Thieme Chemistry Journals Awardees - Where Are They Now? Titanium-Catalyzed Hydroaminoalkylation of Vinylsilanes and a One-Pot Procedure for the Synthesis of 1,4-Benzoazasilines

Article abstract of DOI:10.1055/s-0036-1589048

Vinylsilanes undergo intermolecular alkene hydroaminoalkylation with secondary amines in the presence of a titanium mono(aminopyridinato) catalyst to give the branched hydroaminoalkylation products with high regioselectivity. Corresponding reactions of a suitable (2-bromophenyl)vinylsilane combined with a subsequent intramolecular Buchwald-Hartwig amination result in the development of an elegant one-pot procedure for the synthesis of 1,4-benzoazasilines.

Full text of DOI:10.1055/s-0036-1589048

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
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A
de
L. H. Lühning et al.
Letter
Synlett
Thieme Chemistry Journals Awardees – Where Are They Now?
Titanium-Catalyzed Hydroaminoalkylation of Vinylsilanes and a
One-Pot Procedure for the Synthesis of 1,4-Benzoazasilines
Lars H. Lühning
R1 R1
Si
R1 R1
Si
Hydroamino-
alkylation
Michael Rosien
Sven Doye*
H
N
NH
R2
R2
13 examples
up to 90% yield
Br
Br
Institut für Chemie, Universität Oldenburg,
Carl-von-Ossietzky-Straße 9–11, 26111 Oldenburg,
Germany
Buchwald–Hartwig
amination
One-pot procedure
1) Hydroaminoalkylation
2) Buchwald–Hartwig amination
R1 R1
Si
doye@uni-oldenburg.de
10 examples
up to 79% yield
N
R2
1,4-Benzoazasilines
Received: 29.03.2017
Accepted after revision: 10.05.2017
Published online: 18.07.2017
DOI: 10.1055/s-0036-1589048; Art ID: st-2017-b0214-l
Abstract Vinylsilanes undergo intermolecular alkene hydroaminoal-
kylation with secondary amines in the presence of a titanium mo-
no(aminopyridinato) catalyst to give the branched hydroaminoalkyla-
tion products with high regioselectivity. Corresponding reactions of a
suitable (2-bromophenyl)vinylsilane combined with a subsequent intra-
molecular Buchwald–Hartwig amination result in the development of
an elegant one-pot procedure for the synthesis of 1,4-benzoazasilines.
Key words amination, amines, palladium, silicon, titanium
Sven Doye was born in Berlin (West), Germany in 1967. Between 1986
and 1990 he studied chemistry at the Technical University of Berlin. He
received his diploma degree in 1990 from the same University and his
PhD in 1993 from the University of Hannover. During his graduate stud-
ies under the supervision of Prof. E. Winterfeldt, he worked on the ste-
reoselective synthesis of the sesquiterpene (–)-myltaylenol. Between
1994 and 1996 he spent two years in industry working for BASF AG in
Ludwigshafen, Germany. After a subsequent year of post-doctoral re-
search at the Massachusetts Institute of Technology in Cambridge, USA,
with Prof. S. L. Buchwald (1996–1997), he returned to the University of
Hannover in 1998. Since then he has been working independently in
the fields of synthetic organic chemistry and catalysis. From October
2003 to September 2006 he was Professor of Organic Chemistry at the
University of Heidelberg, Germany and since September 2006 he has
been Professor of Organic Chemistry at the University of Oldenburg,
Germany. From September 2002 to January 2003 he was also Guest
Professor at Cardiff University, Wales, UK. Sven Doye was a recipient of
the 2002 Thieme Chemistry Journal Award for young investigators.
