Hydroaminoalkylation/Buchwald-Hartwig amination sequences for the synthesis of benzo-annulated seven-membered nitrogen heterocycles

Article abstract of DOI:10.1016/j.tet.2019.04.041

Reaction sequences consisting of an initial intermolecular titanium-catalyzed hydroaminoalkylation of a suitably ortho-bromophenyl-substituted alkene and a subsequent intramolecular Buchwald-Hartwig amination are used for the synthesis of benzazepine, ben

Full text of DOI:10.1016/j.tet.2019.04.041

Accepted Manuscript
Hydroaminoalkylation/Buchwald-Hartwig amination sequences for the synthesis of
benzo-annulated seven-membered nitrogen heterocycles
Tobias Kaper, Sven Doye
PII:
S0040-4020(19)30453-3
https://doi.org/10.1016/j.tet.2019.04.041
TET 30286
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 February 2019
Revised Date: 12 April 2019
Accepted Date: 16 April 2019
Please cite this article as: Kaper T, Doye S, Hydroaminoalkylation/Buchwald-Hartwig amination
sequences for the synthesis of benzo-annulated seven-membered nitrogen heterocycles, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.04.041.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Hydroaminoalkylation/Buchwald-Hartwig
amination sequences for the synthesis of
benzo-annulated seven-membered nitrogen
heterocycles
Leave this area blank for abstract info.
Tobias Kaper, Sven Doye*
Institut für Chemie, Universität Oldenburg, Carl-von-Ossietzky-Str. 9-11, 26129 Oldenburg, Germany

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Hydroaminoalkylation/Buchwald-Hartwig amination sequences for the synthesis of
benzo-annulated seven-membered nitrogen heterocycles
Tobias Kaper, Sven Doye∗
Institut für Chemie, Universität Oldenburg, Carl-von-Ossietzky-Str. 9-11, 26129 Oldenburg, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Reaction sequences consisting of an initial intermolecular titanium-catalyzed
hydroaminoalkylation of a suitably ortho-bromophenyl-substituted alkene and a subsequent
intramolecular Buchwald-Hartwig amination are used for the synthesis of benzazepine,
benzoxazepine, and benzothiazepine derivatives. While in the latter two cases, the
hydroaminoalkylation products obtained from an allyl (2-bromophenyl) ether or an allyl (2-
bromophenyl) thioether must be purified prior to the subsequent palladium-catalyzed amination
step, both reactions can be combined to an efficient one-pot procedure for the synthesis of
Available online
Keywords:
Amines
Azepanes
Hydroaminoalkylation
Palladium
2
,3,4,5-tetrahydrobenzo[b]azepines when 4-(2-bromophenyl)-1-butene and various N-
methylanilines are used as the starting materials.
2
009 Elsevier Ltd. All rights reserved.
Titanium
1
. Introduction
membered rings of the target compounds. However, on the other
hand, even one of the earliest reports on the palladium-catalyzed
amination of aryl halides [9] which is now known as the
Buchwald-Hartwig amination [10] contains an example of the
conversion of a suitable 4-(2-bromophenyl)butylamine into a
Benzo-annulated,
nitrogen-containing,
seven-membered
heterocycles such as benzazepines [1], benzodiazepines [2],
benzoxazepines [3], or benzothiazepines [4] represent an
important class of compounds in medicinal chemistry with
various pharmacological properties (Figure 1). For example, the
ACE inhibitor benazepril (a benzazepine derivative) [5] and the
calcium channel blocker diltiacem (a benzothiazepine derivative)
2
,3,4,5-tetrahydrobenzo[b]azepine. Based on this result and our
own achievements in the field of titanium-catalyzed alkene
hydroaminoalkylation [11,12], we recently developed new one-
pot procedures for the synthesis of 1,5-benzodiazepines [13] and
[
6] are used to treat high blood pressure, while many members of
1
,5-benzoazasilepines [14] which take place by an initial
the benzodiazepine family (e.g. clobazam) are commonly known
as psychoactive drugs.
regioselective intermolecular hydroaminoalkylation reaction of
an N-allyl-2-bromoaniline or an allyl(2-bromophenyl)silane and a
subsequent intramolecular Buchwald-Hartwig amination
(
Scheme 1, E = NR, SiMe ). In this context it is worth
2
mentioning that closely related one-pot procedures that combine
a titanium- or a tantalum-catalyzed alkene hydroaminoalkylation
with
a subsequent palladium-catalyzed Buchwald-Hartwig
amination have also been developed for the synthesis of 1,4-
benzoazasilines [15] or indolines [16] and in addition, a titanium-
catalyzed alkyne hydroamination was used as the initial step of a
corresponding one-pot indole synthesis [17]. On the other hand,
to the best of our knowledge, corresponding reaction sequences
for the synthesis of benzazepine, benzoxazepine, and
Figure 1. Pharmacologically relevant examples of benzo-
annulated, nitrogen-containing, seven-membered heterocycles.
benzothiazepine derivatives (Scheme 1, E = CH , O, S) have not
been reported yet.
From
a
synthetic point of view, classical chemical
2
transformations such as condensation reactions which form
amide or imine moieties [7] or 1,4-addition reactions of hetero
atom nucleophiles to α,β-unsaturated carbonyl compounds [8]
have often been used as key steps to build up the seven-
Although hydroaminoalkylation reactions of alkenes with
secondary amines can be achieved in the presence of selected late
transition metal catalysts [18], group 4 [11] and group 5 [19]
—
——
∗
Corresponding author. Fax: +49-441-798-3329; e-mail: doye@uni-oldenburg.de

2
Tetrahedron
or MAN
metal catalysts offer a number of significan
A
t a
C
dv
C
an
E
ta
P
ge
T
s.
E
F
D
W
U
ithSCth
R
eseIPre
T
sults in hand, we then directly attempted to
example, the latter catalysts do not require the presence of a
directing or protecting group on the nitrogen of the amine
substrate and in addition, terminal alkyl-substituted alkenes are
usually converted into the branched hydroaminoalkylation
products with good to excellent regioselectivities.
perform the hydroaminoalkylation of 2 with 3 and a subsequent
Buchwald-Hartwig amination following a one-pot protocol
(Scheme 3). For that purpose, we first repeated the reaction
between 2 and 3 under the reaction conditions described above.
Then 2.5 mol% Pd (dba) , 7 mol% RuPhos, NaOtBu and
2
3
additional toluene were directly added to the obtained crude
hydroaminoalkylation reaction mixture and the resulting mixture
was heated to 110 °C for 24 h. Finally, the crude product was
purified by flash column chromatography to give to the desired
2
,3,4,5-tetrahydrobenzo[b]azepine 6 in 89 % yield. Interestingly,
the two-step one-pot procedure from 2 to 6 gave a better isolated
yield than the initial hydroaminoalkylation reaction from which
product 5 could only be isolated in 83 % yield. A plausible
explanation for this observation is the decreased polarity of the
tertiary amine 6 compared to the secondary amine 5 which
facilitates the final chromatographic purification.
Scheme 1. Synthesis of benzo-annulated seven-membered
nitrogen-containing
heterocycles
by
alkene
hydroaminoalkylation/Buchwald-Hartwig amination sequences.
