Hydroaminoalkylation of Allylsilanes and a One-Pot Procedure for the Synthesis of 1,5-Benzoazasilepines

Article abstract of DOI:10.1002/chem.201605923

Allylsilanes undergo highly regioselective intermolecular alkene hydroaminoalkylation with secondary amines in the presence of a titanium mono(formamidinate) catalyst. Corresponding reactions of a suitable allyl(2-bromophenyl)silane which exclusively deliver the branched hydroaminoalkylation products combined with a subsequent Buchwald–Hartwig amination result in the development of an elegant one-pot procedure for the synthesis of literature-unknown silicon analogues of 1,5-benzodiazepines, the so-called 1,5-benzoazasilepines.

Full text of DOI:10.1002/chem.201605923

A Journal of
Accepted Article
Title: Hydroaminoalkylation of Allylsilanes and a One-Pot Procedure for
the Synthesis of 1,5-Benzoazasilepines
Authors: Sven Doye, Lars H. Lühning, Julia Strehl, and Marc
Schmidtmann
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Hydroaminoalkylation of Allylsilanes and a One-Pot Procedure for
the Synthesis of 1,5-Benzoazasilepines
Lars H. Lühning, Julia Strehl, Marc Schmidtmann, and Sven Doye*[a]
Abstract: Allylsilanes undergo highly regioselective intermolecular
alkene hydroaminoalkylation with secondary amines in the presence
of a titanium mono(formamidinate) catalyst. Corresponding reactions
of a suitable allyl(2-bromophenyl)silane which exclusively deliver the
nervous system and as a result, they show sedative, muscle
relaxant, anticonvulsant, and anxiolytic effects.[5,6] Very recently,
we were able to develop a new one-pot procedure for the
synthesis of 1,5-benzodiazepines.[ The corresponding reaction
7]
branched hydroaminoalkylation products combined with
a
sequence includes an initial highly regioselective titanium-
catalyzed intermolecular hydroaminoalkylation,[
8,9]
which takes
subsequent Buchwald-Hartwig amination result in the development
of an elegant one-pot procedure for the synthesis of literature-
unknown silicon analogues of 1,5-benzodiazepines, so-called 1,5-
benzoazasilepines.
3
place by the addition of an α-C(sp )–H bond of an N-
methylaniline across a C–C double bond of an N-allyl-2-
bromoaniline, and
a subsequent intramolecular Buchwald-
[
10]
Hartwig amination (Scheme 1, path A). In continuation of this
study and inspired by the fact that until now, unsaturated silanes
have not been used as substrates for titanium-catalyzed
hydroaminoalkylation reactions, we recently decided to
investigate the scope of allylsilanes as starting materials for
corresponding transformations. However, in this context it must
be noted that Schafer et al. already achieved the
hydroaminoalkylation of allyltrimethylsilane with N-methylaniline
in the presence of a tantalum catalyst.[11] Interestingly, by
choosing allyl(2-bromophenyl)silanes as starting materials, the
literature-unknown silicon analogues of 1,5-benzodiazepines,
so-called 1,5-benzoazasilepines (Scheme 1, path B), should be
accessible by a one-pot procedure that is similar to our 1,5-
benzodiazepines synthesis. In this context, it has to be
Introduction
Until the early 1960´s, organosilicon compounds were widely
regarded as
a biologically ineffective class of chemical
substances.[ However, after this opinion had been changed
1]
through the investigation of the unusual high toxicity of silatranes
by Voronkov et al., organosilicon chemistry became more and
more popular in the pharmaceutical sector during the past
decades.[3] While one method for the development of new drugs
is the high-throughput synthesis and high-throughput screening
approach, an alternative possibility is the sila-substitution (Si/C
exchange) in known drug scaffolds.[3,4] The feasibility of the latter
approach which was pioneered by the Tacke-group,[4a-c,e-k] has
[
2]
mentioned that Voronkov et al.[ as well as Tacke et al.
12]
[13]
already synthesized closely related 1,4-azasilepanes, which lack
the benzo-annulation of the seven-membered ring, by using
alternative strategies and very recently, a lot of effort has been
spent on the development of new pathways for the
strongly been underlined by a large number of examples in
which sila-substitution significantly affects the features of a drug.