Since the discovery of the hydroaminoalkylation of
alkenes1 by Maspero et al. in the late 1970s2a a lot of effort
has been spent on the improvement of this highly atom-ef-
ficient reaction that allows the direct addition of α-C(sp3)–
H bonds of primary or secondary amines across C–C double
bonds (Scheme 1). While corresponding reactions can be
achieved in the presence of catalytic amounts of group 5
metal,2 ruthenium,3 iridium,4 zirconium,5 or titanium6 com-
plexes, in the latter case, the regioselectivity of the addition
reaction can be controlled by the structure of the ligands of
the titanium catalyst. For example, hydroaminoalkylation
reactions performed in the presence of the bis(aminopyrid-
inato) titanium catalyst I (Figure 1) selectively convert sty-
renes into the linear regioisomers6j while the mono(forma-
midinato) titanium catalyst II, which was initially synthe-
sized by Eisen et al.,7 and the mono(aminopyridinato)
titanium catalyst III favor the formation of the branched re-
gioisomers.6k,m Interestingly, II turned out to be catalytical-
ly far more active than III and as a consequence, it was even
possible to achieve hydroaminoalkylation reactions of un-
activated 1,1- and 1,2-disubstituted alkenes and styrenes in
the presence of II. On the other hand better regioselectivi-
ties were usually observed with catalyst III. However, very
recently we found that even II catalyzes the highly regiose-
lective formation of branched hydroaminoalkylation prod-
ucts from allylamines and allylsilanes. Taking advantage of
this fact, we were already able to develop new one-pot pro-
cedures for the synthesis of 1,5-benzodiazepines6o and 1,5-
benzoazasilepines6p (Scheme 2, path A) which rely on an
initial regioselective hydroaminoalkylation reaction of an
N-allyl-2-bromoaniline or an allyl(2-bromophenyl)silane
and a subsequent intramolecular Buchwald–Hartwig ami-
nation.8
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
L. H. Lühning et al.
Letter
Synlett
with N-methylanilines have been reported. While the group
of Hultzsch used a chiral niobium binaphtholate catalyst for
the highly regioselective synthesis of a branched hydroami-
noalkylation product,2i Hartwig et al.2c employed catalytic
amounts of Ta(NMe2)5, and in the presence of this catalyst,
dimethylphenylvinylsilane (1) and N-methylaniline (3)
were converted into the hydroaminoalkylation products 4a
and 4b in a ratio of only 64:36 in favor of the branched re-
gioisomer 4a (Scheme 3). On the other hand, Schafer et al.
reported that the linear hydroaminoalkylation product is
formed as the major regioisomer from trimethylvinylsilane
(2) in the presence of a phosphoramidate tantalum cata-
lyst.2j From a mechanistic point of view,2c,d,i,6e it is generally
accepted that metallaaziridines,2e,5,6n which are formed
from the reacting amine and a metal catalyst by N–H and
C–H bond activation, represent the catalytically active spe-
cies of hydroaminoalkylation reactions. These three-mem-
bered ring intermediates are able to form the new C–C bond
by insertion of an alkene into the metal–carbon bond.
Hydroamino-
alkylation
H
N
R
R
+
+
Ph
N
Ph
N
H
Ph
R
H
branched
linear
Scheme 1 Hydroaminoalkylation of styrene
Ph
Ph
N
N
N
H
2
Ti(NMe2)2
I
iPr iPr
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
H
N
N
iPr
iPr
Ti(NMe2)3
Ti(NMe2)3
II
III
Figure 1 Selected titanium catalysts for hydroaminoalkylation reac-
tions of alkenes
Path A:
Path B:
previous work
this work
H
N
Si
R
Si
Ph
Ph
Ph
N
Hydro-
amino-
alkylation
Hydro-
amino-
alkylation
Ta(NMe2)5
(4 mol%)
4a, 50%
Si
X
H
1
+
+
Br
Br
toluene
160–165 °C
38 h
H
H
N
4b, 28%
Si
N
Ph
Ph
4a/4b = 64:36
Ph
X
Si
3
NH
R
branched regioisomers
NH
Br
R
Br
Scheme 3 Tantalum-catalyzed hydroaminoalkylation of dimethyl-
phenylvinylsilane (1) with N-methylaniline (3) reported by Hartwig et
al.2c
Buchwald–
Hartwig
amination
Buchwald–
Hartwig
amination
X
Si
We started our study with two control experiments in
which dimethylphenylvinylsilane (1) was reacted with N-
methylaniline (3) in toluene at 160 °C (sealed Schlenk tube)
in the presence of 10 mol% of either Ta(NMe2)5 or Ti(NMe2)4
(Table 1, entries 1 and 2). Not surprisingly and in good
agreement with Hartwig's result, the homoleptic tantalum
complex Ta(NMe2)5 turned out to be a competent catalyst
for this reaction. While in this case, the hydroaminoalkyla-
tion products 4a and 4b could be isolated in 80% combined
yield, Ti(NMe2)4 did not show any catalytic activity. The fact
that the Ta(NMe2)5-catalyzed reaction showed a surprising-
ly good regioselectivity of 91:9 in favor of the branched
product 4a made it possible to isolate 4a in pure form (71%
yield) after flash column chromatography. However, in this
context it should be noted that the separation of the two re-
gioisomers 4a and 4b turned out to be extremely challeng-
ing and as a result, we paid particular attention to an im-
provement of the regioselectivity of the hydroaminoalkyla-
tion. As expected and in good agreement with
corresponding reactions of styrenes,6j the bis(aminopyridi-
nato) catalyst I favored the formation of the linear regioiso-
mer 4b but unfortunately, the regioselectivity was only
modest (4a/4b = 29:71, Table 1, entry 3). As a direct conse-
quence of the modest regioselectivity and the challenging
N
R
N
R
1,4-Benzoazasilines
X = NMe 1,5-Benzodiazepines
X = SiMe
2 1,5-Benzoazasilepines
Scheme 2 Reaction sequences for the formation of 1,5-benzodiaze-
pines,6o 1,5-benzoazasilepines,6p and 1,4-benzoazasilines
In continuation of our studies with silicon-containing
alkene building blocks, we now present an additional inves-
tigation of vinylsilanes as a new class of starting materials
for titanium-catalyzed hydroaminoalkylation reactions and
we also describe the use of a (2-bromophenyl)vinylsilane
for the development of an additional hydroaminoalkyla-
tion–Buchwald–Hartwig amination sequence which in this
case gives access to 1,4-benzoazasilines (Scheme 2, path B).