2
. Results and discussion
Initial hydroaminoalkylation reactions of 4-phenyl-1-butene
(1) and 4-(2-bromophenyl)-1-butene (2) with N-methylaniline (3,
Scheme 2) were performed in the presence of the titanium
formamidinate catalyst I that was originally used by Eisen et al.
as a polymerization catalyst [20]. In this context, it is important
to mention that catalysts I was also found to exhibit exceptionally
high catalytic activity in hydroaminoalkylation reactions which
for example, even allows the use of 1,2-disubstituted alkenes as
starting materials [21]. Further advantages of catalyst I are the
high regioselectivity in favor of the branched products observed
in hydroaminoalkylation reactions of mono-substituted alkenes
such as allylbenzene [21] and the fact that this catalyst has
Scheme 3. One-pot hydroaminoalkylation/Buchwald-Hartwig
amination sequence for the synthesis of 2,3,4,5-tetrahydro-
benzo[b]azepine 6.
already
hydroaminoalkylation/Buchwald-Hartwig amination sequences
13,14]. Our study started with an initial experiment in which the
been
used
successfully
in
one-pot
[
Table 1. One-pot procedure for the synthesis of 2,3,4,5-
tetrahydrobenzo[b]azepines.
non-halogenated substrate 4-phenyl-1-butene (1) was reacted
with N-methylaniline (3) in toluene at 140 °C for 24 h in the
presence of 10 mol% of catalyst I (Scheme 2). After the
corresponding branched hydroaminoalkylation product 4 had
been obtained in excellent yield of 93 %, the halogenated
substrate 4-(2-bromophenyl)-1-butene (2) was also reacted with 3
under identical conditions and as observed before [13], the
presence of the ortho-bromo substituent in 2, which is required
for the planned subsequent intramolecular Buchwald-Hartwig
amination, did not lead to a dramatically reduced yield. Even in
this case, the branched hydroaminoalkylation product 5 could be
isolated in 83 % yield. In this context, it should also be
mentioned that in both experiments, formation of linear
hydroaminoalkylation products was not observed by GC-
analysis.
a
Entry
R
Yield (%)
88 (16)
70 (17)
85 (18)
80 (19)
77 (20)
59 (21)
71 (22)
79 (23)
62 (24)
1
2
3
4
5
6
7
8
9
p-Me (7)
p-OMe (8)
p-F (9)
iPr iPr
p-OCF (10)
3
1
2
: X = H
: X = Br
X
10 mol%
m-Me (11)
p-iPr (12)
p-Cl (13)
p-SMe (14)
m-F (15)
I
N
N
+
X
NH
iPr
iPr
HN
toluene
40 °C, 24 h
Ti(NMe2)3
1
I
3
4
5
: X = H, 93 %
: X = Br, 83 %
Scheme 2. Hydroaminoalkylation of 4-phenyl-1-butene (1)
and 4-(2-bromophenyl)-1-butene (2) with N-methylaniline (3) in
the presence of catalyst I.
a
Reaction conditions: 1) 4-(2-bromophenyl)-1-butene (2,
64 mg, 2.2 mmol), aniline (2.0 mmol), I (109 mg, 0.2
4
mmol, 10 mol%), toluene (1 mL), 140 °C, 24 h; 2) Pd (dba)
2
3

3
(
7
1
46 mg, 0.05 mmol, 2.5 mol%), RuPhos (65 mg
.0 mol%), NaOtBu (261 mg, 2.7 mmol), toluene (5 mL),
10 °C, 24 h. Isolated yield.
A
, 0
C
.1
C
4
E
mm
P
o
T
l,ED MA
T
N
ab
U
le
S
3.
C
H
R
yd
I
roaminoalkylation of allyl thioethers with N-
P
T
methylaniline (3).
To investigate the scope of the new one-pot procedure for the
synthesis of 2,3,4,5-tetrahydrobenzo[b]azepines, we then reacted
with the para- and meta-substituted N-methylanilines 7-15
Table 1). In this context, it should be mentioned that we did not
2
(
use any ortho-substituted N-methylanilines because these
substrates are known to react sluggishly in titanium-catalyzed
hydroaminoalkylation reactions [12e,13,21]. As can be seen from
Table 1, 2 reacts smoothly with 7-15 to give the desired 2,3,4,5-
tetrahydrobenzo[b]azepines 16-24 in good to very good yields of
a
Entry
X
Catalyst (mol%) T (°C) t (h) Yield (%)
1
2
3
4
H
10
10
10
20
20
140
140
140
160
160
24
48
24
24
48
45 (31)
55 (31)
14 (32)
55 (32)
71 (32)
H
5
9-88 %. Overall, it turned out that the one-pot procedure not
Br
Br
Br
only tolerates alkyl and ether substitution but also the presence of
pharmacologically relevant fluoro and thioether substituents. In
addition, the chloro substituent present in product 22 offers
various possibilities for further functionalization.
5
a
Reaction conditions: allyl thioether (2.2 mmol), N-
methylaniline (3, 214 mg, 2.0 mmol), I (10 or 20 mol%),
toluene (1 mL), 140 or 160 °C, 24 or 48 h. Isolated yield.
In comparison with 4-phenyl-1-butene (1), the corresponding
allyl ether 25 (Table 2) was then found to be significantly less
reactive in hydroaminoalkylation reactions with N-methylaniline
Additional hydroaminoalkylation reactions performed with
the allyl thioethers 29 and 30 (Table 3) and N-methylaniline (3)
then revealed a comparably reduced reactivity of the sulfur
derivatives and as a result, it was again necessary to heat the
reaction mixture to 160 °C for 48 h in the presence of 20 mol%
of I to convert the allyl (2-bromophenyl) thioether 30 into the
corresponding hydroaminoalkylation product 32 in 71 % yield
(3). While under the reaction conditions described above (10
mol% I, 140 °C, 24 h) 1 had been converted into the
hydroaminoalkylation product 4 in 93 % yield (Scheme 2), the
allyl ether 25 delivered the desired product 27 in only 47 % yield
(
Table 2, entry 1). However, the yield could easily be improved
to acceptable 70 % by extending the reaction time to 48 h (Table
, entry 2). On the other hand, hydroaminoalkylation reactions of
2
(
Table 3, entry 5).
allyl (2-bromophenyl) ether (26) turned out to be even more
challenging. In the presence of 10 mol% of catalyst I, reactions
performed at 140 or 160 °C for 24 or 48 h (Table 2, entries 3-5)
gave the corresponding product 28 only in disappointing yields
between 7 and 15 %. Fortunately, it finally turned out that the
yield of the hydroaminoalkylation reaction could be improved to
6
4
0 % with a catalyst loading of 20 mol% and a reaction time of
8 h at 160 °C (Table 2, entry 7).
Table 2. Hydroaminoalkylation of allylethers with N-
methylaniline (3).
Scheme 4. Attempted one-pot procedure for the synthesis of
benzoxazepine and benzothiazepine derivatives.
After suitable reaction conditions
hydroaminoalkylation of the ortho-bromo substituted allyl ether
6 and the allyl thioether 30 had been identified, we used these
for
the
2
conditions for one-pot hydroaminoalkylation/Buchwald-Hartwig
amination sequences which were expected to directly give access
to the benzoxazepine derivative 33 and the benzothiazepine
derivative 34 (Scheme 4). However, although for the second
reaction, the conditions that had already been used successfully
a
Entry
X
Catalyst (mol%) T (°C) t (h) Yield (%)
1
2
3
4
5
6
H
10
10
10
10
10
20
20
140
140
140
140
160
160
160
24
48
24
48
24
24
48
47 (27)
70 (27)
15 (28)
13 (28)
7 (28)
for
the
one-pot
synthesis
of
the
2,3,4,5-
H
tetrahydrobenzo[b]azepines (Scheme 3, Table 1) were applied,
these experiments failed. In both cases, complex reaction
mixtures were formed during the one-pot experiments and it was
not possible to isolate the expected products 33 and 34 in pure
form. GC-analysis of the crude reaction mixtures showed that
both steps, the initial hydroaminoalkylation and the subsequent
cyclization reaction, did not go to completion and in addition, the
obtained product mixtures were contaminated with relatively
large amounts of further impurities like the formamidine which is
formed by decomposition of catalyst I during the workup
procedure. In this context, it must be regarded as a severe
drawback that a catalyst loading of 20 mol% of I had to be
applied for the initial hydroaminoalkylation reactions of the
Br
Br
Br
Br
Br
55 (28)
60 (28)
7
a
Reaction conditions: allyl ether (2.2 mmol), N-methylaniline
3, 214 mg, 2.0 mmol), I (10 or 20 mol%), toluene (1 mL), 140
(
or 160 °C, 24 or 48 h. Isolated yield.

4
Tetrahedron
ot MA
substrates 26 and 30. Additional attempts to a
A
chi
C
ev
C
e t
E
he
P
o
T
ne
E
-p
D
w
N
ith
U
th
S
o
C
se
R
r
I
eported in the literature. New compounds were
P
T
additionally characterized by infrared (IR) spectroscopy, GC-MS
and high resolution mass spectrometry (HRMS). NMR spectra
were recorded on the following spectrometers: Bruker Fourier
reaction sequences by the use of a pre-formed palladium catalyst
generated in situ by heating a toluene mixture of Pd (dba) and
RuPhos did not lead to improved results.