For example, the different geometry and bond lengths of Si-C
(
187 pm) and C-C bonds (154 pm) as well as the different pK
values of silanols (pKa(DMSO) of Ph SiOH = 16.6) compared to
alcohols (pKa(DMSO) of Ph COH = 17.0) are important aspects
a
enantioselective
benzothiazepines.[
synthesis
of
closely
related
1,5-
3
14]
In addition, the synthesis of fully
3
unsaturated 1-benzosilepines has also been described before.[15]
which may favor sila-substituted drugs over the corresponding
carbon species.[3] In addition, silicon analogues are generally
more lipophilic, which makes them less prone to hepatic
metabolism. On the other hand, the increase of the lipophilicity
also influences the ability to cross the blood/brain barrier.[4b] The
latter effect should be even more significant when, for example,
a nitrogen atom is replaced by a silicon atom. Therefore,
pharmaceuticals interacting with the central nervous system,
especially with the brain, may benefit from the introduction of a
silicon atom into their structures. However, relatively little
attention has been paid to the exchange of nitrogen with silicon
in known drug scaffolds.
Benzodiazepines are able to bind to the inhibitory important
GABA receptors (GABA: γ-aminobutyric acid) of the central
[
a]
L. H. Lühning, J. Strehl, Dr. M. Schmidtmann, Prof. Dr. S. Doye
Institut für Chemie
Universität Oldenburg
Scheme 1. One-pot procedures for the preparation of 1,5-benzodiazepines
Carl-von-Ossietzky-Straße 9-11
and 1,5-benzoazasilepines.
26111 Oldenburg (Germany)
E-Mail: doye@uni-oldenburg.de
Supporting information for this article is given via a link at the end of
the document.
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Results and Discussion
other hand, sterically demanding ortho-substituted N-
methylanilines were found to be challenging substrates and as a
result, slightly reduced yields between 59 % and 74 % were
obtained with N-methyl-ortho-toluidine. In addition, a successful
reaction of N-methyl-ortho-chloroaniline could only be achieved
with sterically less demanding allylsilane 1b but even in this
case, the product 5b could only be isolated in a disappointing
yield of 6 %. With regard to the results obtained with meta- and
Initially, a series of titanium[9] and tantalum catalysts,[16] that had
already been identified to be active in hydroaminoalkylation
reactions,[8] were used for a brief catalyst screening (Figure 1,
Table 1) in which allyldimethylphenylsilane (1a) was tried to
react with N-methylaniline (2). First of all, it was recognized that
2 4
Ti(NMe ) as well the aminopyridinato titanium catalysts I and II
do not show any catalytic activity at 140 °C (Table 1, entries 1-3), para-substituted N-methylanilines, it becomes clear that besides
while at the same temperature, complexes III, IV, Ind
5-indenyl), and Ta(NMe
do catalyze the desired reaction
Table 1, entries 4, 5, 8, and 10). Among the active catalysts,
titanium mono(formamidinate) complex IV initially synthesized
by Eisen et al.[17] gave the best result which led to the formation
of the desired branched hydroaminoalkylation product 3a in
excellent yield of 90 % (Table 1, entry 5). Inspired by the well-
established fact, that hydroaminoalkylation reactions performed
2
TiMe
2
(Ind
alkyl substitution, the presence of fluoro, chloro, and bromo
substituents is also tolerated. The excellent yields in which the
chloro- and bromo-substituted products 8a-8c, 9a-9c, 13a-13c,
and 14a-14c (76-96 %) were formed deserve particular attention
because bromo and chloro substituents offer various possibilities
for further functionalization.[18] In addition, it should be mentioned
that in former studies, halogenated substrates often gave poor
results in hydroaminoalkylation chemistry.[9d,g,h] Since the same
is true for reactions of the electron acceptor-substituted starting
material N-methyl-para-trifluoromethylaniline, it was not
surprising to find that under the reaction conditions, this
substrate does not react at all with the allylsilanes 1a-1c.
However, on the other hand, the hydroaminoalkylation products
=
(
2 5
)
2 2
with the catalyst Ind TiMe often give improved yields at lower
temperatures,[9d] we also performed selected reactions at lower
temperatures. However, while a significantly improved yield of
71 % was indeed obtained with the catalyst Ind
2 2
TiMe at 105 °C
(
compared to 10 % at 140 °C, Table 1, entries 8 and 9), the
catalytic performance of IV could not be improved, neither at
lower nor at higher temperatures (Table 1, entries 5-7).