Although sila substitution (Si/C exchange) in known drug
scaffolds is regarded as a promising possibility for the de-
velopment of new drugs,9 it must be mentioned that the
corresponding silicon-containing analogues of 1,2,3,4-tet-
rahydroquinolines have rarely been described in the litera-
ture10 and additionally, only a few group 5 metal catalyzed
hydroaminoalkylation reactions of vinylsilanes such as di-
methylphenylvinylsilane (1)2c or trimethylvinylsilane (2)2c,i,j
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
L. H. Lühning et al.
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separation of the regioisomers, pure 4b could only be iso-
lated in 48% yield which is significantly lower than the com-
bined yield of 4a and 4b (76%). Formamidinato titanium
catalyst II then turned out to be the most active catalyst
which gave the products 4a and 4b in a total yield of 85%
but only with a decreased regioselectivity of 85:15 in favor
of the branched isomer 4a (Table 1, entry 4). This led to a
significantly reduced yield of pure 4a (54%) after chromato-
graphic purification. Gratifyingly, we finally found that the
mono(aminopyridinato) titanium complex III is able to cat-
alyze the hydroaminoalkylation of 1 with 3 at 160 °C with
an excellent regioselectivity of 95:5 in favor of the branched
isomer 4a. The improved regioselectivity significantly facil-
itated the chromatographic purification and as a result,
pure 4a was isolated in 72% yield (Table 1, entry 5) while
only a small additional amount of a mixture of 4a and 4b
(6% yield) was obtained. Although the combined yield of
78% (4a + 4b) was slightly lower than in the case of
Ta(NMe2)5, we decided to run all further experiments with
catalyst III because the better regioselectivity was expected
to generally minimize problems associated with the separa-
tion of regioisomeric products.
conditions. Reactions performed with additional para- and
meta-substituted N-methylanilines then showed that be-
sides alkyl substitution, the presence of fluoro, chloro, bro-
mo, ether, and thioether substituents is tolerated (Table 2,
entries 4–12). In all these cases, the hydroaminoalkylation
reactions took place with excellent regioselectivity in favor
of the branched isomer and in addition, good to excellent
combined yields of the branched and the linear product
(63–90%) were achieved. Although chromatographic sepa-
ration of the regioisomeric products remained challenging,
most of the pure branched regioisomers 20a–30a could be
isolated in reasonable yields (52–83%). Only in the case of
the meta-bromophenyl derivative 26a (17% yield) a satisfy-
ing purification of the branched isomer could not be
achieved (Table 2, entry 8). Although the dialkylamines N-
methylcyclohexylamine (17) and N-methylbenzylamine
(18) did not undergo successful hydroaminoalkylation with
1 in the presence of catalyst III, we found that these reac-
tions can be catalyzed with Eisen´s formamidinato titanium