To circumvent the problems that are caused by an incomplete
hydroaminoalkylation reaction and the formamidine
contamination of the product which increases with an increasing
catalyst loading in the hydroaminoalkylation step, we finally
decided to perform the palladium-catalyzed cyclization reactions
with the purified hydroaminoalkylation products 28 and 32
2
3
3
00, Bruker Avance DRX 500 or Bruker Avance III, 500 MHz.
1
All H NMR spectra are reported in δ units (ppm) relative to the
signal of TMS at 0.00 ppm or relative to the signal of CDCl at
.26 ppm. J values are given in Hz. All C NMR spectra are
3
13
7
reported in δ units (ppm) relative to the central line of the triplet
for CDCl at 77.0 ppm. Infrared spectra were recorded on a
3
Bruker Vector 22 spectrometer or a Bruker Tensor 27
spectrometer (ATR). MS analyses were performed on a Thermo
Scientific DFS (CI or EI) or a Waters Q-TOF Premier (ESI+,
TOF) spectrometer. High resolution mass spectra (HRMS) were
recorded on a Waters Q-TOF Premier spectrometer in EI or ESI
mode (ESI+, TOF). GC-MS analyses were performed on a
Thermo Finnigan Focus gas chromatograph (column: Agilent
DB- 5, length = 30 m, inner diameter = 0.32 mm, film thickness
(Scheme 5). Fortunately, in these cases, the intramolecular
Buchwald-Hartwig amination reactions took place smoothly to
give the desired benzoxazepine derivative 33 and the
benzothiazepine derivative 34 in good yields of 77 % and 91 %,
respectively (Scheme 5).
=
0.25
vinyl)polysiloxane) equipped with a DSQ mass detector (EI). GC
analyses were performed on Shimadzu GC-2010 gas
chromatograph equipped with a flame ionization detector.
ꢀm,
(94
%-methyl)-(5
%-phenyl)-(1
%-
a
4
.1. General procedures
General procedure A for the hydroaminoalkylation of
alkenes with N-methylaniline: An oven-dried Schlenk tube
equipped with a Teflon stopcock and a magnetic stirring bar was
transferred into a nitrogen-filled glovebox and charged with
catalyst I (0.2 mmol, 10 mol% or 0.4 mmol, 20 mol%) and
toluene (0.5 mL). Afterwards N-methylaniline (214 mg, 2.0
mmol), the alkene (2.2 mmol) and toluene (0.5 mL) were added.
After heating the mixture to 140 or 160 °C for 24 or 48 hours, the
crude product was purified by flash chromatography (SiO2).
Scheme 5. Synthesis of benzoxazepine and benzothiazepine
derivatives.
3
. Conclusion
In summary, it was shown that reaction sequences consisting
of
an
initial
intermolecular
titanium-catalyzed
hydroaminoalkylation of
a
suitably ortho-bromophenyl-
substituted alkene and a subsequent intramolecular Buchwald-
Hartwig amination can be used for the synthesis of benzazepine,
benzoxazepine, and benzothiazepine derivatives. While in the
latter two cases, the hydroaminoalkylation products obtained
from an allyl (2-bromophenyl) ether or an allyl (2-bromophenyl)
thioether must be purified prior to the subsequent palladium-
catalyzed amination step, both reactions can be combined to an
efficient one-pot procedure for the synthesis of benzazepine
derivatives when 4-(2-bromophenyl)-1-butene and various N-
methylanilines are used as the starting materials.
General procedure B for the one-pot synthesis of 2,3,4,5-
tetrahydrobenzo[b]azepines: An oven-dried Schlenk tube
equipped with a Teflon stopcock and a magnetic stirring bar was
transferred into a nitrogen-filled glovebox and charged with
catalyst I (109 mg, 0.2 mmol, 10 mol%) and toluene (0.5 mL).
Afterwards the N-methylaniline (2.0 mmol), 4-(2-bromophenyl)-
1
-butene (464 mg, 2.2 mmol) and toluene (0.5 mL) were added.
After the mixture had been heated to 140 °C for 24 hours, the
Schlenk tube was cooled to room temperature and transferred
back into a nitrogen-filled glovebox. Then Pd (dba) (46 mg, 0.05
2
3
4
. Experimental section
mmol, 2.5 mol%), RuPhos (65 mg, 0.14 mmol, 7 mol%),
NaOtBu (261 mg, 2.7 mmol) and toluene (5 mL) were added.
After heating the mixture to 110 °C for additional 24 hours, the
Unless otherwise noted, all reactions were performed under an
inert atmosphere of nitrogen in oven-dried Schlenk tubes (Duran
glassware, 100 mL, ø = 30 mm) equipped with Teflon stopcocks
crude product was purified by flash chromatography (SiO2).
®
and magnetic stirring bars (15 × 4.5 mm). Toluene was purified
by distillation from sodium wire and degassed. Catalyst I [20]
and the alkenes [22-24] were synthesized according to literature
procedures. Prior to use, all substrates were distilled and
degassed. Catalyst I, the alkenes, the N-methylanilines, and
toluene were stored in a nitrogen-filled glove box (M. Braun,
Unilab). All other chemicals were purchased from commercial
sources and were used without further purification. For flash
chromatography, silica gel from GRACE Davison (particle size
General procedure C for the intramolecular Buchwald-
Hartwig amination: An oven-dried Schlenk tube equipped with
a Teflon stopcock and a magnetic stirring bar was transferred into
a nitrogen-filled glovebox and charged with the respective
starting material [28 (1.66 mmol) or 32 (1.39 mmol)], toluene (1
mL), Pd (dba) (2.5 mol%), RuPhos (7 mol%), NaOtBu (1.3
2 3
equiv), and toluene (4 mL). After heating the mixture to 110 °C
for 24 hours, the crude product was purified by flash
chromatography (SiO
.2. Synthesis of N-(2-methyl-4-phenylbutyl)aniline (4)
General procedure A (10 mol% I, 140 °C, 24 h) was used to
).
2
0
.037-0.063 mm) was used. Light petroleum ether (b.p. 40-60 °C,
4
PE), tert-butyl methyl ether (MTBE), CH Cl and EtOAc used
2
2
for flash chromatography were distilled prior to use. For thin
layer chromatography, silica on TLC aluminium foils with
fluorescent indicator 254 nm from Fluka was used. The
substances were detected with UV light and iodine. All products
that have already been reported in the literature were identified
synthesize compound 4. After purification by flash
chromatography (PE/MTBE, 40:1), 4 (445 mg, 1.86 mmol, 93 %)
1
was isolated as a yellow oil. H NMR (500 MHz, CDCl ): δ =
3
7.42-7.39 (m, 2 H, Ar-H), 7.32-7.26 (m, 5 H, Ar-H), 6.83-6.80
1
13
by comparison of the obtained H NMR and C NMR spectra
(m, 1 H, Ar-H), 6.71-6.69 (m, 2 H, Ar-H), 3.77 (s, 1 H, NH),

5
1
3
1
3
1
1
=
.19 (dd, J = 12.3, 5.6 Hz, 1 H, CH ), 3.04 (dd
A
, J
C
=
C
12
E
.3
P
, 6
T
.9
E
H
D
z, MA1.