Interestingly, and in contrast to corresponding reactions of
16a-16c which possess
a
pharmacologically relevant
trifluoromethoxy substituent could be isolated in excellent yields
between 83 % and 87 %. This result is in good agreement with
the performance of additional ether-substituted N-methylanilines
which led to the formation of the corresponding methoxy- or
phenoxy-substituted products 15a-15c and 17a-17c in 74-87 %
yield. Finally, it was even possible to isolate the thiomethyl ether
products 18a-18c in good yields of 74-87 %.
styrenes,[9d,k]
hydroaminoalkylation product were not formed from allylsilane
a in the presence of catalysts IV or Ind TiMe . Although
corresponding regioselectivities were also obtained with
catalysts III or Ta(NMe , the better yield of 90 % obtained with
detectable
amounts
of
the
linear
1
2
2
2 5
)
IV (Table 1, entry 5) led to the decision to run all further
experiments with formamidinate catalyst IV at 140 °C.
Table
1.
Catalyst
screening
for
the
hydroaminoalkylation
of
[
a]
allyldimethylphenylsilane (1a) with N-methylaniline (2).
Entry
Catalyst
T [°C]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
Ti(NMe
2
)
4
140
140
140
140
140
120
160
140
105
140
0
I
0
II
0
III
IV
IV
IV
71
90
65
78
10
71
70
Figure 1. Titanium catalysts for hydroaminoalkylation reactions of alkenes.
To investigate the scope of the hydroaminoalkylation of
2
Ind TiMe
2
2
allylsilanes,
a large number of ortho-, meta-, and para-
2
Ind TiMe
substituted N-methylanilines were then reacted with
allyldimethylphenylsilane (1a), allyltrimethylsilane (1b), or
allyltriphenylsilane (1c) under the conditions of Table 1, entry 5
using 10 mol% of catalyst IV. During this study which is
summarized in Table 2, it was first recognized that the reactivity
of the allylsilane is not significantly influenced by the nature of
the substituents bound to the silicon center and correspondingly,
all three allylsilanes 1a-1c gave comparable results. On the
2 5
Ta(NMe )
[a] Reaction conditions: allyldimethylphenylsilane (1a, 2.2 mmol, 388 mg), N-
methylaniline (2, 2.0 mmol, 214 mg), catalyst (0.2 mmol, 10 mol%), toluene (1
mL), T, 24 h. [b] Isolated yield.
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Table 2. Hydroaminoalkylation of allylsilanes with various N-methylanilines.[a]
Additional attempts to achieve corresponding reactions of
allyldimethylphenylsilane (1a) with dialkylamines turned out to
be successful under identical reaction conditions with N-
methylcyclohexylamine and N-methylbenzylamine (Table 3).
However, the generally reduced reactivity of dialkylamines in
hydroaminoalkylation reactions[8,9,11,16] is in good agreement with
the reduced yield of 50 % in which product 19 was obtained from
1a and N-methylcyclohexylamine (Table 3, entry 1). On the
other hand, a simple prolongation of the reaction time from 24 h
to 48 h raised the yield to 76 % (Table 3, entry 2). The reaction
of N-methylbenzylamine with 1a gave access to product 20 in
good yield of 70 % (Table 3, entry 3) but in this case, the
alkylation of the amine took place selectively at the benzylic
position and not at the usually preferred methyl group. The latter
observation has been made before during closely related
hydroaminoalkylation studies with this substrate.[
9g,j]
Table 3. Hydroaminoalkylation of allyldimethylphenylsilane (1a) with
dialkylamines.[
a]
Entry
t [h]
R1
R2
Yield [%][b]
1
2
3
24
48
24
H
Cy
Cy
Me
50 (19)
76 (19)
70 (20)
H
Ph
[
a] Reaction conditions: allyldimethylphenylsilane (1a, 2.2 mmol, 388 mg),
dialkylamine (2.0 mmol), IV (0.2 mmol, 109 mg, 10 mol%), toluene (1 mL),
40 °C, t. [b] Isolated yield.
1
As mentioned above, a reasonable synthetic approach towards
,5-benzoazasilepines, which represent the silicon analogues of
1
pharmaceutically relevant 1,5-benzodiazepines, consists of an
initial hydroaminoalkylation of allyl(2-bromophenyl)silanes and a
subsequent
intramolecular
Buchwald-Hartwig
amination
(
Scheme 1, path b). Correspondingly, we next focused on the
hydroaminoalkylation of allyl(2-bromophenyl)dimethylsilane (21)
which to our delight, took place smoothly with N-methylaniline
(
2) under standard conditions to give the desired product 22 in
excellent yield of 91 % (Scheme 2).