complex II (Table 2, entries 13 and 14). Interestingly, in the
Table 2 Hydroaminoalkylation of Dimethylphenylvinylsilane (1) with
Various Secondary Aminesa
Table 1 Catalyst Screening for the Hydroaminoalkylation of Dimeth-
ylphenylvinylsilane (1) with N-Methylaniline (3)a
R1
Si
R2
Ph
N
Si
Ph
19a–32a
H
Ph
N
H
III (10 mol%)
4a
H
N
R2
Si
+
catalyst (10 mol%)
+
H
Ph
N
toluene
160 °C, 24 h
Si
R1
+
+
19b–32b
H
Ph
Ph
toluene
temp., 24 h
4b
Si
N
H
R2
1
3
1
5–18
Ph
Si
N
Ph
Ph
R1
Entry Catalyst
Temp
(°C)
Yield of a + b Yield of major isomer Ratio
(%)
Entry R1
R2
Yield of a+ b Yield of major isomer Ratio
(%)
(%)b (a/b)c
(%)b
(a/b)c
1
2
3
4
5
Ta(NMe2)5
160
160
140
140
160
80
4a 71
91:9
–
1
2
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
5 o-Me-C6H4
6 m-Me-C6H4
7 p-Me-C6H4
8 m-F-C6H4
9 p-F-C6H4
14
19a 14
91:9
Ti(NMe2)4
–
–
85
76
77
90
89
80
78
77
82
78
63
55
54
20a 71
21a 71
22a 52
23a 83
24a 59
25a 72
26a 17
27a 65
28a 73
29a 69
30a 58
31a 55d
32b 54d
96:4
96:4
96:4
95:5
95:5
94:6
95:5
95:5
96:4
97:3
95:5
>99:1
<1:99
I
76
85
78
4b 48
4a 54
4a 72
29:71
85:15
95:5
3
II
III
4
5
a Reaction conditions: dimethylphenylvinylsilane (1, 357 mg, 2.20 mmol), N-
methylaniline (3, 214 mg, 2.00 mmol), toluene (1 mL), catalyst (0.20 mmol,
10 mol%), temp, 24 h, isolated yields.
6
10 m-Cl-C6H4
11 p-Cl-C6H4
12 m-Br-C6H4
13 p-Br-C6H4
14 p-MeO-C6H4
15 p-F3CO-C6H4
16 p-MeS-C6H4
17 Cy
7
b Yield of the pure regioisomer obtained after flash chromatography.
c Determined by GC analysis prior to flash chromatography.
8
9
To investigate the scope of the new process, we subse-
quently performed additional hydroaminoalkylation reac-
tions of dimethylphenylvinylsilane (1) with various second-
ary amines (Table 2). As observed before,6 the efficiency of
the reaction catalyzed by III is strongly influenced by the
steric bulk of the amine and correspondingly, the sterically
less hindered N-methyltoluidines 6 and 7 gave the hy-
droaminoalkylation products in much better yields than N-
methyl-o-toluidine (5, Table 2, entries 1–3). In this context,
it should also be mentioned that o-fluoro-, o-chloro, and o-
bromo-N-methylaniline failed to react under the employed
10
11
12
13
14
18 Me
a Reaction conditions: dimethylphenylvinylsilane (1, 357 mg, 2.20 mmol),
amine (2.00 mmol), toluene (1 mL), III (154 mg, 0.20 mmol, 10 mol%), 160
°C, 24 h, isolated yields.
b Yield of the pure regioisomer obtained after flash chromatography.
c Determined by GC analysis prior to flash chromatography.
d II (109 mg, 0.20 mmol, 10 mol%), 140 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
L. H. Lühning et al.
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case of N-methylcyclohexylamine (17), the branched regio-
isomer 31a was formed exclusively (55% yield), while N-
methylbenzylamine (18) was selectively converted into the
linear product 32b (54% yield). As observed before,2e,6g,j the
reaction of 17 took place at the sterically less hindered
methyl group exclusively while alkylation of 18 only oc-
curred in the benzyl position.