N
15
U
(m
S
,
C
1
R
H
I
,
P
CH ), 0.93 (d, J = 6.8 Hz, CH ) ppm. C{ H}
2 3
T
2
H, CH ), 2.88-2.82 (m, 1 H, CH ), 2.76-2.70 (m, 1 H, CH ),
NMR (125 MHz, DEPT, CDCl ): δ = 146.4 (C), 145.6 (C), 141.4
2
2
2
3
.95-1.88 (m, 2 H, CH , CH), 1.67-1.60 (m, 1 H, CH ), 1.16 (d, J
(C), 130.5 (CH), 129.6 (CH), 128.6 (CH), 127.2 (CH), 126.1
(CH), 125.5 (C), 112.8 (CH), 55.7 (CH ), 35.0 (CH ), 32.9 (CH ),
2
2
13
1
6.5 Hz, 3 H, CH ) ppm. C{ H} NMR (125 MHz, JMOD,
3
2
2
2
CDCl ): δ = 148.4 (C), 142.4 (C), 129.1 (CH), 128.3 (CH), 128.3
31.9 (CH), 20.2 (CH ), 19.4 (CH ) ppm. GC-MS: m/z (%) = 251
3 3
+ +
3
(
CH), 125.7 (CH), 117.0 (CH), 112.7 (CH), 50.1 (CH ), 36.5
(100) [M] , 208 (47), 194 (10), 174 (6). HRMS (EI, 70 eV): [M]
2
+
+
(
=
7
2
1
1
CH ), 33.2 (CH ), 32.5 (CH), 17.9 (CH ) ppm. GC-MS: m/z (%)
calculated for C H N : 251.1669, found: 251.1663 [M] . IR
2
2
3
18 21
+
+
239 (50) [M] , 106 (100), 91 (10), 77 (14) [C H ] . HRMS (EI,
(ATR, neat): 1/λ = 3023, 2918, 1616, 1598, 1569, 1513, 1489,
1454, 1436, 1369, 1350, 1315, 1284, 1257, 1206, 1189, 1175,
1132, 1115, 1086, 1053, 1010, 944, 895, 844, 801, 776, 758, 742,
6
5
+
+
0 eV): [M] calculated for C H N : 239.1669, found:
17 21
39.1667. IR (ATR, neat): 1/λ = 3419, 3053, 3024, 2925, 2856,
−1
601, 1505, 1472, 1454, 1430, 1379, 1319, 1256, 1179, 1153,
703, 645, 624 cm .
−1
117, 1068, 1030, 991, 904, 866, 745, 691, 619 cm .
4
.6. Synthesis of 1-(4-methoxyphenyl)-3-methyl-2,3,4,5-
4
.3. Synthesis of N-(4-(2-bromophenyl)-2-methylbutyl)aniline (5)
tetrahydro-1H-benzo[b]azepine (17)
General procedure A (10 mol% I, 140 °C, 24 h) was used to
synthesize compound 5. After purification by flash
General procedure B was used to synthesize compound 17.
After purification by flash chromatography (PE/MTBE, 40:1), 17
(374 mg, 1.40 mmol, 70 %) was isolated as a yellow oil. H
1
chromatography (PE/MTBE, 40:1), 5 (512 mg, 1.66 mmol, 83 %)
1
was isolated as a yellow oil. H NMR (500 MHz, CDCl ): δ =
NMR (500 MHz, CDCl
7.19 (m, 1 H, Ar-H), 7.16-7.12 (m, 2 H, Ar-H), 6.80-6.77 (m, 2
H, Ar-H), 6.64-6.61 (m, 2 H, Ar-H), 3.98 (d, J = 14.2 Hz, CH ),
3.77 (s, 3 H, CH ), 2.84 (dd, J = 14.2, 11.2 Hz, 1 H, CH ), 2.74-
2.67 (m, 2 H, CH, CH ), 2.15-2.05 (m, 1 H, CH ), 1.94-1.88 (m,
1 H, CH ), 1.25-1.18 (m, 1 H, CH ), 0.95 (d, J = 6.8 Hz, CH
ppm. C{ H} NMR (125 MHz, DEPT, CDCl ): δ = 151.5 (C),
147.12 (C), 142.5 (C), 140.8 (C), 130.4 (CH), 128.0 (CH), 127.1
(CH), 125.5 (C), 114.8 (CH), 114.7 (CH), 56.3 (CH ), 55.7
(CH ), 34.8 (CH ), 32.9 (CH ), 32.1 (CH), 19.4 (CH ) ppm. GC-
3
): δ = 7.27-7.26 (m, 1 H, Ar-H), 7.23-
3
7
(
.76-7.74 (m, 1 H, Ar-H), 7.43-7.39 (m, 4 H, Ar-H), 7.28-7.25
m, 1 H, Ar-H), 6.94-6.91 (m, 1 H, Ar-H), 6.84-6.82 (m, 2 H, Ar-
H), 3.93 (br. s, 1 H, NH), 3.33 (dd, J = 12.3, 6.0 Hz, 1 H, CH2),
2
3
2
3
2
.19 (dd, J = 12.1, 7.2 Hz, 1 H, CH ), 3.09-3.03 (m, 1 H, CH ),
2
2
2
2
.98-2.92 (m, 1 H, CH ), 2.09-2.04 (m, 1 H, CH), 2.02-1.95 (m, 1
2
2
)
3
2
13
1
H, CH ), 1.77-1.69 (m, 1 H, CH ), 1.31 (d, J = 6.6 Hz, CH ) ppm.
3
2
2
3
13
1
C{ H} NMR (125 MHz, DEPT, CDCl ): δ = 148.4 (C), 141.7
3
(
(
(
=
[
(
1
6
C), 132.7 (CH), 130.1 (CH), 129.1 (CH), 127.5 (CH), 127.4
2
CH), 124.3 (C), 117.0 (CH), 112.6 (CH), 50.0 (CH ), 34.9
3
2
2
3
2
+
CH ), 33.6 (CH ), 32.8 (CH), 17.9 (CH ) ppm. GC-MS: m/z (%)
MS: m/z (%) = 267 (100) [M] , 252 (28), 224 (12), 210 (19).
HRMS (EI, 70 eV): [M] calculated for C18
2
2
3
+
+
+
+
317 (19) [M] , 106 (100), 77 (11) [C H ] . HRMS (EI, 70 eV):
H
21ON : 267.1618,
6
5
+
79
+
M] calculated for C H BrN : 317.0774, found: 317.0762. IR
found: 267.1615. IR (ATR, neat): 1/λ = 2994, 2925, 2831, 1617,
17
20
ATR, neat): 1/λ =3079, 3049, 3021, 2914, 1601, 1505, 1470,
1576, 1506, 1489, 1453, 1349, 1289, 1238, 1176, 1126, 1085,
−1
437, 1379, 1319, 1258, 1179, 1153, 1075, 1022, 991, 866, 744,
1065, 1038, 944, 895, 814, 797, 757, 643, 621 cm .
−1
91, 658, 628, 592, 575 cm .
4
.7. Synthesis of 1-(4-fluorophenyl)-3-methyl-2,3,4,5-tetrahydro-
4
.4. Synthesis of 3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-
1H-benzo[b]azepine (18)
benzo[b]azepine (6)
General procedure B was used to synthesize compound 18.
After purification by flash chromatography (PE/MTBE, 40:1), 18
(434 mg, 1.70 mmol, 85 %) was isolated as a yellow oil. H
General procedure B was used to synthesize compound 6.
After purification by flash chromatography (PE/MTBE, 40:1), 6
1
1
(422 mg, 1.78 mmol, 89 %) was isolated as a yellow oil. H
NMR (500 MHz, CDCl ): δ = 7.27-7.26 (m, 1 H, Ar-H), 7.24-
3
NMR (500 MHz, CDCl ): δ = 7.28-7.26 (m, 1 H, Ar-H), 7.24-
7.20 (m, 1 H, Ar-H), 7.18-7.13 (m, 2 H, Ar-H), 6.87-6.83 (m, 2
H, Ar-H), 6.54-6.52 (m, 2 H, Ar-H), 3.97 (d, J = 14.4 Hz, 1 H,
3
7
.13 (m, 5 H, Ar-H), 6.67 (m, 1 H, Ar-H), 6.60-6.59 (m, 2 H, Ar-
H), 4.04 (d, J = 14.5 Hz, CH ), 2.82-2.77 (m, 1 H, CH ), 2.69,-
CH
CH
2
), 2.83 (dd, J = 14.2, 11.3 Hz, 1 H, CH
, CH), 2.14-2.05 (m, 1 H, CH ), 1.93-1.87 (m, 1 H, CH
), 0.93 (d, J = 6.8 Hz, 3 H, CH )1 ppm.
