h, extraction with
CH2Cl2 (3 × 20 mL). FCC [Rf = 0.2 (hexanes–CH2Cl2, 98:2)] gave the pure
compound 829 as a pale beige solid; yield: 190 mg (0.70 mmol, 70%);
mp 60–62 °C; purity (HPLC, method a): 98%; tR = 1.7 min.
MS (ESI): m/z = 238 [M + H]+, 127.
HRMS (ESI): m/z [M + H]+ calcd for C17H20N+: 238.1590; found:
238.1591.
IR (KBr): 3058, 3025, 3002, 2954, 2925, 2870, 1589, 1495, 1450, 1373,
Ethyl 4-(Phenethylamino)benzoate (11)
1354, 1277, 1245, 1181, 1094, 1069, 1019, 748, 727, 699, 554 cm–1
.
Prepared from ethyl 4-aminobenzoate (165 mg, 1.00 mmol) and enol
ether 1 (3 equiv) in CH2Cl2 (3.0 mL); reaction time: 77 h, extraction
with EtOAc (2 × 80 mL). FCC [Rf = 0.2 (hexanes–EtOAc, 9:1)] gave the
pure compound 1131 as a yellow oil; yield: 129 mg (0.48 mmol, 48%);
purity (HPLC, method e): 91%; tR = 1.5 min.
1H NMR (CD2Cl2, 400 MHz): δ = 7.35–7.17 (m, 9 H, 3-H, 5-H, 3′-H, 5′-
H, 2′′′-H, 3′′′-H, 4′′′-H, 5′′′-H, 6′′′-H), 7.00–6.92 (m, 6 H, 2-H, 4-H, 6-H,
2′-H, 4′-H, 6′-H), 3.97–3.90 (m, 2 H, 1′′-H), 2.99–2.92 (m, 2 H, 2′′-H).
13C NMR (CD2Cl2, 101 MHz): δ = 148.4 (C-1, C-1′), 140.2 (C-1′′′), 129.8
(C-3, C-5, C-3′, C-5′), 129.4 (C-2′′′, C-6′′′), 129.0 (C-3′′′, C-5′′′), 126.8 (C-
4′′′), 121.8 (C-4, C-4′), 121.5 (C-2, C-6, C-2′, C-6′), 54.5 (C-1′′), 34.2 (C-
2′′).
IR (film): 3374, 3060, 3027, 2979, 2933, 2869, 1700, 1605, 1526,
1276, 1174, 1107, 1023, 837, 770, 699 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
K. Vögerl et al.
Paper
Synthesis
1H NMR (CD2Cl2, 400 MHz): δ = 7.85–7.81 (m, 2 H, 2′-H, 6′-H), 7.37–
7.30 (m, 2 H, 3′′′-H, 5′′′-H), 7.27–7.21 (m, 3 H, 2′′′-H, 4′′′-H, 6′′′-H),
6.59–6.55 (m, 2 H, 3′-H, 5′-H), 4.27 (q, J = 7.1 Hz, 3 H, CH2CH3, NH),
3.45 (t, J = 7.1 Hz, 2 H, 1′′-H), 2.93 (t, J = 7.1 Hz, 2 H, 2′′-H), 1.34 (t, J =
7.1 Hz, 3 H, CH2CH3).
1H NMR (DMSO-d6, 400 MHz): δ = 9.68 (br s, 1 H, NH), 7.48 (dd, J = 7.9,
1.0 Hz, 2 H, 5-H, 8-H), 7.32–7.18 (m, 3 H, 3′′-H, 4′′-H, 5′′-H), 7.20–7.11
(m, 3 H, 7-H, 2′′-H, 6′′-H), 7.05 (td, J = 7.3, 1.0 Hz, 1 H, 6-H), 4.34–4.26
(m, 2 H, 1′-H), 4.08 (s, 2 H, 1-H), 3.31–3.25 (m, 2 H, 3-H), 2.96–2.88
(m, 4 H, 4-H, 2′′-H).