Table 3 Hydroaminoalkylation of Various Vinylsilanes with N-Meth-
ylaniline (3)a
R2 R2
Si
Ph
R1
N
R2 R2
38a–43a
H
H
N
III (10 mol%)
Si
Ph
+
R1
+
R2 R2
Si
toluene
160 °C, 24 h
38b–43b
H
2, 33–37
3
N
During additional hydroaminoalkylation experiments
performed with N-methylaniline (3) and various other vi-
nylsilanes (Table 3) it was initially found that the reaction of
trimethylvinylsilane (2) performed with 10 mol% of III at
160 °C gives the regioisomers 38a and 38b as an insepara-
ble mixture and in addition, only a modest total yield of
58% was obtained. However, it should be noted that neither
at 140 °C nor at 180 °C an improved result could be
achieved. Although the yield further decreased to only 30%
when sterically demanding triphenylvinylsilane (33) was
used as the substrate (Table 3, entry 2), in this case, the sep-
aration of the two regioisomers could be realized. Interest-
ingly, a corresponding reaction performed at 140 °C with 10
mol% of the formamidinato titanium catalyst II gave the
products 39a and 39b in a significantly improved total yield
of 75% (Table 3, entry 3). Because in this case, the reduced
regioselectivity of only 88:12 did not cause severe separa-
tion problems it was even possible to isolate the pure
branched product 39a in 67% yield. The fact that methoxy-
substituted phenyl groups bound to the silicon centers of
vinyl silanes represent well-established silicon protecting
groups11 which offer the possibility of removal and subse-
quent functionalization reactions, inspired us to perform
additional hydroaminoalkylations with 34, 35, and 36 (Ta-
ble 3, entries 4–6). Among these substrates, the para-me-
thoxyphenyl-protected vinylsilane 34 gave the best result
and correspondingly, the branched product 40a could be
isolated in 83% yield. While (2,4,6-trimethoxyphenyl)di-
methylvinylsilane (36) decomposed under the reaction con-
ditions, (2,6-dimethoxyphenyl)dimethylvinylsilane (35)
gave access to a mixture of the branched and the linear hy-
droaminoalkylation product 41a and 41b in 68% yield but
unfortunately, in this case, successful separation of the re-
gioisomers could not be achieved. Finally, vinylsilane 37
possessing an ortho-bromophenyl substituent that offers
the possibility of a subsequent intramolecular Buchwald–
Hartwig amination underwent smooth hydroaminoalkyla-
tion reaction in the presence of III to give the corresponding
branched product 43a in 58% yield (Table 3, entry 7).
R1
Ph
Entry R1
R2
Yield of Yield of major Ratio
a + b (%) isomer (%)b
(a/b)c
1
2
3
4
5
6
7
Me
Ph
Ph
2 Me
33 Ph
33 Ph
34 Me
35 Me
36 Me
37 Me
58
30
75
90
68
–
38a –
97:3
93:7
88:12
95:5
95:5
–
39a 30
39a 67d
40a 83
41a –
p-MeO-C6H4
2,6-(MeO)2C6H3
2,4,6-(MeO)3C6H2
o-Br-C6H4
42a –
67
43a 58
94:6
a Reaction conditions: silane (2.20 mmol), N-methylaniline (3, 214 mg, 2.00
mmol), toluene (1 mL), III (154 mg, 0.20 mmol, 10 mol%), 160 °C, 24 h, iso-
lated yields.
b Yield of the pure regioisomer obtained after flash chromatography.
c Determined by GC analysis prior to flash chromatography.
d II (109 mg, 0.20 mmol, 10 mol%), 140 °C.
