Fast Titanium-Catalyzed Hydroaminomethylation of Alkenes and the Formal Conversion of Methylamine

Article abstract of DOI:10.1002/anie.202001111

The scientific interest in catalytic hydroaminoalkylation reactions of alkenes has vastly increased over the past decade, but these reactions have struggled to become a viable option for general laboratory or industrial use because of reaction times of several days. The titanium-based catalytic system introduced in this work not only reduces the reaction time by several orders of magnitude, into the range of minutes, but the catalyst is also demonstrated to be easily available from common starting materials, at a cost of approximately 1 € per millimole of catalyst. We were also able to formally perform C?H activation of methylamine and achieve coupling to a broad variety of alkenes, through silyl protection of the amine and simple deprotection by water.

Full text of DOI:10.1002/anie.202001111

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Fast Titanium-Catalyzed Hydroaminomethylation of Alkenes and
the Formal Conversion of Methylamine
Authors: Jens Bielefeld and Sven Doye
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202001111
Angew. Chem. 10.1002/ange.202001111
Link to VoR: http://dx.doi.org/10.1002/anie.202001111
http://dx.doi.org/10.1002/ange.202001111

10.1002/anie.202001111
Angewandte Chemie International Edition
RESEARCH ARTICLE
Fast Titanium-Catalyzed Hydroaminomethylation of Alkenes and
the Formal Conversion of Methylamine
Jens Bielefeld, Sven Doye*
[a]
J. Bielefeld, S. Doye
Universität Oldenburg
Institut für Chemie
Carl-von-Ossietzky-Strasse 9-11, 26129 Oldenburg (Germany)
E-mail: doye@uni-oldenburg.de
Supporting information for this article is given via a link at the end of the document.
Ti(NMe2)4 as the titanium source. We wanted to solve this
problem by using TiBn4, which is known to potentially be a better
precursor,[8] but could not isolate a well-defined complex of this
precursor with the formamidine 1. Instead, in situ generation of
the catalyst by quenching TiBn4 with the substrate amine and
subsequent addition of the ligand (see Scheme 1) proved to be
a very simple, quick and reliable method to access a highly
active catalyst.[4,9] We specifically chose TiBn4 as the desired
precursor, because it can be easily prepared on a multigram
scale from very inexpensive starting materials (TiCl4 and BnCl)
within only a few hours of work, making it available to any
laboratory that is equipped with Schlenk glassware. We
developed a very cost and time effective protocol for its
synthesis (see the Supporting Information) and likewise, we
provide a synthesis for ligand precursor 1 that is focused on
general availability; it can be reliably synthesized from p-
anisidine and cyclopentadiene without any need for Schlenk
techniques. We calculated the total material cost to be 1.12 €
per millimole of catalyst (see the Supporting Information).
Abstract: The scientific interest in catalytic hydroaminoalkylation
reactions of alkenes has vastly increased over the past decade, but
these catalyses have always struggled to become a viable option for
general laboratory or industrial use, due to common reaction times of
several days. The titanium-based catalytic system introduced in this
work not only reduces the reaction time by several orders of
magnitude into the range of minutes, but is also demonstrated to be
easily available from common starting materials, at a cost of about 1
€ per millimole of catalyst. We were also able to formally C-H-
activate methylamine and achieve coupling to a broad variety of
alkenes, through silyl-protection of the amine and simple
deprotection by water.
Introduction
The catalytic hydroaminoalkylation of alkenes with N-
methylamines is of high interest especially for the industry,
because it uses the same alkene substrates and produces the
same products as the already industrially applied
hydroformylation with subsequent reductive amination, while
avoiding multiple reaction steps.[1] This direct approach has the
potential of severely decreasing the cost, energy and amount of
workup associated with synthesizing sophisticated amines from
alkenes. A lot of research was kickstarted in 2007 when Herzon
and Hartwig reported the first use of N-arylalkylamines;[2] the
following decade afforded a vastly increased scope of substrates
and several different catalytic systems, most notably based on
group 4 and group 5 metals.[3] However, long reaction times
have been a persistent problem throughout, with common
durations ranging from 24 h to 96 h.[3] Very recently, a
remarkable advance was made by DiPucchio, Roşca and
Schafer using a tantalum ureate complex, putting the shortest
reported reaction time for a catalytic hydroaminoalkylation of an
alkene at only 2 h (4-vinylcyclohexene with N-methylaniline)
while maintaining an excellent isolated yield.[4] This,
unfortunately, has so far been an exception in this field of
chemistry.
