Dimethylamine as a Substrate in Hydroaminoalkylation Reactions

Article abstract of DOI:10.1002/anie.201708959

Transition-metal-catalyzed hydroaminoalkylations of alkenes have made great progress over the last decade and are heading to become a viable alternative to the industrial synthesis of amines through hydroformylation of alkenes and subsequent reductive amination. In the past, one major obstacle of this progress has been an inability to apply these reactions to the most important amines, methylamine and dimethylamine. Herein, we report the first successful use of dimethylamine in catalytic hydroaminoalkylations of alkenes with good yields. We also report applicability for a variety of alkenes to show the tolerance of the reaction towards different functional groups. Additionally, we present a catalytic dihydroaminoalkylation reaction using dimethylamine, which has never been reported before.

Full text of DOI:10.1002/anie.201708959

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Accepted Article
Title: Dimethylamine as Substrate in Hydroaminoalkylation Reactions
Authors: Jens Bielefeld and Sven Doye
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708959
Angew. Chem. 10.1002/ange.201708959
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Dimethylamine as Substrate in Hydroaminoalkylation Reactions
Jens Bielefeld and Sven Doye*
Abstract: Transition metal catalyzed hydroaminoalkylations of
alkenes have made great progress over the last decade and are
heading to become a viable alternative to the industrial synthesis of
amines through hydroformylation of alkenes and subsequent
reductive amination. In the past, one major obstacle of this progress
has been the inability to apply these reactions to the most important
amines, methylamine and dimethylamine. Herein, we report the first
successful use of dimethylamine in catalytic hydroaminoalkylations of
alkenes with good yields. We also report the applicability for a variety
of alkenes to show the tolerance of the reaction towards different
functional groups. Additionally, we present the dihydroaminoalkylation
reaction using dimethylamine, which has never been reported before.
determined our production cost, including all chemicals and
solvents, to be 59 € (synthesis and calculation are given in the
supporting information).
It is established that the widespread industrial synthesis of amines
through hydroformylation of alkenes and subsequent reductive
amination can, in principle, be replaced by
a
direct
hydroaminoalkylation of alkenes with amines. This concept not
only allows to skip one reaction step, it also offers the possibility
to make the overall synthesis more energy efficient and to replace
cobalt or rhodium containing hydroformylation catalysts[1] with
inexpensive catalysts that are based on less toxic metals such as
titanium.[
Scheme 1. Mechanism of the Ti-catalyzed hydroaminoalkylation of alkenes.[11]
The mechanism of alkene hydroaminoalkylation employing
2]
catalyst 1 can be assumed based on kinetic studies we published
in 2011.[11] As the equilibrium in Scheme
1 suggests,
Hydroaminoalkylations were first reported in 1980 by Clerici and
Maspero, who were able to react dimethylamine with alkenes
using Group 4 and Group 5 metal catalysts.[3] However, the
reaction was only shown with unfunctionalized alkenes and
afforded mostly poor yields; only traces of product were observed
with Ti-, V- and Mo-catalysts. Due to the low activity, relatively
expensive catalysts (Zr, Nb, Ta) and harsh reaction conditions (up
to 200 °C),[ the scientific interest in this reaction type remained
minimal until Herzon and Hartwig reported in 2007 that
dimethylamine is activated through deprotonation of the methyl
group, leading to a titanaazaridine and free dimethylamine. We
would like to emphasize that this also means that a high
concentration of free dimethylamine will inhibit the reaction. Since
the reaction can, in theory, take place at any α-C−H-bond of
amines,
a broad variety of products could be expected
3,4]
(Scheme 2).
N-arylalkylamines possess
a
much higher reactivity in
hydroaminoalkylations.[5] The overall research then began to
focus mostly on N-alkylanilines and up to now, no relevant
improvements on gaseous amines were made.[6,7]
Because dimethylamine is (alongside methylamine) by far the
most important substrate for this reaction,[8] we considered it
essential for the overall importance and the industrial applicability
of hydroaminoalkylation reactions to develop a reliable and
inexpensive method to facilitate its addition to alkenes in good
yields. We recently found the titanium complex 1, that had first
been reported by Eisen et al. as a catalyst for the polymerization
of propylene,[9] to be active in the α-C−H-activation of
dimethylamine. In 2015, this catalyst has been shown by us to be
highly active in hydroaminoalkylations with N-methylaniline, even
capable of converting notoriously difficult subtrates like styrenes
and internal alkenes.[10]
To underline how inexpensive and available this titanium catalyst
is, we synthesized a 48 g batch (88 mmol) of 1 from TiCl and
4
Scheme 2. Hypothetical products of alkene hydroaminoalkylations with
dimethylamine (b = branched, l = linear).