13C NMR (CD2Cl2, 101 MHz): δ = 167.1 (C-1), 152.4 (C-4′), 139.6 (C-
1′′′), 131.8 (C-2′, C-6′), 129.3 (C-2′′′, C-6′′′), 129.1 (C-3′′′, C-5′′′), 127.0
(C-4′′′), 119.3 (C-1′), 112.0 (C-3′, C-5′), 60.7 (CH2CH3), 45.0 (C-1′′), 35.8
(C-2′′), 14.8 (CH2CH3).
13C NMR (DMSO-d6, 101 MHz): δ = 138.5 (C-1′′), 136.0 (C-8a), 129.0
(C-2′′, C-6′′), 128.3 (C-3′′, C-5′′), 128.0 (C-9a), 126.5 (C-4′′), 125.8 (C-
4b), 121.6 (C-7), 119.1 (C-6), 118.0 (C-5), 109.7 (C-8), 105.5 (C-4a),
44.5 (C-1′), 41.2 (C-3), 39.1 (C-1), 35.7 (C-2′), 18.2 (C-4).
MS (ESI): m/z = 368, 270 [M + H]+.
MS (ESI): m/z = 277 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H20NO2+: 270.1489; found:
HRMS (ESI): m/z [M + H]+ calcd for C19H21N2+: 277.1699; found:
270.1488.
277.1699.
2,4,6-Trichloro-N-phenethylaniline (12)
Methyl 4-[2-(10H-Phenothiazin-10-yl)ethyl]benzoate (15)
Prepared from 2,4,6-trichloroaniline (193 mg, 0.982 mmol) and enol
ether 1 (2 equiv) in CH2Cl2 (2.0 mL); reaction time: 4 h, extraction
with EtOAc (2 × 60 mL). FCC [Rf = 0.2 (hexanes–CH2Cl2, 87:13)] gave
the pure compound 12 as a pale yellow oil; yield: 156 mg (0.52 mmol,
52%); purity (HPLC, method a): 97%; tR = 2.1 min.
Prepared on a larger scale from phenothiazine (501 mg, 2.51 mmol)
and methyl (E/Z)-4-(2-methoxyvinyl)benzoate23 (1.44 g in 1 portion,
7.49 mmol, 3 equiv), using TFA (1.88 mL, 24.4 mmol) and triethylsi-
lane (4.0 mL, 25.0 mmol) in CH2Cl2 (3.8 mL); reaction time: 1 h, ex-
traction with CH2Cl2 (3 × 50 mL). FCC [Rf = 0.4 (CH2Cl–hexanes, 1:1)]
gave the pure compound 15 as pale yellow crystals; yield: 731 mg
IR (film): 3386, 3084, 3063, 3028, 2925, 2854, 1559, 1482, 1452,
(2.02 mmol, 81%); mp 91–92 °C; purity (HPLC, method c): >99%; tR
=
1382, 1242, 1084, 857, 798, 745, 698 cm–1
.
1.3 min.
1H NMR (CD2Cl2, 400 MHz): δ = 7.33–7.27 (m, 2 H, 3′′-H, 5′′-H), 7.24
(s, 2 H, 3-H, 5-H), 7.23–7.20 (m, 3 H, 2′′-H, 4′′-H, 6′′-H), 4.08 (s, 1 H,
NH), 3.60 (q, J = 6.8, 9 Hz, 2 H, 1′-H), 2.86 (t, J = 7.2 Hz, 2 H, 2′-H).
IR (KBr): 3055, 3029, 3005, 2951, 2853, 1713, 1609, 1569, 1484, 1457,
1429, 1335, 1284, 1245, 1177, 1113, 1018, 751, 730, 706 cm–1
.
1H NMR (CD2Cl2, 500 MHz): δ = 7.96–7.91 (m, 2 H, 2′-H, 6′-H), 7.35–
7.30 (m, 2 H, 3′-H, 5′-H), 7.19 (td, J = 7.9, 1.5 Hz, 2 H, 2′′′-H, 8′′′-H),
7.15 (dd, J = 8.0, 1.3 Hz, 2 H, 4′′′-H, 6′′′-H), 6.98–6.92 (m, 4 H, 1′′′-H,
3′′′-H, 7′′′-H, 9′′′-H), 4.15–4.10 (m, 2 H, 2′′-H), 3.87 (s, 3 H, CH3), 3.17–
3.11 (m, 2 H, 1′′-H).