C{ H} NMR (125 MHz, DEPT, CDCl ): δ = 154.3 (d, JC,F
2
), 2.71-2.62 (m, 2 H,
2
2
2
1
.61 (m, 2 H, CH, CH ), 2.16-2.09 (m, 1 H, CH ), 1.91-1.87 (m,
2
2
2
),
2
2
H, CH ), 1.22-1.14 (m, 1 H, CH ), 0.93 (d, J = 6.8 Hz, CH )
1.24-1.16 (m, 1 H, CH
2
3
2
2
2
13
1
13
1
ppm. C{ H} NMR (125 MHz, DEPT, CDCl ): δ = 147.6 (C),
3
=
3
1
46.0 (C), 141.5 (C), 130.5 (CH), 129.1 (CH), 128.7 (CH), 127.2
235 Hz, C), 146.4 (C), 144.4 (C), 141.3 (C), 130.6 (CH), 128.4
2
(CH), 126.4 (CH), 116.3 (CH), 112.4 (CH), 55.5 (CH ), 35.1
(CH), 127.3 (CH), 126.2 (CH), 115.4 (d, JC,F = 22 Hz, CH),
2
3
(CH ), 32.8 (CH ), 31.8 (CH), 19.4 (CH ) ppm. GC-MS: m/z (%)
113.7 (d, JC,F = 7 Hz, CH), 56.1 (CH
2
), 34.9 (CH
) ppm. GC-MS: m/z (%) = 255 (100) [M] ,
3
), 32.8 (CH ),
2 2
+
2
2
3
+
+
=
237 (100) [M] , 194 (100), 91 (37), 77 (24) [C H ] . HRMS
31.9 (CH), 19.3 (CH
212 (85), 198 (13), 91 (20), 77 (6) [C
[M] calculated for C17H18FN : 255.1418, found: 255.1416. IR
6
5
+
+
+
(EI, 70 eV): [M] calculated for C H N : 237.1512, found:
6
H
5
] . HRMS (EI, 70 eV):
17
19
+
+
2
2
1
8
37.1510. IR (ATR, neat): 1/λ = 3060, 3022, 2948, 2923, 2869,
846, 1593, 1496, 1456, 1370, 1352, 1340, 1316, 1298, 1257,
219, 1190, 1175, 1156, 1118, 1095, 1065, 1039, 990, 994, 895,
(ATR, neat): 1/λ = 3053, 3022, 2949, 2926, 2870, 2847, 1503,
1490, 1455, 1370, 1370, 1352, 1304, 1285, 1250, 1223, 1193,
1176, 1159, 1120, 1084, 1065, 1040, 945, 895, 813, 778, 758,
−1
65, 841, 768, 743, 689, 629, 599, 582 cm .
−1
7
45, 691, 642, 621, 572 cm .
4
.5. Synthesis of 3-methyl-1-(p-tolyl)-2,3,4,5-tetrahydro-1H-
benzo[b]azepine (16)
4.8. Synthesis of 3-methyl-1-(4-(trifluoromethoxy)phenyl)-
2
,3,4,5-tetrahydro-1H-benzo[b]azepine (19)
General procedure B was used to synthesize compound 16.
After purification by flash chromatography (PE/MTBE, 40:1), 16
General procedure B was used to synthesize compound 19.
1
(442 mg, 1.76 mmol, 88 %) was isolated as a yellow oil. H
After purification by flash chromatography (PE/MTBE, 40:1), 19
1
NMR (500 MHz, CDCl ): δ = 7.27-7.26 (m, 1 H, Ar-H), 7.24-
(514 mg, 1.60 mmol, 80 %) was isolated as a brown oil. H NMR
3
7
.20 (m, 1 H, Ar-H), 7.18-7.14 (m, 2 H, Ar-H), 6.98-6.96 (m, 2
H, Ar-H), 6.54-6.53 (m, 2 H, Ar-H), 4.02 (d, J = 14.4 Hz, CH2),
.82-2.77 (m, 1 H, CH ), 2.70-2.63 (m, 2 H, CH, CH ), 2.24 (s, 3
(500 MHz, CDCl
1 H, Ar-H), 7.20-7.15 (m, 2 H, Ar-H), 6.98-6.96 (m, 2 H, Ar-H),
6.53-6.49 (m, 2 H, Ar-H), 3.97 (d, J = 14.6 Hz, 1 H, CH ), 2.82
(dd, J = 14.2, 11.5 Hz, 1 H, CH ), 2.66-2.58 (m, 2 H, CH , CH),
3
): δ = 7.28-7.26 (m, 1 H, Ar-H), 7.25-7.21 (m,
2
2
2
2
H, CH ), 2.14-2.06 (m, 1 H, CH ), 1.91-1.86 (m, 1 H, CH ), 1.22-
2
2
3
2
2

6
Tetrahedron
14 MA
2
.14-2.05 (m, 1 H, CH ), 1.92-1.82 (m, 1 H
A
, C
C
H
C
)
E
, 1
P
.2
T
2-
E
1.
D
H
N
z, 1
U
H
S
,
C
CHRI),
P
2
T
.82-2.77 (m, 1 H, CH ), 2.66-2.58 (m, 2 H, CH ,
2 2
2
2
2
1
3
1
(m, 1 H, CH ), 0.92 (d, J = 6.8 Hz, 3 H, CH ) ppm. C{ H}
CH), 2.12-2.04 (m, 1 H, CH ), 1.90-1.87 (m, 1 H, CH ), 1.21-
2
3
2
2
1
3
1
NMR (125 MHz, DEPT, CDCl ): δ = 146.5 (C), 145.6 (C), 141.5
1.13 (m, 1 H, CH ), 0.92 (d, J = 6.8 Hz, 3 H, CH ) ppm. C{ H}
2 3
3
(
C), 139.8 (C), 130.7 (CH), 128.6 (CH), 127.5 (CH), 126.8 (CH),
NMR (125 MHz, JMOD, CDCl ): δ = 146.3 (C), 145.6 (C), 141.5
3
1
1
3
+
22.1 (CH), 120.8 (q, J = 255 Hz, C), 112.7 (CH), 55.8 (CH2),
(C), 130.6 (CH), 128.9 (CH), 128.6 (CH), 127.4 (CH), 126.7
(CH), 121.0 (C), 113.5 (CH), 55.7 (CH ), 35.0 (CH ), 32.8 (CH ),
C,F
5.1 (CH ), 32.8 (CH ), 31.8 (CH), 19.3 (CH ) ppm. MS (ESI,
2
2
3
2
2
2
+
): m/z (%) = 322 (45) [M+H] , 220 (75), 176 (100), 162 (60).
31.8 (CH), 19.3 (CH ) ppm. MS (ESI, +): m/z (%) = 272 (8)
3
+
+
+
+
HRMS (ESI, +): [M+H] calculated for C H F N : 322.1409,
found: 322.1419. IR (ATR, neat): 1/λ = 3058, 3024, 2951, 2928,
[M+H] , 237 (8), 216 (13), 181 (100). HRMS (ESI, +): [M+H]
calculated for C H ClN : 272.1202, found: 272.1206. IR (ATR,
18
19 3
+
17
19
2
1
7
872, 2849, 1492, 1455, 1376, 1355, 1248, 1220, 1204, 1154,
124, 1085, 1065, 1040, 1008, 945, 917, 896, 828, 804, 778, 765,
48, 724, 700, 668, 650, 626, 614, 582, 559 cm .
neat): 1/λ = 3063, 3038, 2949, 2925, 2870, 2847, 1592, 1489,
1454, 1439, 1371, 1352, 1308, 1283, 1259, 1250, 1219, 1176,
1127, 1097, 1085, 1064, 1040, 1022, 999, 944, 925, 895, 842,
−1
−1
8
11, 772, 750, 725, 699, 650, 637, 622, 583, 559 cm .
4
.9. Synthesis of 3-methyl-1-(m-tolyl)-2,3,4,5-tetrahydro-1H-
benzo[b]azepine (20)
4.12. Synthesis of 3-methyl-1-(4-(methylthio)phenyl)-2,3,4,5-
tetrahydro-1H-benzo[b]azepine (23)
General procedure B was used to synthesize compound 20.