[*]
M. Sc. J. Bielefeld, Prof. Dr. S. Doye
Universität Oldenburg, Institut für Chemie
Carl-von-Ossietzky-Straße 9-11, 26129 Oldenburg (Germany)
E-mail: doye@uni-oldenburg.de
Fortunately, the α-C−H-activation strongly prefers methyl groups
over methylene groups and the according iso-alkylamines (4 and
5) were never observed as side products under the reaction
Supporting information for this article is given via a link at the end of
the document.
conditions depicted in this work. The catalyst 1 is also known to
generally possess a very good regioselectivity (Sregio) towards
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Angewandte Chemie International Edition
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COMMUNICATION
branched products; the linear side product 2l and the
branched-linear side product 3bl were therefore usually only
observed in trace amounts. The hypothetical linear-linear product
The reactions had to be carried out in ampoules small enough to
ensure that no significant outgassing of dimethylamine takes
place (sealed 5 mL-ampoules were used for approximately 2 mL
of reaction mixture). The conversion of alkene can easily be
enhanced by increasing the reaction time, but at the cost of
severely impairing the product selectivity (i.e. the
hydroaminoalkylation of 4-phenylbutene over 6 d gives isolated
yields of 58 % of 2b and 27 % of 3bb). As shown in Table 1, the
obtained yields are typically decent to good while selectivities are
very good to excellent. To our knowledge, these are the first
examples of dimethylamine being converted in catalytic
hydroaminoalkylations of alkenes with satisfactory yields. A wide
variety of functional groups are tolerated without problems, such
as tertiary amines, ethers, silanes, less reactive alkenes and
protected alcohols, although the tendency to undergo a second
addition of alkene from 2 to 3 is slightly influenced by the
functionalization. Styrenes are converted to pharmaceutically
interesting phenethylamines; unfortunately, the yields and
regioselectivities are low (an average yield of 14 % of
phenethylamine is isolated). This is not surprising, as styrenes are
known to be demanding substrates and catalyst 1 has already
been reported by us to possess rather mediocre regioselectivity
when applied to styrene.[ Nevertheless, this is the first example
3ll was not observed in any instance.
To furthermore ensure a good product selectivity (Sprod) towards
the monohydroaminoalkylation products (2b and 2l), finding the
optimal load of dimethylamine turned out to be the key factor. A
load
too
low
shifts
the
selectivity
towards
the
dihydroaminoalkylation products (3bb and 3bl). We would like to
emphasize that, because dimethylamine evaporates easily from
solutions at elevated reaction temperatures, several other factors
(
i.e. solvent, amount of solvent, size of reaction vessel, pressure)
have a similar, indirect effect on the yield and selectivity of this
reaction. On the other hand, a dimethylamine load too high can
easily inhibit the reaction entirely due to destabilization of the
titanaaziridine intermediate (see equilibrium in Scheme 1). We
found a slight excess of dimethylamine (including the three
dimethylamide ligands of the catalyst) over alkene to provide the
best compromise between yield and selectivity.
Table 1. Monohydroaminoalkylation.[a]
10]
of
dimethylamine
being
converted
in
a
catalytic
hydroaminoalkylation of styrenes at all.
Alkene
t
d]
Yield
[%][
S
regio
[c]
S
[2/3]
prod
[c]
We did not observe any product formation with internal alkenes
(attempted with 2-octene and 3-octene), cycloalkenes (attempted
with cyclopentene and cyclohexene), dienes [attempted with
(E)-1-phenyl-1,3-butadiene and (E)-1,3-decadiene], and acetal-
protected ketones [attempted with 2-(but-3-en-1-yl)-2-methyl-1,3-
dioxolane]. The conversion of most of these substrates has
already been reported with more reactive amines (mostly
N-methylaniline),[10] so it is reasonable to believe that more active
catalysts in the future might be able to achieve a reaction between
them and dimethylamine.