Scheme 2. Hydroaminoalkylation of allyl(2-bromophenyl)dimethylsilane (21).
[a] Reaction conditions: silane (2.2 mmol), N-methylaniline (2.0 mmol), IV (0.2
mmol, 109 mg, 10 mol%), toluene (1 mL), 140 °C, 24 h. Yields refer to isolated
yields.
With key-intermediate 22 in hand, a brief ligand screening for the
Buchwald-Hartwig amination was then conducted using
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Pd
2
(dba)
3
(dba = dibenzylideneacetone) as the palladium source
flask at the same time. To finally investigate the scope of the
one-pot procedure, we then reacted additional ortho-, meta-, and
para-substituted N-methylanilines with allylsilane 21. As
expected and in good agreement with the results obtained for
the hydroaminoalkylation of simple allylsilanes presented in
Table 2, it was found that para- or meta-substituted N-
methylanilines undergo smooth reaction to give the desired 1,5-
benzoazasilepines in good yields between 66 % and 84 %
(Table 5, entries 3-11). On the other hand, it is worth mentioning
that even the sterically demanding ortho-methyl-substituted 1,5-
benzoazasilepine 24 could be isolated in a moderate yield of
47 % (Table 5, entry 2). However, overall, the results presented
in Table 5 clearly show that besides alkyl and ether substitution,
the one-pot procedure also tolerates the presence of
pharmacologically promising fluoro, chloro, trifluoromethyl, and
thioether substituents. Finally, confirmation of the successful
synthesis of the 1,5-benzoazasilepines could be achieved by a
single crystal X-ray analysis of the para-methyl-substituted
product 26 which is shown in Figure 2.[19]
and sodium tert-butoxide as a base (Table 4). Although rac-
BINAP had already been identified to be a good ligand for the
corresponding formation of 1,5-benzodiazepines,[7] the
cyclization of 22 which delivered the 1,5-benzoazasilepine 23
only took place with a moderate yield of 64 % in the presence of
this ligand (Table 4, entry 1). While even worse yields were
obtained with the ligands JohnPhos and dppf (Table 4, entries 2
and 3), the use of the biphenyl-based ligands XPhos or RuPhos
finally gave access to the desired product 23 in significantly
improved yields of 82 % and 93 %, respectively (Table 4, entries
4
and 5).
Table 4. Ligand screening for the intramolecular Buchwald-Hartwig amination
of hydroaminoalkylation product 22.[a]
Table 5. Scope of the one-pot procedure for the synthesis of 1,5-
benzoazasilepines.[
a]
Entry
Ligand
Yield [%][b]
1
2
3
4
5
rac-BINAP
JohnPhos
dppf
64
36
53
82
93
Entry
R
Yield [%][b]
83 (23)
47 (24)
81 (25)
81 (26)
78 (27)
65 (28)
70 (29)
74 (30)
66 (31)
84 (32)
84 (33)
XPhos
1
2
3
4
5
6
7
8
9
H
RuPhos
o-Me
m-Me
p-Me
m-F
p-F
[
2 3
a] Reaction conditions: silane (1.0 mmol, 362 mg), Pd (dba) (0.025 mmol, 23
t
mg, 2.5 mol%), ligand (0.1 mmol, 10 mol%), NaO Bu (1.5 mmol, 144 mg),
toluene (3 mL), 110 °C, 24 h. [b] Isolated yield.