After purification by flash chromatography (PE/MTBE, 40:1), 20
General procedure B was used to synthesize compound 23.
After purification by flash chromatography (PE/MTBE, 40:1), 23
(447 mg, 1.58 mmol, 79 %) was isolated as a brown oil. H NMR
1
(397 mg, 1.55 mmol, 77 %) was isolated as a yellow oil. H
1
NMR (500 MHz, CDCl ): δ = 7.27-7.16 (m, 4 H, Ar-H), 7.05-
3
7
.02 (m, 1 H, Ar-H), 6.50-6.49 (m, 1 H, Ar-H), 6.41-6.36 (m, 2
(500 MHz, CDCl ): δ = 7.28-7.26 (m, 1 H, Ar-H), 7.24-7.21 (m,
3
H, Ar-H), 4.02 (d, J = 14.3 Hz, 1 H, CH ), 2.80-2.75 (m, 2 H,
1 H, Ar-H), 7.19-7.16 (m, 4 H, Ar-H), 6.54-6.52 (m, 2 H, Ar-H),
3.99 (d, J = 14.5 Hz, 1 H, CH ), 2.82-2.77 (m, 1 H, CH ), 2.65-
2
CH ), 2.69-2.61 (m, 2 H, CH , CH), 2.23 (s, 3 H, CH ), 2.14-2.07
2
2
3
2
2
(
0
m, 1 H, CH ), 1.90-1.86 (m, 1 H, CH ), 1.20-1.13 (m, 1 H, CH ),
2.62 (m, 2 H, CH , CH), 2.39 (s, 3 H, CH ), 2.15-2.06 (m, 1 H,
2
2
2
2
3
13
1
.93 (d, J = 6.7 Hz, 3 H, CH ) ppm. C{ H} NMR (125 MHz,
CH ), 1.91-1.86 (m, 1 H, CH ), 1.21-1.14 (m, 1 H, CH ), 0.93 (d,
3
2
2
2
13
1
DEPT, CDCl ): δ = 147.6 (C), 146.1 (C), 141.5 (C), 138.8 (C),
J = 6.8 Hz, 3 H, CH ) ppm. C{ H} NMR (125 MHz, JMOD,
3
3
1
1
3
+
30.5 (CH), 130.0 (CH), 128.7 (CH), 127.2 (CH), 126.3 (CH),
CDCl ): δ = 146.6 (C), 145.7 (C), 141.4 (C), 131.4 (CH), 130.5
3
17.4 (CH), 113.2 (CH), 109.8 (CH), 55.6 (CH ), 35.1 (CH ),
(CH), 128.6 (CH), 127.3 (CH), 126.6 (CH), 123.0 (C), 113.0
(CH), 55.6 (CH ), 35.0 (CH ), 32.8 (CH ), 31.9 (CH), 19.3 (CH ),
2
2
2.9 (CH ), 31.9 (CH), 21.9 (CH ), 19.4 (CH ) ppm. MS (ESI,
2
3
3
2
2
2
3
+
+
): m/z (%) = 252 (43) [M+H] , 196 (100), 181 (63), 108 (16), 91
19.1 (CH ) ppm. MS (ESI, +): m/z (%) = 284 (51) [M+H] , 237
(40), 181 (100), 138 (18). HRMS (ESI, +): [M+H] calculated for
C H NS : 284.1470, found: 284.1473. IR (ATR, neat): 1/λ =
3
+
+
+
+
(30) [C H ] . HRMS (ESI, +): [M+H] calculated for C H N :
7
7
18 22
+
2
2
1
9
52.1742, found: 252.1752. IR (ATR, neat): 1/λ = 3024, 2948,
922, 2867, 1604, 1596, 1577, 1522, 1490, 1454, 1366, 1350,
327, 1293, 1254, 1224, 1170, 1132, 1100, 1041, 1022, 991, 931,
18
22
3063, 3028, 2947, 2916, 2868, 2845, 1589, 1553, 1491, 1454,
1437, 1371, 1351, 1306, 1280, 1280, 1258, 1249, 1219, 1191,
1175, 1132, 1105, 1084, 1063, 1039, 966, 945, 895, 866, 842,
−1
05, 879, 857, 841, 813, 757, 742, 690, 659, 630, 605, 583 cm .
−1
8
12, 778, 750, 647, 623, 583, 559 cm .
4
.10. Synthesis of 1-(4-isopropylphenyl)-3-methyl-2,3,4,5-
tetrahydro-1H-benzo[b]azepine (21)
4.13. Synthesis of 1-(3-fluorophenyl)-3-methyl-2,3,4,5-
tetrahydro-1H-benzo[b]azepine (24)
General procedure B was used to synthesize compound 21.
After purification by flash chromatography (PE/MTBE, 40:1), 21
General procedure B was used to synthesize compound 24.
After purification by flash chromatography (PE/MTBE, 40:1), 24
(316 mg, 1.24 mmol, 62 %) was isolated as a yellow oil. H
1
(514 mg, 1.18 mmol, 59 %) was isolated as a yellow oil. H
1
NMR (500 MHz, CDCl ): δ = 7.28-7.27 (m, 1 H, Ar-H), 7.24-
3
7
.14 (m, 3 H, Ar-H), 7.05-7.01 (m, 2 H, Ar-H), 6.57-6.56 (m, 2
NMR (500 MHz, CDCl ): δ = 7.28-7.25 (m, 1 H, Ar-H), 7.24-
3
H, Ar-H), 4.02 (d, J = 14.4 Hz, 1 H, CH ), 2.85-2.77 (m, 2 H,
7.16 (m, 3 H, Ar-H), 7.07-7.02 (m, 1 H, Ar-H), 6.35-6.31 (m, 2
H, Ar-H), 6.27-6.24 (m, 1 H, Ar-H), 3.96 (d, J = 14.6 Hz, 1 H,
2
CH , CH), 2.72-2.63 (m, 2 H, CH , CH), 2.17-2.06 (m, 1 H,
2
2
CH ), 1.92-1.86 (m, 1 H, CH ), 1.23 (d, J = 6.9 Hz, 3 H, CH ),
CH ), 2.80 (dd, J = 13.9, 11.8 Hz, 1 H, CH2), 2.66-2.60 (m, 2 H,
2
2
3
2
1
.22 (d, J = 6.8 Hz, 3 H, CH ), 1.21-1.17 (m, 1 H, CH ), 0.93 (d,
CH , CH), 2.15-2.06 (m, 1 H, CH ), 1.92-1.87 (m, 1 H, CH ),
1.21-1.13 (m, 1 H, CH ), 0.93 (d, J = 6.8 Hz, 3 H, CH ) ppm.
2 3
13 1 1
3
2
2
2
2
13
1
J = 6.8 Hz, 3 H, CH ) ppm. C{ H} NMR (125 MHz, JMOD,
CDCl ): δ = 146.4 (C), 145.8 (C), 141.4 (C), 136.7 (C), 130.4
3
C{ H} NMR (125 MHz, DEPT, CDCl ): δ = 163.2 (d, J
=
3
3
C,F
3
(CH), 128.6 (CH), 127.1 (CH), 126.9 (CH), 126.1 (CH), 112.6
242 Hz, C), 148.5 (d, J = 11 Hz, C), 144.4 (C), 140.5 (C),
C,F
3
(CH), 55.7 (CH ), 35.9 (CH ), 32.9 (CH), 32.9 (CH ), 32.0 (CH),
129.6 (CH), 129.1 (d, J = 10 Hz, CH), 127.6 (CH), 126.4
2
2
2
C,F
2
2
2
4.2 (CH ), 24.2 (CH ), 19.4 (CH ) ppm. MS (ESI, +): m/z (%) =
(CH), 125.9 (CH), 106.9 (CH), 101.7 (d, J = 22 Hz, CH), 98.3
(d, J = 26 Hz, CH), 54.7 (CH ), 34.1 (CH ), 31.8 (CH ), 30.9
3
3
3
C,F
+
3
80 (32) [M+H] , 238 (11), 182 (100), 134 (3). HRMS (ESI, +):
C,F
2
2
2
+
+
+
[
(
M+H] calculated for C H N : 280.2063, found: 280.2065. IR
ATR, neat): 1/λ = 3062, 3023, 2954, 2925, 2868, 1614,
(CH), 18.3 (CH ) ppm. MS (ESI, +): m/z (%) = 256 (5) [M+H] ,
20
26
3
+
200 (100), 180 (45). HRMS (ESI, +): [M+H] calculated for
C H FN : 256.1494, found: 256.1502. IR (ATR, neat): 1/λ =
+
1
1
8
598,1567, 1512, 1490, 1454, 1370, 1351, 1304, 1281, 1255,
219, 1191, 1176, 1147, 1124, 1085, 1052, 1040, 1022, 944, 895,
17
19
3065, 3026, 2949, 2925, 2871, 2848, 1619, 1596, 1576, 1489,
1455, 1377, 1354, 1319, 1299, 1265, 1250, 1221, 1200, 1186,
−1
65, 843, 817, 782, 752, 699, 644, 624, 579 cm .