We then wanted to modify the reaction conditions to instead
selectively give the dihydroaminoalkylation product 3bb in a one-
pot synthesis. The methylalkylamines, like 2b, which appear as
intermediates in this reaction, are already known to be challenging
substrates in hydroaminoalkylations, thereby making product
selectivity the main concern. We employed a very effective
method to completely turn around the product selectivity by simply
increasing the volume of the reaction vessel (sealed 100 mL-
Schlenk tubes were used for approximately 2 mL of reaction
mixture). Under the reaction conditions (140 °C), dimethylamine
is then almost entirely gaseous and thus the dimethylamine
concentration in solution is very low. The intermediate 2b remains
liquid under the reaction conditions and is therefore the preferred
target for further C−H-bond activation, leading selectively to the
dihydroaminoalkylation product 3bb. Due to steric hindrance and
low activity of 1 in the activation of methylene groups, 3bb is
roughly inert over the investigated timespan and doesn't undergo
further addition to alkene (see 5 in Scheme 2). Additionally,
because this type of catalyst generally experiences substrate
inhibition (see equilibrium in Scheme 1) to some extent, the lower
amine concentration in solution also leads to substantially shorter
reaction times.
b]
[
[2b/2l]
2
6
6
6
6
6
6
3
2
2
4
66
> 99/1
99/1
95/5
97/3
31[d,e]
54[d]
45[d]
55
97/3
83/17
86/14
83/17
91/9
99/1
96/4
43
98/2
57
98/2
81/19
92/8
43
97/3
28[d]
22[d]
24
53/47
56/44
68/32
95/5
96/4
99/1
[
a] Reaction conditions: alkene (1.5 mmol), 1 (82 mg, 0.15 mmol, 10 mol%),
HNMe (0.95 M in toluene, 1.37 mL, 1.3 mmol) in an 5 mL-ampoule, 140 °C,
-6 d. [b] Isolated yield of 2b. For styrenes, the isolated yield of 2b + 2l is
given. [c] Selectivities were determined by GC-analysis prior to
chromatography. [d] Due to its volatility, the product was tosylated prior to
chromatography. [e] The reaction occurs at the terminal alkene exclusively.
2
2
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Angewandte Chemie International Edition
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and easily obtainable. We hope that this work can increase the
public and industrial interest in this rapidly growing field of
chemistry.
Table 2. Dihydroaminoalkylation.[a]
Experimental Section
Alkene
t
d]
Yield
[%][
S
regio
S
[2/3]
prod
[c]
b]
[c]
[
[3bb/3bl]
General information: Hydroaminoalkylation mixtures were prepared in a
glovebox under N
before use.
2
atmosphere. All substances were dried and degassed
2
4
6
2
4
2
2
3
6
4
2
61
31[d]
48
65
55
45
70
73
6
95/5
7/93
8/92
88/12
80/20
96/4
General procedure for the monohydroaminoalkylation:
mL-ampoule was charged with catalyst 1 (82 mg, 0.15 mmol, 10 mol%),
alkene (1.5 mmol) and dimethylamine solution (0.95 M in toluene, 1.37 mL,
.3 mmol). The ampoule was sealed and heated to 140 °C for 2-6 d. The
A
5
6/94
1
product 2b was either isolated by chromatography or (in case of volatile
products) tosylated. For tosylation, the crude reaction mixture was diluted
15/85
8/92
with CH
2 M, 5.3 mL, 11 mmol) were added. The mixture was stirred over night
and then extracted with CH Cl (3×20 mL). The combined organic layers
were dried with MgSO , concentrated and purified by chromatography.
2 2
Cl (20 mL), then TosCl (679 mg, 3.56 mmol) and NaOH solution
(
95/5
2
2
4
95/5
6/94
General procedure for the dihydroaminoalkylation: A 100 mL-Schlenk
tube with magnetic stir bar and Teflon stopcock was charged with
catalyst 1 (76 mg, 0.14 mmol, 5 mol%), alkene (3.0 mmol) and
dimethylamine solution (1.49 M in toluene, 0.94 mL, 1.4 mmol). The tube
was sealed and heated to 140 °C for 2-6 d. The product 3bb was isolated
by chromatography.
95/5
7/93
95/5
7/93
39/61
43/57
88/12
29/71
30/70
50/50
4
Acknowledgements
3
We thank the Deutsche Forschungsgemeinschaft for financial
support of this project. We thank Jessica Reimer for support of
the experimental work.