Buchwald–Hartwig amination (Table 4). For that purpose,
hydroaminoalkylation reaction mixtures in toluene which
contained 37, 10 mol% of III, and a suitable N-methylaniline
were heated to 160 °C for 24 hours and afterwards, the re-
agents necessary for the Buchwald–Hartwig amination (2.5
mol% Pd2(dba)3, 7.0 mol% RuPhos, NaOt-Bu, toluene) were
added, and the resulting reaction mixtures were heated to
110 °C for additional 24 hours.12 The fact that the intramo-
lecular Buchwald–Hartwig amination converts branched
hydroaminoalkylation products into 1,4-benzoazasilines
(six-membered rings, 44a–53a) while linear hydroaminoal-
kylation products deliver 1,5-benzoazasilepines (seven-
membered rings, 44b–53b) was clearly underlined by the
observation of both products in every crude reaction mix-
ture (GC analysis). However, in good agreement with the re-
gioselectivities observed before (Tables 2 and 3), formation
of the 1,4-benzoazasiline was strongly favored in all cases
and in addition, all 1,4-benzoazasilines 44a–53a could be
isolated as pure compounds after flash column chromatog-
raphy. In this context, it is worth to mention that the best
yield (79%) was obtained with unfunctionalized N-meth-
ylaniline (3) while the chloro- and trifluoromethoxy-sub-
stituted N-methylanilines 10, 11, and 15 delivered the cor-
responding 1,4-benzoazasilines 49a, 50a, and 52a only in
yields between 30% and 41% (Table 4, entries 6, 7, and 9). In
addition, modest yields (47–56%) were obtained in the case
of methyl, fluoro, methoxy, or thiomethyl substitution (Ta-
ble 4, entries 2–5, 8, and 10). While the one-pot procedure
gave 44a in significantly improved yield of 79% compared to
A subsequent brief ligand screening for the Buchwald–
Hartwig amination of 43a (Scheme 4) performed with rac-
BINAP (79%), JohnPhos (79%), DPEPhos (90%), XPhos (94%),
and RuPhos (94%) then revealed that XPhos and RuPhos are
the best ligands for the formation of the 1,4-benzoazasiline
44a and correspondingly, we chose less expensive RuPhos
for the final experiments in which we combined the hy-
droaminoalkylation of 37 with a subsequent intramolecular
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
L. H. Lühning et al.
Letter
Synlett
the two-step synthesis of 44a which delivered the product
in only 55% overall yield (58% and 94%), additional control
experiments for the synthesis of the para-fluoro-substitut-
ed product 48a showed that in this case the yields of the
one-pot procedure (56%) and the two-step synthesis (63%
and 90%; overall 57%) are almost identical.
initial regioselective hydroaminoalkylation of a (2-bro-
mophenyl)vinylsilane with a subsequent intramolecular
Buchwald–Hartwig amination was developed.
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft for financial support
of our research as well as Jessica Reimer and Sonja Timmer for experi-
mental assistance.
Pd2(dba)3 (1.0 mol%)
ligand (2.0 mol%)
Si
NaOtBu
Si
Ph
N
H
N
toluene
110 °C, 24 h
Br
Supporting Information
Ph
44a
43a
Supporting information for this article is available online at
Scheme 4 Ligand screening for the Buchwald–Hartwig amination of
43a
https://doi.org /10.1055/s-0036-1589048.
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p
p
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u
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References and Notes
Table 4 Scope of the One-Pot Procedure for the Synthesis of 1,4-Ben-
zoazasilinesa
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Z.-L. Chin. J. Inorg. Chem. 2014, 30, 53. (c) Chong, E.; Garcia, P.;
Schafer, L. L. Synthesis 2014, 46, 2884.
Si
1) III (10 mol%)
toluene,
160 °C, 24 h
N
R
Si
44a–53a
44b–53b
(2) Group 5 metal catalysts: (a) Clerici, M. G.; Maspero, F. Synthesis
1980, 305. (b) Nugent, W. A.; Ovenall, D. W.; Holmes, S. J.
Organometallics 1983, 2, 161. (c) Herzon, S. B.; Hartwig, J. F.
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J. Am. Chem. Soc. 2008, 130, 14940. (e) Eisenberger, P.; Ayinla, R.
O.; Lauzon, J. M. P.; Schafer, L. L. Angew. Chem. Int. Ed. 2009, 48,
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L. L. Pure Appl. Chem. 2010, 82, 1503. (g) Zi, G.; Zhang, F.; Song,
H. Chem. Commun. 2010, 46, 6296. (h) Reznichenko, A. L.; Emge,
T. J.; Audörsch, S.; Klauber, E. G.; Hultzsch, K. C.; Schmidt, B.
Organometallics 2011, 30, 921. (i) Reznichenko, A. L.; Hultzsch,
K. C. J. Am. Chem. Soc. 2012, 134, 3300. (j) Garcia, P.; Lau, Y. Y.;
Perry, M. R.; Schafer, L. L. Angew. Chem. Int. Ed. 2013, 52, 9144;
Angew. Chem. 2013, 125, 9314. (k) Zhang, Z.; Hamel, J.-D.;
Schafer, L. L. Chem. Eur. J. 2013, 19, 8751. (l) Dörfler, J.; Doye, S.
Eur. J. Org. Chem. 2014, 2790. (m) Chong, E.; Brandt, J. W.;
Schafer, L. L. J. Am. Chem. Soc. 2014, 136, 10898.
H
+
N
R
2)
Pd2(dba)3 (2.5 mol%)
RuPhos (7.0 mol%)
NaOtBu, toluene
110 °C, 24 h
Br
37
Si
3, 6–11,
14–16
N
R
Entry
R
Yield (%) of ab
Ratio (a/b)c
1
2
3 Ph
44a 79
45a 52
46a 48
47a 49
48a 56
49a 41
50a 30
51a 55
52a 33
53a 47
96:4
94:6
94:6
90:10
92:8
90:10
93:7
93:7
89:11
94:6
6 m-Me-C6H4
7 p-Me-C6H4
8 m-F-C6H4
3
4
5
9 p-F-C6H4
6
10 m-Cl-C6H4
11 p-Cl-C6H4
14 p-MeO-C6H4
15 p-F3CO-C6H4
16 p-MeS-C6H4
7
(3) Ruthenium catalysts: (a) Jun, C.-H.; Hwang, D.-C.; Na, S.-J. Chem.