13C NMR (CD2Cl2, 126 MHz): δ = 167.3 (C-1), 145.6 (C-9a′′′, C-10a′′′),
145.2 (C-4′), 130.1 (C-2′, C-6′), 129.4 (C-3′, C-5′), 129.0 (C-1′), 128.0
(C-4′′′, C-6′′′), 127.9 (C-2′′′, C-8′′′), 126.0 (C-4a′′′, C-5a′′′), 123.2 (C-3′′′,
C-7′′′), 116.2 (C-1′′′, C-9′′′), 52.4 (CH3), 48.8 (C-2′′), 33.8 (C-1′′).
13C NMR (CD2Cl2, 101 MHz): δ = 142.2 (C-1), 139.5 (C-1′′), 129.3 (C-2′′,
C-6′′), 129.1 (C-3, C-5, C-3′′, C-5′′), 127.0 (C-4′′), 126.5 (C-2, C-6), 125.5
(C-4), 49.0 (C-1′), 37.5 (C-2′).
MS (ESI): m/z = 304 [M + H]+, 302 [M + H]+, 300 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H13Cl3N+: 300.0108; found:
300.0109.
4-Nitro-N-phenethylaniline (13)
Prepared from 4-nitroaniline (138 mg, 0.999 mmol) and enol ether 1
(3 equiv) in CH2Cl2 (2.5 mL); reaction time: 5 h, extraction with EtOAc
(2 × 60 mL). FCC [Rf = 0.3 (hexanes–EtOAc, 9:1)] gave the pure com-
pound 1332 as yellow crystals; yield: 99 mg (0.41 mmol, 41%); mp 59–
60 °C; purity (HPLC, method d): >99%; tR = 1.2 min.
MS (ESI): m/z = 362 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H20NO2S+: 362.1209; found:
362.1207.
10-(4-Methoxyphenyl)-10H-phenothiazine (16)
IR (KBr): 3347, 3083, 3026, 2932, 2889, 2858, 2789, 1601, 1535, 1470,
Prepared from phenothiazine (199 mg, 1.00 mmol) and (E/Z)-1-me-
thoxy-4-(2-methoxyvinyl)benzene24 (246 mg in 2 portions, 1.50
mmol, 1.5 equiv) in CH2Cl2 (2.0 mL); reaction time: 4 h, extraction
with CH2Cl2 (2 × 80 mL). FCC [Rf = 0.3 (hexanes–EtOAc, 19:1)] gave the
pure compound 16 as a pale yellow oil; yield: 228 mg (0.68 mmol,
68%); purity (HPLC, method a): >99%; tR = 1.8 min.
1293, 1184, 1108, 838, 750, 697, 661 cm–1
.
1H NMR (CD2Cl2, 400 MHz): δ = 8.08–8.03 (m, 2 H, 3-H, 5-H), 7.37–
7.30 (m, 2 H, 3′′-H, 5′′-H), 7.28–7.22 (m, 3 H, 2′′-H, 4′′-H, 6′′-H), 6.59–
6.53 (m, 2 H, 2-H, 6-H), 4.64 (s, 1 H, NH), 3.50 (td, J = 7.1, 5.7 Hz, 2 H,
1′-H), 2.95 (t, J = 7.1 Hz, 2 H, 2′-H).
13C NMR (CD2Cl2, 101 MHz): δ = 153.8 (C-1), 139.1 (C-1′′), 138.5 (C-4),
129.3 (C-3′′, C-5′′), 129.2 (C-2′′, C-6′′), 127.2 (C-4′′), 126.8 (C-3, C-5),
111.6 (C-2, C-6), 45.0 (C-1′), 35.6 (C-2′).
IR (film): 3061, 2995, 2931, 2833, 1611, 1512, 1458, 1336, 1284,
1246, 1178, 1108, 1036, 822, 749, 728 cm–1
.
1H NMR (CD2Cl2, 400 MHz): δ = 7.22–7.13 (m, 6 H, 2-H, 4-H, 6-H, 8-H,
2′′-H, 6′′-H), 6.96 (dd, J = 8.2, 1.1 Hz, 2 H, 1-H, 9-H), 6.94 (td, J = 7.4, 1.2
Hz, 2 H, 3-H, 7-H), 6.87–6.82 (m, 2 H, 3′′-H, 5′′-H), 4.09–4.02 (m, 2 H,
1′-H), 3.77 (s, 3 H, CH3), 3.07–2.99 (m, 2 H, 2′-H).
