Titanium-Catalyzed Intermolecular Hydroaminoalkylation of Alkenes with Tertiary Amines

Article abstract of DOI:10.1002/anie.202100431

The first cationic titanium catalyst system for the intermolecular hydroaminoalkylation of alkenes with various tertiary alkylamines is presented. Corresponding reactions which involve the addition of the α-C?H bond of a tertiary amine across the C?C double bond of an alkene take place at temperatures close to room temperature with excellent regioselectivity to deliver the branched products exclusively. Interestingly, for selected amines, α-C?H bond activation occurs not only at N-methyl but also at N-methylene groups.

Full text of DOI:10.1002/anie.202100431

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 9936–9940
International Edition:
German Edition:
doi.org/10.1002/anie.202100431
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ꢀ
C H Activation
Titanium-Catalyzed Intermolecular Hydroaminoalkylation of Alkenes
with Tertiary Amines
Dennis Geik, Michael Rosien, Jens Bielefeld, Marc Schmidtmann, and Sven Doye*
Abstract: The first cationic titanium catalyst system for the
intermolecular hydroaminoalkylation of alkenes with various
tertiary alkylamines is presented. Corresponding reactions
ꢀ
which involve the addition of the a-C H bond of a tertiary
ꢀ
amine across the C C double bond of an alkene take place at
temperatures close to room temperature with excellent regio-
selectivity to deliver the branched products exclusively. Inter-
ꢀ
estingly, for selected amines, a-C H bond activation occurs not
only at N-methyl but also at N-methylene groups.
T
ertiary amines are important structural motifs in natural
products (e.g. alkaloids) and are indispensable for the
development of agrochemicals or pharmaceuticals.[1] For
example, more than 15% of the 200 top selling small
molecule drugs in 2018 contain a tertiary amine moiety.[1b]
An attractive synthetic approach for the synthesis of various
amines that has raised a lot of attention in recent years is the
hydroaminoalkylation of alkenes which allows the 100%
Scheme 1. Intermolecular hydroaminoalkylation of alkenes with secon-
dary or tertiary N-alkylamines in the presence of group 3, 4 or 5
catalysts.
ꢀ
atom economic addition of the a-C H bond of simple amines
[2]
ꢀ
across the C C double bond of alkenes (Scheme 1).
group. However, alkene hydroaminoalkylation with tertiary
amine substrates that do not contain an extra directing group
could already be achieved in the presence of cationic
scandium catalysts (Scheme 1b).[7] Unfortunately, scandium
must be regarded as a highly expensive metal[8] and the
catalysts, which need to be synthesized by laborious processes,
are only active at elevated temperatures of 70–1208C.[7a,c,e]
Based on our experiences in the development of titanium-
catalyzed hydroaminoalkylation reactions of alkenes,
allenes,[9] and alkynes,[10] and the fact that non-toxic titanium
is the second most abundant transition metal in the earthꢀs
crust,[11] we recently started a project to identify an alter-
native, less expensive, titanium-based catalyst system for the
intermolecular hydroaminoalkylation of alkenes with simple
tertiary amines (Scheme 1c).
While in the case of titanium-catalyzed hydroaminoalky-
lation reactions of unsaturated substrates with primary or
secondary amines neutral titanaaziridines formed from a neu-
tral titanium (IV) precursor and the amine substrate are
accepted to be the catalytically active species,[12] correspond-
ing scandium-catalyzed reactions of tertiary amines involve
the formation of cationic metallaaziridine intermediates
(Scheme 2, M = Sc, n = 1).[7b,d] Because analogous cationic
titanaaziridines (Scheme 2, M = Ti, n = 2) should be formed
from tertiary amines and cationic titanium (IV) complexes,
Corresponding addition reactions can be achieved with late
transition metal catalysts,[3] following
a photo-catalytic
approach,[4] or most efficiently with early transition metal
catalysts.[5–7] In the latter case, neutral group 4[5] and 5[6] metal
catalysts have extensively been used for a plethora of
successful hydroaminoalkylation reactions of alkenes with
primary or secondary amines (Scheme 1a) but unfortunately,
tertiary amines do not react successfully with alkenes in the
presence of these catalysts. This lack of reactivity must be
regarded as a severe restriction to the use of hydroaminoal-
kylation reactions, because it prohibits the use of simple
tertiary amines as starting materials for the synthesis of more
sophisticated tertiary amine products. Although a few late
transition metal-catalyzed hydroaminoalkylation reactions
with tertiary amines have been reported,[3,4] in these cases,
the amine must contain an additional metal-binding directing
[*] M. Sc. D. Geik, M. Sc. M. Rosien, M. Sc. J. Bielefeld,
Dr. M. Schmidtmann, Prof. Dr. S. Doye
Institut fꢀr Chemie, Universitꢁt Oldenburg
Carl-von-Ossietzky-Straße 9–11, 26129 Oldenburg (Germany)
E-mail: doye@uni-oldenburg.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.202100431.