Because overall the best result of the intramolecular Buchwald-
Hartwig amination of 22 was obtained with RuPhos, this ligand
was then used for the finally planned development of a one-pot
procedure for the synthesis of 1,5-benzoazasilepines from
m-Cl
p-Cl
p-OMe
allyl(2-bromophenyl)silanes (Table 5). For that purpose,
a
hydroaminoalkylation reaction mixture of allylsilane 21 and N-
methylaniline (1) in toluene was initially heated to 140 °C for 24
h in the presence of 10 mol% of catalyst IV. Afterwards, 2.5
10
p-OCF
3
mol% Pd
2
(dba)
3
, 7 mol% RuPhos, sodium tert-butoxide and
11
p-SMe
additional toluene were added and the resulting reaction mixture
was heated to 110 °C for additional 24 h. The yield of 83 % in
[a] Reaction conditions: 1) silane (23, 2.2 mmol, 562 mg), N-methylaniline (2.0
mmol), IV (0.2 mmol, 109 mg, 10 mol%), toluene (1 mL), 140 °C, 24 h. 2)
which
1,5-benzoazasilepine
23
was
obtained
after
Pd
2
(dba)
3
(0.05 mmol, 46 mg, 2.5 mol%), RuPhos (0.14 mmol, 66 mg, 7
t
chromatographic purification (Table 5, entry 1) again underlines
the well-established fact that the Buchwald-Hartwig amination
tolerates the presence of the reagents used in
mol%), NaO Bu (3.0 mmol, 288 mg), toluene (5 mL), 110 °C, 24 h [b] Isolated
yield.
[7]
hydroaminoalkylation reactions. However, the sensitivity of the
titanium catalyst against alcohols and carbonyl compounds rules
out the possibility to develop a related one-pot protocol in which
both the titanium and the palladium catalyst are added to the
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Conclusions
from GRACE Davison (particle size 0.037-0.063 mm) was used. Light
petroleum ether (b.p. 40-60 °C, PE), tert-butyl methyl ether (MTBE),
2 2
CH Cl , and EtOAc used for flash chromatography were distilled prior to
In summary, we have presented the first examples of titanium-
catalyzed hydroaminoalkylation reactions of allylsilanes.
Although a number of different titanium complexes were found to
be competent catalysts for this challenging transformation, best
results were obtained with a titanium mono(formamidinate)
catalyst initially synthesized by the Eisen group. Based on the
finding that allylsilanes are exclusively converted to branched
hydroaminoalkylation products, it was also possible to develop a
one-pot procedure for the synthesis of 1,5-benzoazasilepines.
The corresponding reaction sequence includes an initial
hydroaminoalkylation of an allyl(2-bromophenyl)silane and a
subsequent intramolecular Buchwald-Hartwig amination. Finally,
it is worth mentioning that very recently, we found that vinyl
use. For thin layer chromatography, silica on TLC aluminum foils with
fluorescent indicator 254 nm from Fluka were used. The substances
were detected with UV light or iodine. All products that have already been
1
reported in the literature were identified by comparison of the obtained H
NMR and 13C NMR spectra with those reported in the literature. New
compounds were additionally characterized by infrared (IR) spectroscopy,
GC-MS, high resolution mass spectrometry (HRMS) and 29Si NMR
spectroscopy. NMR spectra were recorded on the following
spectrometers: Bruker Fourier 300, Bruker Avance DRX 500, or Bruker
Avance III, 500 MHz. All 1H NMR spectra are reported in δ units (ppm)
3
relative to the signal of CDCl at 7.26 ppm. J values are given in Hz. All
13
C NMR spectra are reported in δ units (ppm) relative to the central line
at 77.0 ppm. 29Si NMR spectra are reported in δ
of the triplet for CDCl
3
units (ppm) relative to the external standard Me SiHCl (δ = 11.1 ppm) in
2
silanes can also be used for closely related synthetic procedures. relation to SiMe
4
(δ = 0.0 ppm). Infrared spectra were recorded on a
However, the corresponding results will be published separately
in due course.[20]
Bruker Vector 22 spectrometer or a Bruker Tensor 27 spectrometer
(ATR). GC-MS analyses were performed on a Thermo Finnigan Focus
gas chromatograph equipped with a DSQ mass detector and Agilent DB-
5
column (length: 30 m, inner diameter: 0.32 mm, film thickness: 0.25 μm,
(
94%-methyl)-(5%-phenyl)-(1%-vinyl)polysiloxan). GC analyses were
performed on a Shimadzu GC-2010 gas chromatograph equipped with a
flame ionization detector. High resolution mass spectra (HRMS) were
recorded on a Waters Q-TOF Premier spectrometer in EI or ESI mode
(ESI+, TOF).