1
7
172, 1153, 1116, 1093, 997, 974, 933, 909, 884, 865, 821, 777,
54, 700, 680, 632, 602, 582 cm .
4
.11. Synthesis of 1-(4-chlorophenyl)-3-methyl-2,3,4,5-
−1
tetrahydro-1H-benzo[b]azepine (22)
4
.14. Synthesis of N-(2-methyl-3-phenoxypropyl)aniline (27)
General procedure B was used to synthesize compound 22.
After purification by flash chromatography (PE/MTBE, 40:1), 22
General procedure A (10 mol% I, 140 °C, 48 h) was used to
synthesize compound 27. After purification by flash
1
(386 mg, 1.42 mmol, 71 %) was isolated as a yellow oil. H
NMR (500 MHz, CDCl ): δ = 7.28-7.14 (m, 4 H, Ar-H), 7.08-
chromatography (PE/MTBE, 40:1), 27 (338 mg, 1.40 mmol, 70
3
1
7
.04 (m, 2 H, Ar-H), 6.49-6.47 (m, 2 H, Ar-H), 3.96 (d, J = 14.6
%) was isolated as a yellow oil. H NMR (500 MHz, CDCl ): δ =
3

7
7
(
.31-7.27 (m, 2 H, Ar-H), 7.19-7.16 (m, 2 H,
m, 1 H, Ar-H), 6.97-6.91 (m, 2 H, Ar-H), 6.71-6.69 (m, 1 H, Ar-
H), 6.71-6.64 (m, 2 H, Ar-H), 4.21 (br. s, NH), 3.96 (dd, J = 6.4,
.1 Hz, 1 H, CH ), 3.91 (dd, J = 6.4, 9.1 Hz, 1 H, CH ), 3.30 (dd,
A
A
C
r-H
C
)
E
, 6
P
.9
T
7-
E
6.
D
95 MAch
N
ro
U
ma
S
to
C
gr
R
ap
I
h
P
y
T
(PE/MTBE, 40:1), 32 (478 mg, 1.42 mmol, 71
1
%) was isolated as a yellow oil. H NMR (500 MHz, CDCl ): δ =
3
7.49 (dd, J = 7.9, 1.3 Hz, 1 H, Ar-H), 7.22-7.17 (m, 1 H, Ar-H),
7.17-7.09 (m, 3 H, Ar-H), 6.98-6.94 (m, 1 H, Ar-H), 6.67 (t, J =
7.3 Hz, 1 H, Ar-H), 6.58 (d, J = 7.7 Hz, 2 H, Ar-H), 3.21 (dd, J =
13.1, 6.8 Hz, 1 H, CH ), 3.08 (dd, J = 13.1, 6.4 Hz, 1 H, CH ),
9
2
2
J = 7.0, 12.7 Hz, 1 H, CH ), 3.16 (dd, J = 6.1, 12.7 Hz, 1 H,
CH ), 2.33 (oct, J = 6.5 Hz, 1 H, CH), 1.13 (d, J = 6.9 Hz, 3 H,
CH ) ppm. C{ H} NMR (125 MHz, CDCl ): δ = 158.9 (C),
2
2
2
2
13
1
3.05 (dd, J = 12.9, 6.0 Hz, 1 H, CH ), 2.81 (dd, J = 12.6, 7.1 Hz,
3
3
2
1
1
48.2 (C), 129.4 (CH), 129.3 (CH), 120.8 (CH), 117.4 (CH),
14.5 (CH), 112.9 (CH), 71.3 (CH ), 47.9 (CH ), 33.2 (CH), 15.4
1 H, CH ), 2.12 (oct, J = 6.7 Hz, 1 H, CH), 1.11 (d, J = 6.7 Hz, 3
2
13
1
H, CH ) ppm. C{ H} NMR (125 MHz, CDCl ): δ = 147.9 (C),
2
2
3
3
+
(CH ) ppm. GC-MS (EI, 70 eV): m/z (%) = 241 (38) [M] , 106
138.1 (C), 133.0 (CH), 129.3 (CH), 128.1 (CH), 127.7 (CH),
3
+
+
+
(100) [C H N] , 94 (14) [C H O] , 77 (52) [C H ] . HRMS (EI,
126.5 (CH), 123.6 (C), 117.5 (CH), 112.9 (CH), 49.3 (CH ), 38.0
7
8
6
5
6
5
2
+
+
7
2
1
1
0 eV): [M] calculated for C H NO : 241.1467, found:
(CH ), 32.6 (CH), 18.0 (CH ) ppm. GC-MS (EI, 70 eV): m/z (%)
16
19
2
3
79
+
+
41.1460. IR (ATR, neat): 1/λ = 3417, 3056, 2958, 2923, 2874,
599, 1586, 1496, 1467, 1433, 1392, 1320, 1300, 1241, 1173,
153, 1078, 1053, 1001, 988, 881, 869, 812, 747, 690, 611, 601
= 335 (26) [C H BrNS] , 132 (7), 106 (100) [C H N] , 77 (45)
16 18 7 8
+ + 79 +
[C H ] . HRMS (EI, 70 eV): [M] calculated for C H BrNS :
6
5
16 18
335.0338, found: 335.0338. IR (ATR, neat): 1/λ = 3416, 3364,
3052, 3021, 2957, 2927, 2868, 1601, 1558, 1505, 1448, 1427,
−1
cm .
1
7
379, 1320, 1255, 1179, 1154, 1107, 1070, 1040, 1019, 991, 868,
42, 714, 691 cm .