we initially investigated whether mixtures of the well-
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the terms of the Creative Commons Attribution Non-Commercial
NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
[5b]
established hydroaminoalkylation catalysts TiBn4
or
Ind2TiMe[5c] (Ind = h5-indenyl) with Ph3C[B(C6F5)4] catalyze
the hydroaminoalkylation of alkenes with N-methylpiperi-
dine (1a) as an example of a typical tertiary aliphatic amine
(Table 1). The Lewis acid Ph3C[B(C6F5)4] is known to induce
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aminoalkylation reactions with primary or secondary amines
did not lead to good results, we were delighted to see that 4-
phenylbutene (2a) and N-methylpiperidine (1a) smoothly
undergo the desired hydroaminoalkylation reaction at tem-
peratures close to room temperature in the presence of
10 mol% TiBn4 and 8 mol% Ph3C[B(C6F5)4].[14] Best results
were obtained when the starting materials, the catalyst, and
toluene were simply mixed in a vial and stirred on a stirring
plate for 96 h.[15] Although the stirring plate was not purposely
heated, this simple experimental setup led to a reaction
temperature of 288C inside the vial. GC analysis of the crude
reaction mixture revealed that the branched hydroaminoal-
kylation product 3a was formed exclusively and finally, it was
possible to isolate 3a in 99% yield (Table 1, entry 1).
Scheme 2. Simplified catalytic cycle of the hydroaminoalkylation of
alkenes with tertiary amines which includes a cationic metallaaziridine
as the catalytically active species (M=Sc, n=1 or M=Ti, n=2).[7]
As can be seen from Table 1, a wide variety of additional
alkenes (2b–2j) could also be reacted successfully with N-
methylpiperidine (1a) under identical conditions. In the case
of monosubstituted terminal alkenes, the corresponding
branched hydroaminoalkylation products were always
formed exclusively and as a result, the tertiary amines 3a–
3g could be isolated in good to excellent yields of 54–99%
(Table 1, entries 1, 3–5, and 7–9). When allylbenzene (2b) was
used as a substrate, decomposition of product 3b was
observed under the reaction conditions and as a result, the
modest yield of 31% in which 3b was isolated after 96 h
(Table 1, entry 2) could be improved to 77% by decreasing
the reaction time to 18 h (Table 1, entry 3). With regard to the
high oxophilicity of cationic titanium catalysts it is remark-
able that the catalyst not only tolerates a triphenylsilyl
substituent (Table 1, entry 7) but also the presence of a steri-
cally demanding triisopropylsilyl ether (Table 1, entry 8)
which offers a promising possibility for further functionaliza-
tion. The fact that 4-vinylcyclohexene 2g undergoes selective
hydroaminoalkylation at the stericaly less hindered vinyl
group to give 3g as the product (Table 1, entry 9) clearly
demonstrates that internal alkenes are less reactive than
terminal alkenes. Nevertheless, it was possible to convert
norbornene (2i) into the expected hydroaminoalkylation
product 3i in 84% yield (Table 1, entry 11). The assumption
that ring strain plays an important role for reactions of
internal alkenes is strongly underlined by the reaction of
cyclohexene (2j) which delivered the expected product 3j
only in poor yields (Table 1, entries 12 and 13). Interestingly,
1,1-disubstitution of the alkene is better tolerated and as
a consequence, methylenecyclohexane (2h) regioselectively
reacted to the corresponding branched amine 3h in 55% yield
(Table 1, entry 10). In contrast, styrenes could not successfully
be used because these substrates underwent fast polymeri-
zation. To further demonstrate the efficiency of the new
catalyst system, we additionally investigated the reaction of 1-
dodecene (2d) with 1a as a typical example in more detail.
We tried to reduce the catalyst loading, to minimize the
reaction time, and to run the reaction on a multigram scale.