Results and Discussion
The new catalyst introduced in this work, based on a titanium
center and a formamidinato ligand, is now able to convert
terminal alkenes with N-methylanilines within minutes.
Formamidinato-titanium complexes have already been used as
catalysts for hydroaminoalkylation reactions, but were based on
Ti(NMe2)4 as their precursor.[5,6] We found in recent works that
dimethylamine
is
a
very
difficult
substrate
for
Scheme 1. In situ generation of the catalyst and catalytic cycle.
hydroaminoalkylation reactions of alkenes[7] and as such, it acts
as a very potent inhibitor in catalytic systems that employ
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202001111
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 1. Scope of the hydroaminoalkylation of 1-octene with various
secondary amines.
We tested whether 1 or TiBn4 alone would catalyze a
hydroaminoalkylation and found that TiBn4 was able to produce
slight traces of product, yet not to a usable degree. We also
tested the catalytic activity of 1 with Ti(NMe2)4 as the titanium
source and only isolated traces of product.[10] We found that the
catalysis works better when the substrate concentrations are
high, with solvent-free execution yielding the best results. An
excess of alkene not only decreases the reaction time further,
but also ensures that the solution can still be stirred at high
conversions without adding solvent, as the pure reaction
products can be quite viscous. Conducting the reactions in
ampoules under autogenous pressure resulted in high reliability
and good comparability of the results, especially with low boiling
substrates (see Table 1, entry 12 and Table 2, entries 4, 5, 6)
that could otherwise not be heated to 155 °C. It should be noted
that we had no trouble reproducing the results in regular glass
flasks with clamped glass plug for substrates with a boiling point
above 120 °C, as long as the heating time of the respective
vessel was accounted for (we increased the heating time by one
minute for regular 10 mL-flasks and found no significant
difference of yields). For the ampoules used in these
experiments (Table 1 and Table 2), the reaction time over which
the reaction mixture is above 150 °C (which is necessary for this
catalyst to exhibit good performance)[11] is shorter than the
heating time by about one minute. For consistency and
simplification of our experiments, the heating times depicted in
both tables are the total times over which the ampoules are in
contact with a 155 °C oil bath.[12] This means that the actual
reaction time of the hydroaminoalkylation of 1-octene with N-
methylaniline (Table 1, entry 1) amounts to only 3-4 s per
catalytic turnover. To enhance the comparability of the heating
times of different substrates, we tried to stop the reactions at an
isolated yield between 90-95 %; it should be noted that the time
could be increased slightly to achieve a quantitative yield. For
Table 1, entries 2, 8, 11, 12 and Table 2, entries 7, 8, 9, 11, we
noticed that a simple increase of heating time would not
increase the yield much further. Unwanted side reactions could
be responsible for the incomplete yield of 4-vinylcyclohexene
(Table 2, entry 7), while most other incomplete conversions are
likely caused by product inhibition of the catalyst. For o-methyl-
N-methylaniline as well as o-methylstyrene (Table 1, entry 2 and
Table 2, entry 11), it is shown that steric bulk of the substrates
too close to the titanium center can inhibit the reaction almost
entirely. In these cases, it should be expected that a full
conversion of the substrates cannot be achieved by a longer
reaction time alone, since the catalyst will likely deteriorate at
155 °C over 12 h. We also encountered this for other substrates
with steric bulk near the functional group (2-octene, α-
methylstyrene, 3,3-dimethylbut-1-ene, N-methyl-tert-butylamine),