MS (ESI): m/z = 287 [M + formate]–, 241 [M – H]–.
HRMS (ESI): m/z [M – H]– calcd for C14H13N2O2–: 241.0983; found:
241.0984.
13C NMR (CD2Cl2, 101 MHz): δ = 158.9 (C-4′′), 145.7 (C-9a, C-10a),
131.8 (C-1′′), 130.2 (C-2′′, C-6′′), 127.9 (C-2, C-8), 127.8 (C-4, C-6),
125.7 (C-4a, C-5a), 123.0 (C-3, C-7), 116.2 (C-1, C-9), 114.4 (C-3′′, C-
5′′), 55.7 (CH3), 49.6 (C-1′), 32.9 (C-2′).
MS (ESI): m/z = 334 [M + H]+, 135.
HRMS (ESI): m/z [M + H]+ calcd for C21H20NOS+: 334.1260; found:
9-Phenethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (14)
Prepared from 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (173 mg,
1.00 mmol) and enol ether 1 (3 equiv) in CH2Cl2 (2.0 mL); reaction
time: 15 h, extraction with CH2Cl2 (3 × 20 mL). FCC [Rf = 0.2 (CH2Cl2–
MeOH, 98:2, then crystallization from CH2Cl2–hexanes)] gave the
pure compound 14 as pale beige crystals; yield: 54 mg (0.20 mmol,
20%); mp 216–219 °C; purity (HPLC, method f): >99%; tR = 1.5 min.
334.1260.
IR (KBr): 3418, 3054, 3024, 2925, 2782, 2703, 2657, 2631, 2452, 1583,
1465, 1344, 1177, 1066, 880, 738, 706, 532 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
K. Vögerl et al.
Paper
Synthesis
10-[2-(Pyridin-2-yl)ethyl]-10H-phenothiazine (17)
References
Prepared from phenothiazine (199 mg, 1.00 mmol) and (E/Z)-3-(2-
methoxyvinyl)pyridine25 (270 mg in 2 portions, 2.00 mmol, 2 equiv)
in CH2Cl2 (2.0 mL); reaction time: 20 h, extraction with CH2Cl2 (2 × 80
mL). FCC [Rf = 0.5 (hexanes–EtOAc, 19:1)] gave the pure compound 17
as a white solid; yield: 218 mg (0.72 mmol, 72%); mp 94–95 °C; purity
(HPLC, method a): >99%; tR = 0.9 min.
(1) Abdel-Magid, A. F.; Mehrmann, S. J. Org. Process Res. Dev. 2006,
10, 971.
(2) Wekesa, F. S.; Phadke, N.; Jahier, C.; Cordes, D. B.; Findlater, M.
Synthesis 2014, 46, 1046.
(3) Larrosa, M.; Guerrero, C.; Rodríguez, R.; Cruces, J. Synlett 2010,
2101.
(4) Eisch, J. J.; Dua, S. K.; Kovacs, C. A. J. Org. Chem. 1987, 52, 4437.
(5) Haddou, T. B.; Béni, S.; Hosztafi, S.; Malfacini, D.; Calo, G.;
Schmidhammer, H.; Spetea, M. PLOS One 2014, 9, e99231.
(6) Eggler, J. F.; Holland, G. F.; Johnson, M. R.; Volkmann, R. A.
(Pfizer Inc.) US Patent 4738972, 1988.
(7) (a) Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. (b) Kumar,
K.; Michalik, D.; Castro, I. G.; Tillack, A.; Zapf, A.; Arlt, M.;
Heinrich, T.; Böttcher, H.; Beller, M. Chem. Eur. J. 2004, 10, 746.
(8) Jaspers, D.; Doye, S. Synlett 2011, 1444.
(9) Munro-Leighton, C.; Delp, S. A.; Alsop, N. M.; Blue, E. D.;
Gunnoe, T. B. Chem. Commun. 2008, 111.