During these experiments, it turned out that after stirring of
the reaction mixture in a vial at 288C for 18 h in the presence
of 5 mol% TiBn4 and 4 mol% Ph3C[B(C6F5)4], the hydro-
aminoalkylation product 3d is still formed in 51% yield
(Table 1, entry 6). Then an even better yield of 60% could be
obtained from a corresponding experiment which was per-
Table 1: Scope of the titanium-catalyzed hydroaminoalkylation of various
alkenes with N-methylpiperidine (1a).[a]
Entry
1
Alkene
Product
Yield [%][b]
99
2
31
77
92
3[c]
4
5
66
51
64
6[d]
7
8
9
96
54
10
11
55
84
12
16
24
13[e]
[a] Reaction conditions: N-methylpiperidine (1a, 1.00 mmol), alkene
(1.50 mmol), TiBn4 (10 mol%), Ph3C[B(C6F5)4] (8 mol%), toluene
(5 mL), 288C, 96 h, 25 mL vial. [b] Isolated yield. [c] 18 h. [d] Reaction
conditions: 1a (2.00 mmol), alkene (3.00 mmol), TiBn4 (5 mol%),
Ph3C[B(C6F5)4] (4 mol%), toluene (5 mL), 288C, 18 h, 25 mL vial.
[e] 72 h.
benzyl group abstraction from TiBn4.[13] While initial experi-
ments at elevated temperatures (105–1608C) which are
typically required for Ind2TiMe2- or TiBn4-catalyzed hydro-
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Scheme 3. Multigram scale hydroaminoalkylation of 1-dodecene (2d)
with N-methylpiperidine (1a).
formed on a 20 mmol scale in a Schlenk tube at a slightly
elevated temperature of 358C (Scheme 3). In this case, 3.2 g
of product 3d were isolated.
Figure 1. Ellipsoid representation of the molecular structure of 5b·HCl.
Hydrogen atoms are omitted for clarity (exception H1, H1A and H8).
Ellipsoids are drawn at the 50% probability level.[16]
During a subsequent study of the behavior of the closely
related tertiary amines N-methylazepane (1b) and N-meth-
ylpyrrolidine (1c) we then recognized that under the typical
reaction conditions, these substrates are always converted
into two hydroaminoalkylation products. For example, a-
alkylation of N-methylazepane (1b) with 4-phenylbutene
(2a) either took place at the N-methyl substituent or at the a-
CH2-group of the seven-membered ring. As a result, the
corresponding products 4a and 5a were isolated in 22% and
37% yield, respectively (Table 2, entry 1). While in this case,
a-alkylation preferentially takes place at the methylene group
of 1b which leads to a selectivity of 62:38 in favor of 5a,
a corresponding reaction with the sterically more damanding
alkene allyltriphenylsilane (2e) slightly favors alkylation at
the sterically less hindered N-methyl substituent. The corre-
sponding products 4b and 5b could be isolated in 35% and
29% yield, respectively. After hydrochloride formation, we
were able to unambiguously determine the structure of
5b·HCl by single crystal X-ray diffraction (Figure 1).[16]
Additional hydroaminoalkylation reactions performed with
N-methylpyrrolidine (1c) and various alkenes (2a–d) then
revealed that 1c behaves similar but unfortunately, we were
not able to seperate the two hydroaminoalkylation products
which were formed in all theses reactions. However, corre-
sponding product mixtures could be isolated in yields of 18–
36% and GC-analyses showed that again alkylation at the a-
CH2-group of the heterocyclic ring is slightly favored.[15] In
this context, it should be noted that hydroaminoalkylation
reactions of alkenes in which a-CH2-alkylation of an amine is
preferred over a competing a-CH3-alkylation are extremely
rare. To the best of our knowledge, not a single example of
a corresponding scandium-catalyzed process of a tertiary
amine is known and in the case of group 4 or 5 metal-
catalyzed reactions of secondary amines, only additionally
activated amines like N-methylbenzylamine selectively react
at the methylene group.[5d,6c]
Next we turned our attention towards reactions of non-
heterocyclic tertiary amines and we found that for example,
N,N-dimethylcyclohexylamine (1d) easily reacts with various
alkenes (2a–2j) to give the desired hydroaminoalkylation
products 6a–6j in modest to good yields between 44% and
81% (Table 3). Unfortunately, during our entire study, TLC-
Table 3: Scope of the titanium-catalyzed hydroaminoalkylation of vari-
ous alkenes with N,N-dimethylcyclohexylamine (1d).[a]
Entry Alkene
1
Product
t [h] Yield [%][b]
72
72
79
59
2
3
4
5
6
72
72
24
24
81
66
59
64
Table 2: Titanium-catalyzed hydroaminoalkylation of selected alkenes
with N-methylazepane (1b).[a]
7
72
55
8
42
48
72
77
55
44
9
Entry Alkene
R
Sel. 4/5[b] Yield 4 [%][c] Yield 5 [%][c]
1
2
2a
2e
(CH2)2Ph 38:62
CH2SiPh3 54:46
22 (4a)
35 (4b)
37 (5a)
29 (5b)
10
[a] Reaction conditions: N-methylazepane (1b, 1.00 mmol), alkene
(1.50 mmol), TiBn4 (10 mol%), Ph3C[B(C6F5)4] (8 mol%), toluene
(5 mL), 288C, 72h, 25 mL vial. [b] Selectivity was determined by GC
analysis prior to flash chromatography. [c] Isolated yield.