General Procedure for the Hydroaminoalkylation of Allylsilanes, as
Exemplified by the Reaction of Allyldimethylphenylsilane (1a) with
N-Methylaniline (2): 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 IV (109 mg, 0.2 mmol, 10 mol%) and
toluene (0.5 mL). Afterwards, N-methylaniline (2, 214 mg, 2.0 mmol),
allyldimethylphenylsilane (1a, 388 mg, 2.2 mmol), and toluene (0.5 mL)
were added and the mixture was heated to 140 °C for 24 hours. After the
reaction mixture had been cooled to room temperature, the crude product
was purified by flash chromatography (SiO
2-methyl-3-(dimethyl(phenyl)silyl)propyl)aniline (3a, 509 mg, 1.80 mmol,
0 %) as a colorless oil. R = 0.17 (SiO
, PE/MTBE, 40:1). 1H NMR (500
MHz, CDCl ): δ = 7.57-7.47 (m, 2 H), 7.38-7.32 (m, 3 H), 7.16-7.09 (m, 2
2
, PE/MTBE, 40:1) to give N-
(
9
f
2
3
H), 6.65 (tt, J = 0.9 Hz, J = 7.3 Hz, 1 H), 6.50 (dd, J = 0.9 Hz, J = 8.4 Hz,
2 H), 3.65 (br. s, 1 H), 2.96 (dd, J = 6.0 Hz, J = 12.3 Hz, 1 H), 2.84 (dd, J
Figure 2. Single crystal X-ray structure of 1,5-benzoazasilepine 26,[19] ellipsoid
representation at the 50 % probability level, hydrogen atoms are omitted for
clarity. Selected bond length [Å] and angles [°]: Si1-C12 1.872 (2), Si1-C11
=
1
1
1
1

7.2 Hz, J = 12.3 Hz, 1 H), 1.95-1.84 (m, 1 H), 0.99 (dd, J = 4.6 Hz, J =
4.8 Hz, 1 H), 0.96 (d, J = 6.6 Hz, 3 H), 0.70 (dd, J = 8.9 Hz, J = 14.8 Hz,
1.858 (3), Si1-C6 1.857 (2), Si1-C7 1.874 (2), C7-C8 1.540 (3), C8-C9 1.527
H), 0.31 (s, 6 H) ppm. 13C{ H} NMR (125 MHz, DEPT, CDCl
1
3
): δ =
(
(
3), C8-C10 1.523 (3), N1-C1 1.426 (3), N1-C9 1.464 (3), C12-Si1-C11 109.53
15), C11-Si1-C7 111.16 (13), C12-Si1-C7 107.87 (11), C5-C6-Si1 123.41 (16),
48.4 (C), 139.5 (C), 133.5 (CH), 129.2 (CH), 128.9 (CH), 127.8 (CH),
16.9 (CH), 112.6 (CH), 53.1 (CH
2
), 29.5 (CH), 21.9 (CH
2
), 21.0 (CH
3
),
C1-C6-Si1 119.55 (15), C6-Si1-C7 109.87 (10), C13-N1-C9 121.15 (16), C13-
N1-C1 121.23 (16), C1-N1-C9 116.96 (17), C1-N1-C9 116.96(17), C7-C8-C9
1.9 (CH
3
), 2.3 (CH
3
) ppm. 29Si{ H} NMR (99.4 MHz, INEPT, CDCl
1
3
): δ
+
112.23 (17), C7-C8-C10 110.60 (18), C9-C8-C10 110.51 (19).
= 3.6 ppm. GC/MS (EI, 70 eV): m/z (%) = 283 (3) [M] , 135 (33)
+
+
+
[
C
8
H
11Si] , 106 (100) [C
7
H
8
N] , 77 (10) [C
6
H
5
] . HRMS (EI): calcd.
+
1
(
18
C H25NSi) 283.1751, found 283.1750 [M] . IR (ATR, neat): λ = 3417,
3
6
066, 2955, 1602, 1505, 1427, 1320, 1249, 1179, 1111, 829, 791, 746,
Experimental Section
90 cm1
.