where a reaction time of several hours would only deliver traces
of product and could not be increased to appreciable yields. We
were however delighted to see that this catalyst is active enough
to give decent yields with notoriously difficult substrates like
dialkyamines (Table 1, entries 11 and 12) and cycloalkenes
(Table 2, entry 5) within reasonable reaction times. All
substrates except styrenes and trimethylvinylsilane (Table 2,
entries 4, 11, 12, 13) exhibit excellent regioselectivities, which is
consistent with the previously reported uses of formamidinato-
titanium catalysts.[6,7] The overall dramatically increased activity
compared to the already reported uses of a formamidinato-
titanium complex (several minutes instead of 96 h)[5,6] stems
largely from the precursor and reaction conditions; the use of 1
only doubles the catalytic activity compared to the ligand
reported in 2015.[6,13]
Heating
time[b]
[min]
Isolated
yield of
2b [%]
[c]
Amine
Sregio
Entry
Substrate[a]
2b/2l
1
2
60
7
94
8
97/3
2
3
4
99/1
98/2
97/3
94
10
15
95
91
5
6
97/3
96/4
6
90
7
15
15
2
92
82
91
90
96/4
97/3
96/4
96/4
8
9
10
10
11
12
300
120
49
71
98/2
97/3
[a] Reaction conditions: amine (2 mmol), TiBn4 (42 mg, 0.10 mmol, 5
mol%), 1 (53 mg, 0.10 mmol, 5 mol%), 1-octene (561 mg, 5 mmol) in a 5
mL ampoule, 155 °C, t. [b] Heating time refers to the total time over which
the ampoule is held into a 155 °C oil bath. [c] Selectivity was determined
by GC analysis prior to chromatography.
Contrary to the catalyst itself, the ligand precursor
1
possesses an extremely low solubility in most solvents, as we
were only able to dissolve it in chloroform and boiling toluene.
We were able to account for this by grinding 1 into a very fine
powder with a ball mill, which proved to be essential for the
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202001111
Angewandte Chemie International Edition
RESEARCH ARTICLE
effective use in all catalyses with short reaction times. After
catalysis however, the reaction mixture can be quenched with
moist solvents (aliphatic or aromatic hydrocarbons, alcohols,
ethers, dichloromethane) and the ligand precursor (as well as
TiO2) will precipitate. 1 can then be reisolated by simple
extraction of the solid residue with chloroform. While this might
not be of high interest for laboratory use due to its inexpensive
synthesis, the possibility of recycling the ligand could be
desirable in industrial applications.
synthesis of primary amine products) in an intermolecular
hydroaminoalkylation has unfortunately been nearly impossible,
most notably due to the formation of metal imido species or
bridging towards multinuclear metal complexes, which
deactivates the catalyst.[14] This limited scope poses a very
severe restriction to the use of hydroaminoalkylation reactions,
especially because it prohibits the use of the most important
primary amine, methylamine. During the writing of this
manuscript, a method for the conversion of silyl-protected
benzylamine was published, but was limited exclusively to the
activated amine and a narrow scope of alkenes, with reaction
times of 24-240 h.[15]
Table 2. Scope of the hydroaminoalkylation of various alkenes with N-
methylaniline.
Heating
time[b]
[min]
Isolated
yield of
2b [%]
[c]
Alkene
Sregio
Entry
Substrate[a]
2b/2l
Scheme 2. Hydroaminoalkylation of alkenes with TBDMS-protected
methylamine.
1
10
7
97
91
94
98/2
97/3
97/3
Using the already described method with the in situ generated
catalyst and TBDMS-protected methylamine 3 as the amine
substrate (see Scheme 2), we were able to generate primary
amine products in good yield after reaction times of 12 h. After
completion of the catalysis, the free primary amine can be
obtained by hydrolysis. The simplest method we found was to
simply treat the diluted crude reaction mixture with wet solvent
(CH2Cl2/MeOH/H2O = 75/25/1) overnight at room temperature.