Commun. 1998, 1405. (b) Chatani, N.; Asaumi, T.; Yorimitsu, S.;
Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123,
10935.
(4) Iridium catalysts: Pan, S.; Endo, K.; Shibata, T. Org. Lett. 2011,
13, 4692.
8
9
10
a Reaction conditions: 1) (ortho-bromophenyl)dimethylvinylsilane (37, 531
mg, 2.20 mmol), amine (2.00 mmol), toluene (1 mL), III (154 mg, 0.20
mmol, 10 mol%), 160 °C, 24 h; 2) Pd2(dba)3 (46 mg, 0.05 mmol, 2.5 mol%),
RuPhos (65 mg, 0.14 mmol, 7 mol%), NaOt-Bu (288 mg, 3.00 mmol), tolu-
ene (5 mL), 110 °C, 24 h, isolated yields.
(5) Zirconium catalysts: Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.;
Payne, P. R.; Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 2116.
(6) Titanium catalysts: (a) Müller, C.; Saak, W.; Doye, S. Eur. J. Org.
Chem. 2008, 2731. (b) Kubiak, R.; Prochnow, I.; Doye, S. Angew.
Chem. Int. Ed. 2009, 48, 1153; Angew. Chem. 2009, 121, 1173.
(c) Prochnow, I.; Kubiak, R.; Frey, O. N.; Beckhaus, R.; Doye, S.
ChemCatChem. 2009, 1, 162. (d) Kubiak, R.; Prochnow, I.; Doye,
S. Angew. Chem. Int. Ed. 2010, 49, 2626; Angew. Chem. 2010, 122,
2683. (e) Prochnow, I.; Zark, P.; Müller, T.; Doye, S. Angew.
Chem. Int. Ed. 2011, 50, 6401; Angew. Chem. 2011, 123, 6525.
(f) Jaspers, D.; Saak, W.; Doye, S. Synlett 2012, 23, 2098.
(g) Dörfler, J.; Doye, S. Angew. Chem. Int. Ed. 2013, 52, 1806;
Angew. Chem. 2013, 125, 1851. (h) Preuß, T.; Saak, W.; Doye, S.
Chem. Eur. J. 2013, 19, 3833. (i) Chong, E.; Schafer, L. L. Org. Lett.
2013, 15, 6002. (j) Dörfler, J.; Preuß, T.; Schischko, A.;
b Yield of the pure 1,4-benzoazasiline obtained after flash chromatography.
c Determined by GC analysis prior to flash chromatography.
In summary, we have presented the first examples of ti-
tanium-catalyzed hydroaminoalkylation reactions of vinyl-
silanes and in terms of catalytic activity and regioselectivi-
ty, best results were obtained with the titanium mono(ami-
nopyridinato) catalyst III. Additionally, a one-pot procedure
for the synthesis of 1,4-benzoazasilines that combines an
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
L. H. Lühning et al.
Letter
Synlett
Schmidtmann, M.; Doye, S. Angew. Chem. Int. Ed. 2014, 53, 7918;
Angew. Chem. 2014, 126, 8052. (k) Dörfler, J.; Preuß, T.; Brahms,
C.; Scheuer, D.; Doye, S. Dalton Trans. 2015, 44, 12149.
(l) Dörfler, J.; Bytyqi, B.; Hüller, S.; Mann, N. M.; Brahms, C.;
Schmidtmann, M.; Doye, S. Adv. Synth. Catal. 2015, 357, 2265.
(m) Lühning, L. H.; Brahms, C.; Nimoth, J. P.; Schmidtmann, M.;
Doye, S. Z. Anorg. Allg. Chem. 2015, 641, 2071. (n) Manßen, M.;
Lauterbach, N.; Dörfler, J.; Schmidtmann, M.; Saak, W.; Doye, S.;
Beckhaus, R. Angew. Chem. Int. Ed. 2015, 54, 4383; Angew. Chem.
2015, 127, 4458. (o) Weers, M.; Lühning, L. H.; Lührs, V.;
Brahms, C.; Doye, S. Chem. Eur. J. 2017, 23, 1237. (p) Lühning, L.
H.; Strehl, J.; Schmidtmann, M.; Doye, S. Chem. Eur. J. 2017, 23,
4197.