[
a] Reaction conditions: alkene (3.0 mmol), 1 (76 mg, 0.14 mmol, 5 mol%),
HNMe (1.49 M in toluene, 0.94 mL, 1.4 mmol) in a 100 mL-Schlenk tube,
40 °C, 2-6 d. [b] Isolated yield of 3bb. [c] Selectivities were determined by
2
1
Conflict of interest
GC-analysis prior to chromatography. [d] The reaction occurs at the terminal
alkene exclusively.
The authors declare no conflict of interest.
The yields of the dihydroaminoalkylation (as shown in Table 2)
are generally good and selectivities are very good to excellent.
Again, styrenes are the exception, giving very poor yields and
selectivities. Interestingly, even with styrenes the selectivity
towards dihydroaminoalkylation is fair, considering how slow the
reaction takes place compared to the monohydroaminoalkylation
of styrenes shown in Table 1. While this is clearly not a satisfying
procedure to produce 3bb from styenes, it still shows how very
effective the larger reaction vessel is in regulating the product
selectivity.
Keywords: hydroaminoalkylation • titanium • dimethylamine •
alkenes • alkylation
[
[
1]
2]
For a review on hydroformylation reactions, see: R. Franke, D. Selent, A.
Börner, Chem. Rev. 2012, 112, 5675-5732.
2
Titanium metal as well as TiO that precipitates during workup from the
reaction mixtures depicted in this work possess no acute toxicity. For
further information, see: Patty's Toxicology, 6th ed., Vol. 1 (Eds.: E.
Bingham, B. Cohrssen), Wiley, Hoboken, 2012, 428-438.
M. G. Clerici, F. Maspero, Synthesis 1980, 4, 305-306.
[3]
Although two diastereoisomers are expected for the product 3bb,
no significant diastereoisomeric preference towards the chiral or
the meso-product has been observed.[12]
In summary, we successfully demonstrated that dimethylamine
can be used in catalytic hydroaminoalkylations of alkenes, and
that good yields can be achieved with various substrates. We
[4]
W. A. Nugent, D. W. Ovenall, S. J. Holmes, Organometallics 1983, 2,
161-162.
[5]
S. B. Herzon, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 6690-6691.
For a review on hydroaminoalkylation reactions, see: E. Chong, P.
Garcia, L. L. Schafer, Synthesis 2014, 46, 2884-2896.
[
6]
7]
[
Despite low achieved yields, the following article might be of interest for
some readers; it serves as a proof of concept for the reaction of
dimethylamine in the presence of a heterogenous (silica-bound) catalyst:
B. Hamzaoui, J. D. A. Pelletier, M. E. Eter, Y. Chen, E. Abou-Hamad, J.
M. Basset, Adv. Synth. Catal. 2015, 357, 3148-3154.
presented
methods
to
either
obtain
the
monohydroaminoalkylation product or the dihydroaminoalkylation
product, both of which can be synthesized with very good
selectivity. The catalyst needed for this reaction is inexpensive
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Angewandte Chemie International Edition
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[
[
[
[
[
8]
K. Weissermel, H.-J. Arpe, Industrial Organic Chemistry, 4th ed., Wiley-
VCH, Weinheim, 2003, 51-52.
9]
T. Elkin, N. V. Kulkarni, B. Tumanskii, M. Botoshansky, L. J. W. Shimon,
M. S. Eisen, Organometallics 2013, 32, 6337-6352.
10] J. Dörfler, T. Preuß, C. Brahms, D. Scheuer, S. Doye, Dalton Trans. 2015,
4, 12149-12168.
11] I. Prochnow, P. Zark, T. Müller, S. Doye, Angew Chem 2011, 28, 6525-
529; Angew. Chem. Int. Ed. 2011, 50, 6401-6405.
12] The 13C NMR data suggests that both diastereoisomers are formed in
approximately equal amounts. Further details are given in the supporting
information.
4
6
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Entry for the Table of Contents
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Size matters: For the first time since
catalytic hydroaminoalkylation
chemistry started 37 years ago,
dimethylamine can efficiently be
added to alkenes using an
J. Bielefeld, S. Doye*
Page No. – Page No.
Dimethylamine as Substrate in
Hydroaminoalkylation Reactions
inexpensive and easily obtainable Ti-
catalyst. The size of the flask
determines what product this reaction
yields - monohydroaminoalkylation or
dihydroaminoalkylation.
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