Alternatively, if a quicker workup is required, the deprotection
can also be achieved by stirring the crude reaction mixture in
boiling EtOH/H2O (4/1) for one minute.
Terminal alkenes generally work well in the catalysis, unless a
specific steric hindrance close to the C-C double bond inhibits
the reaction. This is most apparent when comparing styrenes,
where o-methylstyrene shows almost no conversion while m-
substitution is tolerated decently and p-substitution is tolerated
well (Table 3, entries 13-16). 2-Octene (Table 3, entry 2) shows
that an internal alkene can be unreactive, while cyclopentene
(Table 3, entry 10) exhibits significant reactivity. The same can
2
3
5
4
5
25
60
75[d]
96
82/18
--
6
7
120
20
90
100/0
97/3
79[e]
8
9
20
6
82
85
97/3
94/6
be
observed
for
1,1-disubstituted
alkenes,
where
α-methylstyrene shows almost no reactivity, while the
conversion of methylenecyclohexane proves that 1,1-
disubstitution can be tolerated and afford good yields (Table 3,
entries 11 and 17). As described in Table 1, the catalytic system
used in this work (1 with TiBn4) can react good substrate amines
like N-methylaniline with terminal alkenes within reaction times
of only a few minutes and usually tolerates halogenated
substrates well. With 3 as substrate, however, a vastly increased
reaction time becomes necessary and side reactions diminish
the yield of halogenated phenethylamines, as seen from
p-chlorostyrene and especially p-bromostyrene (Table 3, entries
20-23). It is also noteworthy that we were unable to successfully
convert an alkene containing a tertiary amine (Table 3, entry 9).
We suspect the tertiary amine to partially deprotect 3, free
methylamine would then immediately disable the catalyst.[14]
This suggests that a successful conversion of a tertiary amine
can only be expected when high steric bulk is present near the
amino group. Overall, the results show that the tolerance
towards steric properties of the substrate varies largely, but a
sterically less demanding alkene is generally advantageous.
Many alkenes and functional groups are tolerated very well,
including dienes, ethers, protected alcohols and silanes (Table
3, entries 3, 5-8, 12).
10
11
12
13
4
60
13
2
91[f]
9[f]
73/27
78/22
68/32
77/23
92[f]
90[f]
[a] Reaction conditions: N-methylaniline (214 mg, 2 mmol), TiBn4 (42 mg,
0.10 mmol, 5 mol%), 1 (53 mg, 0.10 mmol, 5 mol%), alkene (5 mmol) in a
5 mL ampoule, 155 °C, t. [b] Heating time refers to the total time over
which the ampoule is held into a 155 °C oil bath. [c] Selectivity was
determined by GC analysis prior to chromatography. [d] The regioisomers
could not be separated; the isolated yield refers to the fraction of
branched product according to GC analysis. [e] The reaction was
observed at the terminal alkene exclusively. [f] For styrenes, the isolated
yield of 2b + 2l is given. Both regioisomers were isolated separately.
We also discovered that this catalytic system is active enough
to even convert silyl-protected primary amines like the TBDMS-
protected methylamine 3 (Scheme 2) giving direct access to
silyl-protected primary amines via hydroaminomethylation. While
the conversion of primary aminoalkenes in an intramolecular
hydroaminoalkylation has been achieved in the past,[3,8] the
conversion of primary amine substrates (and consequently the
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202001111
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 3. Scope and limitations of the hydroaminoalkylation of alkenes with 3.