(10) Heutling, A.; Pohlki, F.; Bytschkov, I.; Doye, S. Angew. Chem. Int.
Ed. 2005, 44, 2951.
IR (KBr): 3087, 3051, 3033, 2952, 2935, 2864, 1567, 1458, 1335, 1302,
1243, 1195, 1167, 1105, 1032, 853, 753, 714, 624, 506 cm–1
.
1H NMR (CD2Cl2, 400 MHz): δ = 8.44 (d, J = 2.0 Hz, 1 H, 2′′-H), 8.42 (dd,
J = 4.8, 1.7 Hz, 1 H, 6′′-H), 7.55 (ddd, J = 7.8, 2.3, 1.7 Hz, 1 H, 4′′-H),
7.21–7.19 (m, 1 H, 5′′-H), 7.20 (ddd, J = 8.2, 7.3, 1.5 Hz, 2 H, 2-H, 8-H),
7.16 (dd, J = 7.9, 1.5 Hz, 2 H, 4-H, 6-H), 6.95 (dd, J = 8.1, 1.3 Hz, 2 H, 1-
H, 9-H), 6.95 (ddd, J = 7.4, 1.2 Hz, 2 H, 3-H, 7-H), 4.15–4.09 (m, 2 H, 1′-
H), 3.10–3.05 (m, 2 H, 2′-H).
13C NMR (CD2Cl2, 101 MHz): δ = 150.7 (C-2′′), 148.4 (C-6′′), 145.6 (C-
9a, C-10a), 136.7 (C-4′′), 135.1 (C-3′′), 128.1 (C-4, C-6), 127.9 (C-2, C-
8), 126.2 (C-4a, C-5a), 123.8 (C-5′′), 123.3 (C-3, C-7), 116.3 (C-1, C-9),
48.7 (C-1′), 31.0 (C-2′).
MS (ESI): m/z = 305 [M + H]+, 113.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2S+: 305.1107; found:
(11) Hamid, M. H. S. A.; Williams, J. M. J. Chem. Commun. 2007, 725.
(12) Iranpoor, N.; Firouzabadi, H.; Nowrouzi, N.; Khalili, D. Tetrahe-
dron 2009, 65, 3893.
305.1106.
(13) (a) Katritzky, A. R.; Shobana, N.; Harris, P. A. Tetrahedron Lett.
1991, 32, 4247. (b) Katritzky, A. R.; Strah, S.; Belyakov, S. A.
Tetrahedron 1998, 54, 7167.
(14) Katritzky, A. R.; Saczewski, F.; Marson, C. M. J. Org. Chem. 1985,
50, 1351.
(15) Werner, V.; Ellwart, M.; Wagner, A. J.; Knochel, P. Org. Lett.
2015, 17, 2026.
(16) Patel, J. P.; Li, A.-H.; Dong, H.; Korlipara, V. L.; Mulvihill, M. J.
Tetrahedron Lett. 2009, 50, 5975.
(17) Righi, M.; Bedini, A.; Piersanti, G.; Romagnoli, F.; Spadoni, G.
J. Org. Chem. 2011, 76, 704.
(18) Popp, T. A.; Uhl, E.; Ong, D. N.; Dittrich, S.; Bracher, F. Tetrahe-
dron 2016, 72, 1668.
(19) Popp, T. A.; Bracher, F. Synthesis 2015, 47, 3333.
(20) Righi, M.; Topi, F.; Bartolucci, S.; Bedini, A.; Piersanti, G.;
Spadoni, G. J. Org. Chem. 2012, 77, 6351.
10-[2-(Thiophen-2-yl)ethyl]-10H-phenothiazine (18)
Prepared from phenothiazine (199 mg, 1.00 mmol) and (E/Z)-2-(2-
methoxyvinyl)thiophene26 (210 mg in 2 portions, 1.50 mmol, 1.5
equiv) in CH2Cl2 (2.0 mL) reaction time: 3 h, extraction with CH2Cl2 (2
× 80 mL). FCC [Rf = 0.4 (hexanes–EtOAc, 19:1)] gave the pure com-
pound 18 as a resiny white solid; yield: 291 mg (0.94 mmol, 94%); pu-
rity (HPLC, method e): 97%; tR = 3.5 min.