[a] Reaction conditions: N,N-dimethylcyclohexylamine (1d, 1.00 mmol),
alkene (1.50 mmol), TiBn4 (10 mol%), Ph3C[B(C6F5)4] (8 mol%), toluene
(5 mL), 288C, t, 25 mL vial. [b] Isolated yield.
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visualization of the tertiary amines which was essential for the
noted that all attempts to react N,N-dimethylaniline with 4-
final chromatographic purification of the products was
extremly difficult to achieve. It was just sufficiently possible
with a H2PtCl6/KI solution[15] and the modest sensitivity of the
detection might be responsible for some of the modest yields.
However, as observed before, N,N-dimethylcyclohexylamine
(1d) and terminal alkenes were selectively converted into the
branched hydroaminoalkylation products and internal
alkenes gave lower yields than terminal alkenes. Overall,
the reactions of 1d were slightly faster than those of N-
methylpiperidine (1a) which led to reduced reaction times
between 24 h and 72 h.
phenylbutene (2a) or 1-octene (2c) failed so far.
In summary, we have presented the first examples of
titanium-catalyzed hydroaminoalkylation reactions of
alkenes that use tertiary amines as substrates. The cationic
titanium catalyst is generated in situ from readily available
[5f]
TiBn4 and Ph3C[B(C6F5)4]. Successful hydroaminoalkyla-
tion could be achieved with heterocyclic and non-heterocyclic
aliphatic amines as well as mono- and 1,1- or 1,2-disubstituted
alkenes at temperatures close to room temperature. Partic-
ularly interesting is the fact that occasionally, a-CH2-alkyla-
tion of the amine is preferred over a competing a-CH3-
alkylation. Further opimization studies to take advantage of
this promising result and to expand the scope of the reaction
towards aromatic amines are presently underway in our
laboratories.
While corresponding reactions of sterically demanding
amines like N,N-dicyclohexylmethylamine failed, it was also
possible to convert N,N-dimethylbenzylamine (1e), N,N-
dimethylethylamine (1 f), and N,N-dimethylisopropylamine
(1g) into
selected
hydroaminoalkylation
products
(Scheme 4). Interestingly, alkylation of N,N-dimethylbenzyl-
amine (1e), which gave better results at a slightly elevated
temperature of 358C, took place selectively at the methyl
group and not in the activated benzylic position. Although the
yields, obtained from reactions of N,N-dimethylethylamine
(1 f) or N,N-dimethylisopropylamine (1g) are not satifactory
yet, the results clearly support the impression that cationic
titanium catalysts might be useful for potential industrial
applications, for example, hydroaminoalkylation reactions
using gaseous trimethylamine as a substrate. In the case of
N,N-dimethylisopropylamine (1g), two products, a mono-
(9b) and a dialkylated product (10b) were isolated in
a combined yield of 42% from a reaction with 1-octene
(2c). This yield could already be improved to 57% (9b, 47%
and 10b, 10%) by using a catalyst loading of 20 mol% at
a slightly evevated temperature of 358C. Finally, it should be
Acknowledgements
We thank the Research Training Group “Chemical Bond
Activation” (GRK 2226) funded by the Deutsche Forschungs-
gemeinschaft for financial support of our research. Open
access funding enabled and organized by Projekt DEAL.
Conflict of interest
The authors declare no conflict of interest.
ꢀ
Keywords: alkenes · C H activation · hydroaminoalkylation ·
tertiary amines · titanium
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Accepted manuscript online: February 23, 2021
Version of record online: March 24, 2021
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