Isolated
Selectivity
5b/5l
Isolated
Selectivity
Entry
Alkene Substrate
Entry
13
Alkene Substrate
yield [%][a,b]
yield [%][a,b]
5b/5l
1
2
3
4
81
1[c,d]
57[e]
19
> 99/1
29/71
> 96/4[f]
94/6
75
91/9
61/39
95/5
14
1
15
39
16
67[g]
96/4
5
6
7
8
57[d]
81
84/16
> 99/1
96/4
17
18
19
20
3
85
76/24
> 99/1
> 99/1
89/11
44[g]
77[g]
76[g]
34
> 99/1
9
0
--
21
6
76/24
10
11
12
19
63
85
--
22
23
24
14
0
90/10
--
98/2
99/1
67[g]
92/8
[a] Reaction conditions: TiBn4 (42 mg, 0.10 mmol, 5 mol%), 1-tert-butyl-N,1,1-trimethylsilanamine (3, 291 mg, 2 mmol), 1 (53 mg, 0.10 mmol, 5 mol%) and alkene
(5 mmol) in a 5 mL-ampoule, autogenous pressure, 155 °C, 12 h. Deprotection: crude reaction mixture, MeOH (5 mL), H2O (0.2 mL) in CH2Cl2 (15 mL), rt,
overnight. Isolated yield refers to 5b or the tosylated equivalent, the linear side product 5l is removed by chromatography. [b] If not otherwise specified, the
product was tosylated for isolation due to volatility: crude deprotected mixture, TosCl (762 mg, 4.0 mmol), NaOH (2 M, 6 mL, 12 mmol) in CH2Cl2 (30 mL), rt,
overnight. Regioselectivity was then determined by GC after tosylation and before chromatography. [c] The branched product 5b in this case refers to 2-
ethylheptan-1-amine. [d] Both products were obtained as a mixture that could not be separated. The isolated yield refers to the fraction of major product according
to 1H NMR. [e] The product 5b in this case refers to 2-methylhex-5-en-1-amine; one C-C double bond is hydroaminoalkylated under these reaction conditions. [f]
Traces of several side products made it impossible to identify the linear product 5l in GC analyses, we can only say with certainty that the ratio of 5b/5l is higher
than 96/4. [g] The product was isolated as the free amine without tosylation.
The TBDMS-protected methylamine can be replaced by the
TMS-protected equivalent (we present an easy and quick
synthesis of both substrates in the Supporting Information). This
severely decreases the cost of the amine substrate [originating
from the price of TMS-Cl (10 €/mol) compared to TBDMS-Cl
(245 €/mol)] and is therefore advised for all high-volume
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202001111
Angewandte Chemie International Edition
RESEARCH ARTICLE
syntheses. The hydroaminomethylation reaction proceeds
slower for the TMS-protected variant,[16] but the deprotection of
the protected product completes instantly at room temperature
when the reaction mixture is in contact with moist solvents.
However, we estimate that the TBDMS-protected methylamine 3
is more suitable for syntheses on a laboratory scale for several
reasons: Due to its relatively high stability it can be handled
under air and used glassware can be decontaminated in a
controlled manner, while TMS-NHMe will react violently with
water and alcohols, setting free considerable amounts of MeNH2
gas. The TBDMS-protected hydroaminomethylation products
obtained from 5 can be analyzed by GC and TLC and are mostly
stable over 24 h under air, if the solvent (observed for CH2Cl2) is
not specifically wet. The stability is unfortunately not high
enough to allow for a satisfactory column chromatography, we
found that a considerable fraction of the product will be
deprotected (observed for SiO2 and petroleum ether). Instead,
we upscaled the hydroaminomethylation of styrene to the
multigram scale to demonstrate the possibility of isolating the
silyl-protected product 4b by distillation (see Scheme 3). Mostly
due to losses at the distillation step, a reduced yield of 56 % was
isolated (compared to a yield of 75 % that is produced in the
reaction as seen in Table 1, entry 13). The synthesis of
protected amines from alkenes can be a valuable synthetic tool
whenever a further functionalization is required.
are given. Since a direct catalytic hydroaminomethylation of
alkenes with methylamine has not been achieved before and a
considerable
progress
in
reaction
times
of
hydroaminoalkylations with secondary amines is shown, we
think that this work can be of high value for laboratory work and
an important input for potential industrial applications.