4
.15. Synthesis of N-(3-(2-bromophenoxy)-2-methylpropyl)-
−1
aniline (28)
4
.18. Synthesis of 3-methyl-5-phenyl-2,3,4,5-tetrahydrobenzo[b]-
General procedure A (20 mol% I, 160 °C, 48 h) was used to
synthesize compound 28. After purification by flash
[
1,4]oxazepine (33)
chromatography (PE/MTBE, 40:1), 28 (384 mg, 1.20 mmol, 60
General procedure C was used to synthesize compound 33
from 28 (532 mg, 1.66 mmol). After purification by flash
1
%
) was isolated as a yellow oil. H NMR (500 MHz, CDCl ): δ =
3
7
7
.47 (dd, J = 7.9, 1.6 Hz, 1 H, Ar-H), 7.19-7.15 (m, 1 H, Ar-H),
.12-7.08 (m, 2 H, Ar-H), 6.80-6.71 (m, 2 H, Ar-H), 6.66-6.55
chromatography (PE/MTBE, 40:1), 33 (304 mg, 1.27 mmol, 77
1
%) was isolated as a yellow oil. H NMR (500 MHz, CDCl ): δ =
3
(
m, 3 H, Ar-H), 4.25 (br. s, NH), 3.98 (dd, J = 8.9, 4.4 Hz, 1 H,
7.23-7.18 (m, 2 H, Ar-H), 7.12-7.10 (m, 1 H, Ar-H), 7.05-7.01
(m, 2 H, Ar-H), 6.95-6.90 (m, 3 H, Ar-H), 6.81-6.78 (m, 1 H, Ar-
CH ), 3.85 (dd, J = 8.9, 6.8 Hz, 1 H, CH ), 3.26 (dd, J = 12.7, 7.4
2
2
Hz, 1 H, CH ), 3.15 (dd, J = 12.7, 5.3 Hz, 1 H, CH ), 2.35-2.29
H), 4.20 (dd, J = 11.9, 4.1 Hz, 1 H, CH ), 4.12 (dd, J = 14.8, 5.2
2
2
2
13
1
(
(
(
(
m, 1 H, CH), 1.08 (d, J = 7.0 Hz, 3 H, CH ) ppm. C{ H} NMR
Hz, 1 H, CH ), 3.75 (dd, J = 12.0, 4.9 Hz, 1 H, CH ), 3.31 (dd, J
3
2
2
125 MHz, CDCl ): δ = 155.1 (C), 148.3 (C), 133.3 (CH), 129.2
= 14.7, 10.1 Hz, 1 H, CH ), 2.34-2.43 (m, 1 H, CH), 1.00 (d, J =
2
13 1
3
CH), 128.5 (CH), 121.9 (CH), 117.1 (CH), 112.8 (CH), 112.7
CH), 112.1(C), 72.8 (CH ), 48.2 (CH ), 33.1 (CH), 15.4 (CH )
6.9 Hz, 3 H, CH ) ppm. C{ H} NMR (125 MHz, CDCl ): δ =
3 3
155.1 (C), 148.3 (C), 136.9 (C), 129.2 (CH), 127.7 (CH), 125.3
(CH), 122.5 (CH), 121.5 (CH), 118.8 (CH), 116.1 (CH), 75.2
(CH ), 54.3 (CH ), 32.3 (CH), 15.2 (CH ) ppm. GC-MS (EI, 70
2
2
3
7
9
+
ppm. GC-MS (EI, 70 eV): m/z (%) = 319 (25) [C H BrNO] ,
1
HRMS (EI, 70 eV): [M] calculated for C H BrNO :
1
6
18
79
+
+
+
72 (6) [C H4 BrO] , 106 (100) [C H N] , 77 (39) [C H ] .
6 7 8 6 5
+ 79 +
2
2
3
+
+
eV): m/z (%) = 239 (54) [M] , 196 (100), 77 (12) [C H ] . HRMS
6 5
+ +
1
6
18
3
3
1
9
19.0564, found: 319.0566. IR (ATR, neat): 1/λ = 3415, 3380,
338, 3049, 3016, 2959, 2930, 2877, 1602, 1587, 1506, 1480,
462, 1443, 1320, 1276, 1246, 1179, 1154, 1127, 1050, 1029,
(EI, 70 eV): [M] calculated for C H NO : 239.1305, found:
16 17
239.1304. IR (ATR, neat): 1/λ = 3070, 3028, 2957, 1733, 1591,
1490, 1459, 1386, 1364, 1352, 1327, 1304, 1291, 1266, 1245,
1224, 1191, 1153, 1092, 1069, 1035, 1015, 985, 961, 940, 922,
−1
90. 827, 744, 692, 665 cm .
−1
8
50, 787, 744, 691, 627 cm .
4
.16. Synthesis of N-(2-methyl-3-(phenylthio)propyl)aniline (31)
4
.19. Synthesis of 3-methyl-5-phenyl-2,3,4,5-tetrahydrobenzo[b]-
General procedure A (10 mol% I, 140 °C, 48 h) was used to
synthesize compound 31. After purification by flash
[
1,4]thiazepine (34)
chromatography (PE/MTBE, 40:1), 31 (283 mg, 1.10 mmol, 55
General procedure C was used to synthesize compound 34
from 32 (466 mg, 1.39 mmol). After purification by flash
1
%
) was isolated as a yellow oil. H NMR (500 MHz, CDCl ): δ =
3
7
(
.34-7.31 (m, 2 H, Ar-H), 7.28-7.24 (m, 2 H, Ar-H), 7.21-7.12
m, 3 H, Ar-H), 6.69-6.64 (m, 1 H, Ar-H), 6.59-6.57 (m, 2 H, Ar-
H), 3.90 (br. s, NH), 3.23 (dd, J = 12.9, 6.5 Hz, 1 H, CH ), 3.05
chromatography (PE/MTBE, 40:1), 34 (323 mg, 1.26 mmol, 91
1
%) was isolated as a yellow oil. H NMR (500 MHz, CDCl
): δ =
3
7.49 (d, J = 7.7 Hz, 1 H, Ar-H), 7.20-7.16 (m, 4 H, Ar-H), 7.09-
7.06 (m, 1 H, Ar-H), 6.79-6.69 (m, 3 H, Ar-H), 4.06 (dd, J =
2
(dd, J = 12.3, 6.0 Hz, 1 H, CH ), 3.04 (dd, J = 13.0, 6.8 Hz, 1 H,
2
CH ), 2.86 (dd, J = 12.9, 6.8 Hz, 1 H, CH ), 2.09 (oct, J = 6.6 Hz,
15.2, 3.8 Hz, 1 H, CH
3.09 (dd, J = 13.9, 3.6 Hz, 1 H, CH
2.43 (dd, J = 13.9, 6.7 Hz, 1 H, CH
2
2
), 3.27 (dd, J = 15.2, 10.7 Hz, 1 H, CH
), 2.52-2.47 (m, 1 H, CH),
), 1.03 (d, J = 6.6 Hz, 3 H,
) ppm. C{ H} NMR (125 MHz, CDCl ): δ = 147.5 (C),
147.2 (C), 134.0 (C), 132.2 (CH), 129.1 (CH), 128.8 (CH), 127.5
(CH), 125.3 (CH), 117.8 (CH), 114.6 (CH), 54.5 (CH ), 38.0
(CH ), 31.9 (CH), 17.5 (CH ) ppm. GC-MS (EI, 70 eV): m/z (%)
= 255 (66) [M] , 212 (100), 108 (31), 77 (18) [C
2
),
2
2
13
1
1
H, CH), 1.10 (d, J = 6.7 Hz, 3 H, CH ) ppm. C{ H} NMR
2
3
(
(
(
125 MHz, CDCl ): δ = 148.1 (C), 136.8 (C), 129.4 (CH), 129.1
3
13
1
CH), 128.9 (CH), 125.9 (CH), 117.3 (CH), 112.8 (CH), 49.2
CH ), 38.8 (CH ), 33.0 (CH), 17.9 (CH ) ppm. GC-MS (EI, 70
CH
3
3
2
2
3
+
+
eV): m/z (%) = 257 (39) [M] , 109 (11) [C H S] , 106 (100)
[
for C H NS : 257.1233, found: 257.1235. IR (ATR, neat): 1/λ =
2
6
5
+
+
+
C H N] , 77 (45) [C H ] . HRMS (EI, 70 eV): [M] calculated
2
3
7
8
6
5
+
+
+
H
5
] . HRMS
1
6
19
6
+
+
3
1
1
417, 3370, 3057, 3018, 2959, 2927, 2873, 1723, 1604, 1587,
507, 1481, 1439, 1380, 1321, 1263, 1181, 1155, 1123, 1089,
073, 1027, 993, 870, 741, 692, 622, 604 cm .
(EI, 70 eV): [M] calculated for C16H17NS : 255.1076, found:
255.1073. IR (ATR, neat): 1/λ = 3057, 2953, 2934, 2871, 1598,
1581, 1560, 1495, 1472, 1434, 1370, 1351, 1323, 1298, 1260,
−1
1
8
236, 1181, 1156, 1124, 1098, 1057, 1033, 991, 942, 879, 854,
25, 799, 741, 728, 691, 624 cm .
4
.17. Synthesis of N-(3-((2-bromophenyl)thio)-2-
−1
methylpropyl)aniline (32)
Acknowledgments
General procedure A (20 mol% I, 160 °C, 48 h) was used to
synthesize compound 32. After purification by flash

8
Tetrahedron
TED
B. F.; Mitchell, E. A.; Meerpoel, L.; Maes, B. U. W. Adv. Synth.
Catal. 2014, 356, 1610–1618.
We thank the Deutsche Forschungsg
A
em
C
e
C
in
E
sch
P
a
ft
f
or MANUSCRIPT
financial support of our research and M.Sc. Michael Rosien for
experimental assistance.
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