General: Unless otherwise noted, all reactions were performed under an
General Procedure for the One-Pot Synthesis of 1,5-
Benzoazasilepines, as Exemplified by the Synthesis of Product 26:
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 IV (109 mg, 0.2 mmol, 10 mol%) and toluene (0.5
mL). Afterwards, 4,N-dimethylaniline (242 mg, 2.0 mmol), allyl(2-
bromophenyl)dimethylsilane (21, 562 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
inert atmosphere of nitrogen in oven-dried Schlenk tubes (Duran
®
glassware, 100 mL, ø = 30 mm) equipped with Teflon stopcocks and
magnetic stirring bars (15 × 4.5 mm). Toluene was purified by distillation
from sodium wire and degassed. Catalyst IV,[17] the N-methylanilines,
and the allylsilanes were synthesized according to literature
[
21]
procedures. Prior to use, all substrates were distilled or recrystallized
and degassed. Catalyst IV, the N-allylsilanes, 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
back into a nitrogen-filled glovebox. Then Pd
2
(dba)
3
(46 mg, 0.05 mmol,
t
2.5 mol%), RuPhos (66 mg, 0.1 mmol, 7 mol%), NaO Bu (288 mg, 3.0
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Chemistry - A European Journal
10.1002/chem.201605923
FULL PAPER
mmol), and toluene (5 mL) were added. After heating the mixture to
[7]
[8]
M. Weers, L. H. Lühning, V. Lührs, C. Brahms, S. Doye, Chem. Eur. J.
10.1002/chem.201604561.
110 °C for additional 24 hours, the crude product was purified by flash
chromatography (SiO
2
, PE) to give 1,5-benzoazasilepine 26 (480 mg,
For reviews on the hydroaminoalkylation of alkenes, see: a) P. W.
Roesky, Angew. Chem. 2009, 121, 4988-4991; Angew. Chem. Int. Ed.
2009, 48, 4892-4894; b) T.-Q. He, X.-J. Zheng, H. Cai and Z.-L. Xue,
Chin. J. Inorg. Chem. 2014, 30, 53–61; c) E. Chong, P. Garcia, L. L.
Schafer, Synthesis 2014, 46, 2884-2896.
1
1.62 mmol, 81 %) as a colorless solid. R
f
= 0.28 (SiO
2
, PE). H NMR (500
3
MHz, CDCl ): δ = 7.56 (dd, J = 1.5 Hz, J = 7.3 Hz, 1 H), 7.36 (dt, J = 1.5
Hz, J = 7.6 Hz, 1 H), 7.24 (dt, J = 0.9 Hz, J = 7.3 Hz, 1 H), 7.16 (d, J =
7
2
1
.9 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 2 H), 6.55-6.46 (m, 2 H), 3.83 (td, J =
.0 Hz, J = 2.0 Hz, J = 14.3 Hz, 1 H), 2.82 (dd, J = 11.1 Hz, J = 14.3 Hz,
[9]
For examples of titanium-catalyzed hydroaminoalkylation reactions of
alkenes, see: a) C. Müller, W. Saak, S. Doye, Eur. J. Org. Chem. 2008,
2731-2739; b) R. Kubiak, I. Prochnow, S. Doye, Angew. Chem. 2009,
121, 1173-1176; Angew. Chem. Int. Ed. 2009, 48, 1153-1156; c) I.
Prochnow, R. Kubiak, O. N. Frey, R. Beckhaus, S. Doye,
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Dörfler, S. Doye, Angew. Chem. 2013, 125, 1851-1854; Angew. Chem.
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Eur. J. 2013, 19, 3833-3837; i) E. Chong, L. L. Schafer, Org. Lett. 2013,
15, 6002-6005; j) J. Dörfler, T. Preuß, A. Schischko, M. Schmidtmann,
S. Doye, Angew. Chem. 2014, 126, 8052-8056; Angew. Chem. Int. Ed.
H), 1.04 (d, J = 6.8 Hz, 3 H), 0.95-0.83 (m, 1 H), 0.49 (dd, J = 12.0 Hz,
J = 14.3 Hz, 1 H), 0.30 (s, 3 H), 0.00 (s, 3 H) ppm. 13C{ H} NMR (125
1
MHz, JMOD, CDCl
3
): δ = 154.0 (C), 145.8 (C), 139.8 (C), 135.1 (CH),
1
5

30.6 (CH), 129.4 (CH), 127.4 (CH), 125.7 (C), 125.6 (CH), 113.2 (CH),
9.1 (CH
2
), 30.0 (CH), 24.2 (CH
2
), 22.8 (CH
3
), 20.3 (CH
3
3
), 2.6 (CH ),
2.7 (CH
3
) ppm. 29Si{ H} NMR (99.4 MHz, CDCl
1
3
): δ = 4.5 ppm. GC/MS
+
+
(EI, 70 eV): m/z (%) = 295 (93) [M] , 280 (59) [C18
H22NSi] , 118 (35)
+
+
[
C
8 8
H
N] , 91 (53) [C
H
7 7
] . HRMS (EI): calcd. (C19
H25NSi) 295.1751,
+
1
found 295.1748 [M] . IR (ATR, neat): λ = 3064, 3009, 2948, 2917, 2882,
1617, 1584, 1561, 1511, 1467, 1437, 1369, 1347, 1319, 1286, 1252,
1
208, 1188, 1164, 1127, 1085, 1026, 867, 825, 790, 740, 704, 670, 632
cm 1. Colorless crystals suitable for single-crystal X-ray analysis[18] were

2 2
obtained by crystallization from CH Cl at room temperature.