Acknowledgements
We thank the Research Training Group "Chemical Bond
Activation"
(GRK
2226)
funded
by
the
Deutsche
Forschungsgemeinschaft for financial support of our research
and Jessica Reimer for support of the experimental work. We
thank Kirstin Glaser, Karin Grittner and Frank Fleischer for
supplying the ampoules.
Keywords: Amines, Hydroaminoalkylation, Methylamine,
Phenethylamine, Titanium
[1]
For a review on hydroformylation reactions, see: R. Franke, D. Selent,
A. Börner, Chem. Rev. 2012, 112, 5675-5732.
[2]
[3]
S. B. Herzon, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 6690-6691.
For a review on hydroaminoalkylation reactions, see: P. M. Edwards, L.
L. Schafer, Chem. Commun. 2018, 54, 12543-12560.
[4]
[5]
[6]
[7]
[8]
[9]
R. C. DiPucchio, S.-C. Roşca, L. L. Schafer, Angew. Chem. 2018, 130,
3527-3530; Angew. Chem. Int. Ed. 2018, 57, 3469-3472.
T. Elkin, N. V. Kulkarni, B. Tumanskii, M. Botoshansky, L. J. W.
Shimon, M. S. Eisen, Organometallics 2013, 32, 6337-6352.
J. Dörfler, T. Preuß, C. Brahms, D. Scheuer, S. Doye, Dalton Trans.
2015, 44, 12149-12168.
Scheme 3. Multigram scale isolation of the silyl-protected phenethylamine.
Another advantage of the bulkier protective group of 3
compared to the TMS-protected equivalent is the extraordinarily
high regioselectivity; while TMS-NHMe produces a mixture of
branched and linear product as expected for a formamidinato-
titanium catalyst (Table 2, entries 10-13), 3 produces only slight
amounts of linear side product for most styrenes (exceptions are
shown in Table 3, entries 14, 17 and 21). This makes this work
especially useful for the direct synthesis of pharmaceutically
interesting phenethylamines from styrenes, where the
hydroaminoalkylation of alkenes with a formamidinato titanium
catalyst would usually be expected to show very poor
regioselectivity.[6] For most olefins, we were unable to identify
linear product by GC; 2-octene, vinyltrimethylsilane, o-
methylstyrene, -methylstyrene, and pentafluorostyrene (Table
3, entries 2, 5, 14, 17, and 21) were the only olefins yielding
poor regioselectivities, which is not unexpected for these
substrates.
J. Bielefeld, S Doye, Angew. Chem. 2017, 129, 15352-15355; Angew.
Chem. Int. Ed. 2017, 56, 15155-15158.
I. Prochnow, R. Kubiak, O. N. Frey, R. Beckhaus, S. Doye,
ChemCatChem 2009, 1, 162-172.
We previously found the in situ generation of Ti-catalysts to be a
successful strategy for hydroaminoalkylation reactions: J. Dörfler, S.
Doye, Angew. Chem. 2013, 125, 1851-1854; Angew. Chem. Int. Ed.
2013, 52, 1806-1809. The same concept was also shown to be
effective for Ta-catalysts, see reference 4.
[10] Reaction conditions equivalent to Table 2, entry 10: N-methylaniline
(214 mg, 2 mmol), Ti(NMe2)4 (22 mg, 0.10 mmol, 5 mol%), 1 (53 mg,
0.10 mmol, 5 mol%), styrene (521 mg, 5 mmol) in a 5 mL ampoule, 155
°C, 4 min. A yield of 1 % was isolated. However, it should be noted that
good yields can be obtained if the reaction vessel allows for the escape
of gaseous HNMe2. An otherwise identical experiment in a 80 mL-
Schlenk tube with 500 mL balloon and a reaction time of 20 min gave
an isolated yield of 75 % (2b+2l).
[11] We found that the catalyst will tolerate temperatures at least up to 180
°C with increasing catalytic activity; temperatures below 150 °C will
severely decrease the catalytic activity.