IR (film): 3065, 2917, 2849, 1781, 1593, 1571, 1458, 1365, 1335,
1285, 1248, 1193, 1105, 1039, 928, 850, 824, 748, 696 cm–1
.
1H NMR (DMSO-d6, 500 MHz): δ = 7.31 (dd, J = 5.1, 1.3 Hz, 1 H, 5′′-H),
7.22 (ddd, J = 8.2, 7.3, 1.6 Hz, 2 H, 2-H, 8-H), 7.17 (dd, J = 7.6, 1.5 Hz, 2
H, 4-H, 6-H), 7.09 (dd, J = 8.2, 1.1 Hz, 2 H, 1-H, 9-H), 6.96 (td, J = 7.5,
1.1 Hz, 2 H, 3-H, 7-H), 6.96 (dd, J = 3.3, 1.2 Hz, 1 H, 3′′-H), 6.93 (dd, J =
5.0, 3.4 Hz, 1 H, 4′′-H), 4.16–4.11 (m, 2 H, 1′-H), 3.23–3.18 (m, 2 H, 2′-
H).
(21) Appleton, J. E.; Dack, K. N.; Green, A. D.; Steele, J. Tetrahedron
Lett. 1993, 34, 1529.
(22) Cabrero-Antonino, J. R.; Adam, R.; Junge, K.; Beller, M. Chem. Sci.
2017, 8, 6439.
(23) Xiao, Y.; Araldi, G. L.; Zhao, Z.; Reddy, A.; Karra, S.; Brugger, N.;
Fischer, D.; Palmer, E.; Bao, B.; McKenna, S. D. Bioorg. Med.
Chem. Lett. 2008, 18, 821.
13C NMR (DMSO-d6, 126 MHz): δ = 144.5 (C-9a, C-10a), 140.9 (C-2′′),
127.6 (C-2, C-8), 127.2 (C-4, C-6), 126.9 (C-4′′), 125.4 (C-3′′), 124.2 (C-
5′′), 124.0 (C-4a, C-5a), 122.7 (C-3, C-7), 115.9 (C-1, C-9), 47.9 (C-1′),
26.7 (C-2′).
MS (ESI): m/z = 326, 310 [M + H]+, 212.
HRMS (ESI): m/z [M + H]+ calcd for C18H16NS2+: 310.0719; found:
(24) Brown, C. E.; McNulty, J.; Bordon, C.; Yolken, R.; Jones-Brando, L.
Org. Biomol. Chem. 2016, 14, 5951.
310.0718.
(25) Xiao, Y.; Araldi, G. L.; Zhao, Z.; Reddy, A.; Karra, S.; Brugger, N.;
Fischer, D.; Palmer, E.; Bao, B.; Mckenna, S. D. Bioorg. Med. Chem.
Lett. 2008, 18, 821.
Acknowledgment
(26) Winterfeldt, E. Chem. Ber. 1963, 96, 3349.
(27) Clarke, D.; Gilbert, B. C.; Hanson, P.; Kirk, C. M. J. Chem. Soc.,
Perkin Trans. 2 1978, 1103.
We thank Karl Sauvageot-Witzku and Anna Niedrig for technical sup-
port.
(28) El-Hamamy, A. A.; Hill, J.; Townend, J. J. Chem. Soc., Perkin Trans.
1 1983, 573.
(29) Wekesa, F. S.; Phadke, N.; Jahier, C.; Cordes, D. B.; Findlater, M.
Synthesis 2014, 46, 1046.
(30) Mokrosz, J. L.; Bojarski, A. J.; Charakchieva-Minol, S.; Duszynska,
B.; Mokrosz, M. J.; Paluchowska, M. H. Arch. Pharm. (Weinheim)
1995, 328, 604.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591859.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
K. Vögerl et al.
Paper
Synthesis
(31) Albright, J. D.; DeVries, V. G.; Largis, E. E.; Miner, T. G.; Reich, M.
F.; Schaffer, S. A.; Shepherd, R. G.; Upeslacis, J. J. Med. Chem.
1983, 26, 1378.
(32) Manning, R. E. US Patent 3963780 A, 1976.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H