2014, 53, 7918-7922; k) J. Dörfler, T. Preuß, C. Brahms, D. Scheuer, S.
Doye, Dalton Trans. 2015, 44, 12149-12168; l) J. Dörfler, B. Bytyqi, S.
Hüller, N. M. Mann, C. Brahms, M. Schmidtmann, S. Doye, Adv. Synth.
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Nimoth, M. Schmidtmann, S. Doye, Z. Anorg. Allg. Chem. 2015, 641,
2071-2082.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft for financial
support of our research as well as Jessica Reimer, Fenja
Martins, and Sonja Timmer for experimental assistance.
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Chemistry - A European Journal
10.1002/chem.201605923
FULL PAPER
[
18] a) V. Peesapati, U. N. Rao, R. A. Pethrick, J. Ind. Chem. Soc. 1991, 68,
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whole molecules disorder (0.92 : 0.08), the minor sites were restraint to
be equal to the major sites using the SAME instruction within SHELXL,
557 parameters refined, 115 restraints, non H atoms of the major sites
were refined anisotropically, those of the minor sites isotropically,
hydrogen atoms of the major sites were located from the difference
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3
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[19] Compound 26: Colorless crystals, dimensions 0.380 × 0.180 × 0.080
1
mm³, orthorhombic space group Pca2 , unit cell dimensions a =
2
5.9786(6) Å, b = 10.6771(2) Å, c = 12.2213(3) Å, V = 3389.90(13) ų,
appropriate riding models, final residual values R
0.1017 for observed reflections and R = 0.0499, wR
reflections, goodness of fit 1.049, largest diff. peak, hole 0.455 and -
1
= 0.0404, wR
2
=
-
1
Z = 8, ρ = 1.158 Mg/m³, ϴmax = 32.029°, μ = 0.133 mm , radiation
MoKα1, λ = 0.71073 Å, ϕ and ω-scans with Bruker KAPPA APEX-II CCD
1
2
= 0.1086 for all
-
3
at T = 100(2) K, 122891 reflections measured, 11800 unique [Rint
=
0.210
e
Å . CCDC 1511412 contains the supplementary
0
.0510], 10371 observed [I>2σ(I)], an absorption correction was
crystallographic data for compound 26. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
performed based on symmetry related measurements with SADABS (G.
M. Sheldrick, University of Göttingen, Germany, 2014), Tmin = 0.9192,
T
max
=
1.0000, the structure was solved by direct methods with
[20] L. H. Lühning, M. Rosien, S. Doye, Synlett 2017, 28, manuscript in
preparation.
SHELXS and refined against F² employing a full-matrix least-squares
algorithm with SHELXL (G. M. Sheldrick, Acta Crystallogr. Sect. C 2015,
[21] For experimental details, see the Supporting Information.
71, 3-8), the structure has been refined as a racemic twin (0.68 : 0.32),
two molecules are present in the asymmetric unit, both of them showing
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Chemistry - A European Journal
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Entry for the Table of Contents
FULL PAPER
Allylsilanes
regioselective
undergo
highly
L. H. Lühning, J. Strehl, M.
Schmidtmann, S. Doye*
intermolecular
hydroaminoalkylation reactions in
the presence of titanium
a
Page No. – Page No.
mono(formamidinate) catalyst. In
addition, a one-pot procedure that
Hydroaminoalkylation of
Allylsilanes and a One-Pot
Procedure for the Synthesis of
combines
hydroaminoalkylation
with
an
initial
reaction
1,5-Benzoazasilepines
a
subsequent Buchwald-
Hartwig
converts
amination
an
directly
allyl(2-
bromophenyl)silane into 1,5-
benzoazasilepines.
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