Conclusion
[12] Selected data points for the reaction mixtures core temperature after
the ampoule is in contact with the 155 °C oil bath: 120 °C after 35 s,
150 °C (74 s), 155 °C (110 s). Cooldown: 150 °C (14 s), 120 °C (64 s).
No significant conversion of substrate is expected below 120 °C. The
heating profile (and therefore the exact difference between heating time
and reaction time) is expected to be slightly different for substrates with
low boiling points. We did not possess the means to determine the
heating profile for those substrates under autogenous pressure and
thus want to correctly refer to heating times instead.
In summary, we presented a new catalytic system for the
hydroaminoalkylation of alkenes with secondary amines,
composed of a formamidine and TiBn4. The catalyst is shown to
be both easily available and inexpensive; additionally, the ligand
can be reisolated after use if needed. A wide spectrum of
substrates can be converted with a very short reaction time,
excellent selectivity and quantitative yield. The catalyst can also
be used for the hydroaminomethylation of alkenes with silylated
methylamine. The presented method allows for the use of either
the very inexpensive TMS-protected or the exceptionally
regioselective and easy to handle TBDMS-protected
methylamine, both of which are shown to be synthesized
easily.[17] The possibility of isolating the protected products is
demonstrated and methods for simple deprotection with water
[13] Reaction conditions: N-methylaniline (214 mg, 2 mmol), TiBn4 (8.4 mg,
0.02 mmol, 1 mol%), 1 (10.9 mg, 0.02 mmol, 1 mol%), styrene (521 mg,
5 mmol) in a 5 mL ampoule, 155 °C, 20 min. A yield of 42 % (2b+2l)
was isolated. An otherwise identical experiment with N,N'-bis(2,6-
diisopropylphenyl)formamidine instead of 1 as the ligand precursor
delivered an isolated yield of 18 %.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202001111
Angewandte Chemie International Edition
RESEARCH ARTICLE
[14] L. Stelter, T. Teusch, J. Bielefeld, S. Doye, T. Klüner, Chem. Eur. J.
2018, 24, 12485-12489.
[15] During the writing of this manuscript, the following article describing the
hydroaminoalkylation of alkenes with TMS-protected benzylamine was
published: A. Koperniku, P. J. Foth, G. M. Sammis, L. L. Schafer, J. Am.
Chem. Soc. 2019, 141, 18944-18948. Selected example: TMS-
protected benzylamine (0.5 mmol), 4-phenylbutene (0.9 mmol),
Zr(NMe2)4 (10 mol%) in C6D6, 145 °C, 48 h. Combined isolated yield
78 %, regioselectivity 75/25 towards the branched product. 4-
Phenylbutene was also used as a substrate in our screening (see Table
3, entry 19).
[16] Reaction conditions with TMS-protected methylamine: TiBn4 (42 mg,
0.10 mmol, 5 mol%), N,1,1,1-tetramethylsilanamine (206 mg, 2 mmol),
1 (53 mg, 0.10 mmol, 5 mol%) and 4-phenylbutene (661 mg, 5 mmol) in
a 5 mL-ampoule, autogenous pressure, 155 °C, 24 h. Deprotection:
crude reaction mixture, MeOH (5 mL), H2O (0.2 mL) in CH2Cl2 (15 mL),
rt. A yield of 47 % of the primary amine product 4b was isolated. The
equivalent experiment with TBDMS-protected methylamine (Table 3,
entry 19) yielded 76 % of 4b in 12 h.
[17] For details, see the Supporting Information.
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202001111
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
The by far most important amine substrate for C-H-activating reactions, methylamine, can now be coupled to alkenes using a titanium
hydroaminoalkylation catalyst that is inexpensive (1€/g) and easily accessible. Compatibility of methylamine with the catalyst is
achieved by silylation; the products can be isolated with the protective group intact or, through simple deprotection with water, as the
free amine. We present a comprehensive examination of scope and limitations of the new catalyst used herein, which can convert
secondary amines within reaction times as low as two minutes.
7
This article is protected by copyright. All rights reserved.