(12) General Procedure for the One-Pot Synthesis of 1,4-Ben-
zoazasilines, as Exemplified by the Synthesis of Product 44a
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 III (154 mg, 0.20
mmol, 10 mol%) and toluene (0.5 mL). Afterwards, N-methylani-
line (3, 214 mg, 2.00 mmol), (ortho-bromophenyl)dimethylvi-
nylsilane (37, 531 mg, 2.20 mmol), and toluene (0.5 mL) were
added. After the mixture had been heated to 160 °C for 24 h, the
Schlenk tube was cooled to r.t. and transferred back into a nitro-
gen-filled glovebox. Then Pd2(dba)3 (46 mg, 0.05 mmol, 2.5
mol%), RuPhos (66 mg, 0.1 mmol, 7 mol%), NaOt-Bu (288 mg, 3.0
mmol), and toluene (5 mL) were added. After heating the
mixture to 110 °C for additional 24 h, the crude product was
purified by flash chromatography (SiO2, PE), to give 1,4-ben-
zoazasiline 44a (420 mg, 1.57 mmol, 79%) as a colorless oil. Rf =
0.20 (SiO2, PE). 1H NMR (500 MHz, CDCl3): δ = 7.39 (dd, J= 7.2,
1.5 Hz, 1 H), 7.32 (t, J= 7.9 Hz, 2 H), 7.16 (d, J= 7.5 Hz, 2 H), 7.10–
7.03 (m, 2 H), 6.83 (td, J= 7.2, 0.6 Hz, 1 H), 6.66 (d, J= 8.4 Hz, 1 H),
3.85 (dd, J= 13.1, 3.6 Hz, 1 H), 3.55 (dd, J= 13.1, 9.6 Hz, 1 H),
1.30–1.23 (m, 1 H), 1.04 (d, J= 7.5 Hz, 3 H), 0.28 (s, 3 H), 0.26 (s,
3 H) ppm. 13C{1H} NMR (125 MHz, DEPT, CDCl3): δ = 154.1 (C),
149.6 (C), 135.1 (CH), 129.5 (CH), 129.4 (CH), 124.7 (CH), 123.6
(C), 123.1 (CH), 119.2 (CH), 117.8 (CH), 57.5 (CH2), 17.9 (CH),
13.0 (CH3), –1.7 (CH3), –4.4 (CH3) ppm. 29Si{1H} NMR (99.4 MHz,
INEPT, CDCl3): δ = –8.1 ppm. GC–MS (EI, 70 eV): m/z(%) = 267
(40) [M]+, 225 (100) [C14H15NSi]+, 210 (40), 180 (8), 105 (11)
[C7H7N]+, 91 (5) [C6H5N]+. HRMS (EI): m/z calcd for C17H21NSi:
267.1438; found: 267.1440 [M]+. IR (ATR, neat): λ–1 = 2948,
2864, 1585, 1557, 1494, 1472, 1431, 1340, 1248, 1175, 1129,
(7) Elkin, T.; Kulkarni, N. V.; Tumanskii, B.; Botoshansky, M.;
Shimon, L. J. W.; Eisen, M. S. Organometallics 2013, 32, 6337.
(8) For reviews on the Buchwald-Hartwig amination, see:
(a) Hartwig, J. F. Nature (London, U.K.) 2008, 455, 314. (b) Surry,
D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338;
Angew. Chem. 2008, 120, 6438. (c) Schlummer, B.; Scholz, U.
Adv. Synth. Catal. 2004, 346, 1599. (d) Elkema, R.; Anderson, H. L.
Macromolecules 2008, 41, 9930.
(9) For reviews on organosilicon compounds with medicinal appli-
cations, see: (a) Mills, J. S.; Showell, G. A. Expert Opin. Invest.
Drugs 2004, 13, 1149. (b) Franz, A. K.; Wilson, S. O. J. Med. Chem.
2013, 56, 388.
(10) (a) Aoyama, T.; Sato, Y.; Suzuki, T.; Shirai, H. J. Organomet. Chem.
1978, 153, 193. (b) Francois, C.; Boddaert, T.; Durandetti, M.;
Querolle, O.; Van Hijfte, L.; Meerpoel, L.; Angibaud, P.;
Maddaluno, J. Org. Lett. 2012, 14, 2074.
(11) Geyer, M.; Karlsson, O.; Baus, J. A.; Wellner, E.; Tacke, R. J. Org.
Chem. 2015, 80, 5804.
1088, 835, 808, 722, 750, 696, 610 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F