Linear Hydroaminoalkylation Products from Alkyl-Substituted Alkenes

Article abstract of DOI:10.1002/chem.202003223

The regioselective conversion of alkyl-substituted alkenes into linear hydroaminoalkylation products represents a strongly desirable synthetic transformation. In particular, such conversions of N-methylamine derivatives are of great scientific interest, because they would give direct access to important amines with unbranched alkyl chains. Herein, we present a new one-pot procedure that includes an initial alkene hydroaminoalkylation with an α-silylated amine substrate and a subsequent protodesilylation reaction that delivers linear hydroaminoalkylation products with high selectivity from simple alkyl-substituted alkenes. For that purpose, new titanium catalysts have been developed, which are able to activate the α-C?H bond of more challenging α-silylated amine substrates. In addition, a direct relationship between the ligand structure of the new catalysts and the obtained regioselectivity is described.

Full text of DOI:10.1002/chem.202003223

Accepted Article
Accepted Article
Title: Linear Hydroaminoalkylation Products from Alkyl-Substituted
Alkenes
Authors: Michael Warsitz and Sven Doye
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202003223
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01/2020

10.1002/chem.202003223
Chemistry - A European Journal
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Linear Hydroaminoalkylation Products from Alkyl-Substituted
Alkenes
Michael Warsitz and Sven Doye*[a]
[a]
M.Sc. M. Warsitz, Prof. Dr. 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.
Abstract: The regioselective conversion of alkyl-substituted alkenes
into linear hydroaminoalkylation products represents a strongly
desirable synthetic transformation. In particular, such conversions of
N-methylamine derivatives are of great scientific interest, because
they would give direct access to important amines with unbranched
alkyl chains. Herein, we present a new one-pot procedure that
includes an initial alkene hydroaminoalkylation with an α-silylated
amine substrate and a subsequent protodesilylation reaction that
delivers linear hydroaminoalkylation products with high selectivity
from simple alkyl-substituted alkenes. For that purpose, new titanium
catalysts have been developed, which are able to activate the α-C-H
bond of more challenging α-silylated amine substrates. In addition, a
direct relationship between the ligand structure of the new catalysts
and the obtained regioselectivity is described.
must be stated that up to now, no general method for the
hydroaminoalkylation of simple alkyl-substituted alkenes that
results in the selective formation of linear hydroaminoalkylation
products is known. However, very recently, the preferred
formation of linear hydroaminoalkylation products from sterically
more or less demanding alkyl- or silyl-substituted alkenes with N-
trimethylsilylbenzylamine was reported to take place in the
presence of a zirconium catalyst.[7]
The most important industrially practiced synthesis of amines
from alkenes uses a two-step process that combines the
hydroformylation of an alkene and a subsequent reductive
amination.[1] An alternative synthetic approach for the synthesis of
corresponding amines, which can, in principle, deliver the same
amine products, if the same alkene substrates are used, is the
catalytic hydroaminoalkylation of alkenes (Scheme 1). This 100 %
atom economic one-step transformation which has particularly
been studied in recent decades allows the addition of α-C-H
bonds of primary or secondary amines across C-C double
bonds.[2] Unfortunately, hydroaminoalkylation reactions mostly
favor the formation of the corresponding branched products, while
in contrast, linear amine products are easily accessible via the
Scheme 1. Hydroaminoalkylation of allylbenzene (2) with N-methylaniline (1).
industrially
applied
hydroformylation/reductive
amination
sequence from alkyl-substituted alkenes. However, although
most of the group 5 metal and titanium based catalysts[2] convert
aryl-
and
alkyl-substituted
alkenes
into
branched
hydroaminoalkylation products with high regioselectivity, the
bis(aminopyridinato) titanium catalyst I depicted in Scheme 1 was
already found to deliver the linear isomers as the major products
from styrenes[3] and vinylsilanes.[4] In this context, it should be
mentioned
that
ruthenium-[5]
and
iridium[6]-catalyzed
hydroaminoalkylation reactions also give linear isomers
exclusively, but these reactions are limited to amine substrates
that contain additional metal-binding directing groups or the use
of electron-deficient alkenes.
On the other hand,
hydroaminoalkylation reactions of alkyl-substituted alkenes, such
as allylbenzene (2), with N-methylaniline (1) performed in the
presence of titanium catalyst I still lead to the formation of the
branched isomer as the major product (Scheme 1). Overall, it
Scheme 2. Mechanistic details of the hydroaminoalkylation of alkyl-substituted
alkenes with N-alkylanilines.
1
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In order to overcome this synthetic issue, we developed a new
one-pot procedure, which enables the formal conversion of N-
methylanilines and alkyl-substituted alkenes into linear
hydroaminoalkylation products. For that purpose, we considered
to direct the regioselectivity towards the linear isomer by
influencing the regioselectivity-determining step of the
hydroaminoalkylation reaction through steric effects. As can be
seen from the mechanism of the titanium-catalyzed alkene
hydroaminoalkylation (Scheme 2),[8,9] the insertion of the alkene
into the Ti-C bond of the catalytically active titanaaziridine, that is
formed by α-C-H activation from the amine substrate and the
titanium catalyst, can occur in two ways, which as a result, lead to
regioisomeric products. In pathway A (Scheme 2), the alkyl-
substituent of the alkene is oriented towards the substituent R1 of
the substrate amine which causes steric repulsion in the transition
compared to methyl groups, a more active hydroaminoalkylation
catalyst is required for successful reactions with amine 4. To
optimize the reaction with regard to the unsatisfying yield, we
modified the 2,6-bis(phenylamino)pyridinato ligand of catalyst I
and investigated how various substituents at the phenyl rings of
the ligand influence the activity and selectivity of the catalyst.
During the investigation of corresponding titanium catalysts we
found that substituents at the meta-positions (Figure 1,
complexes IV-IX) improve the outcome of the reaction massively
(Table 1, entries 4-9) while substituents at the para- or ortho-
position do not offer significant advantages. We assume that the
new catalysts IV-IX are structural analogues of the structurally
fully characterized complex I[3] which is clearly supported by a
1
comparison of the H and 13C NMR data of IV-IX with those of I
(for details see the Supporting Information). A comparison of the
catalysts IV-VIII in the reaction of N-((trimethylsilyl)methyl)aniline
(4) with allylbenzene (2) showed that the obtained yields as well
as the regioselectivities significantly increase with increasing size
of the meta-substituents of the catalysts. Unfortunately, at the
moment, neither this finding nor the positive effect of the meta-
substitution can be understood. However, the best result could be
achieved in the presence of the TBDMS-substituted catalyst VIII
which delivered the products 5a and 5b in 89 % yield and an
excellent regioselectivity of 7:93 in favor of the linear isomer 5b
(Table 1, entry 8). Additional attempts to reduce the catalyst
loading were carried out with 5 mol% and 2.5 mol% VIII (Table 1,
entries 10-11). However, in both cases, the isolated yields of the
corresponding products decreased, which led to the decision to
run all following reactions with a catalyst loading of 10 mol%.
state if R1
≠
H. After alkene insertion, the resulting
titanapyrrolidine subsequently undergoes aminolysis and
regeneration of the titanaaziridine with simultaneous liberation of
the branched product. The catalytic cycle according to pathway B
which delivers the linear product is analogous, but in contrast, the
insertion of the alkene into the titanaaziridine is sterically not
significantly hindered by the substituent R1 of the amine, because
the alkyl-substituent of the alkene is arranged in opposite direction
to R1. Due to the steric hindrance in pathway A,
hydroaminoalkylation reactions of alkenes should favor pathway
B, which leads to the desired linear products. However, an
essential requirement for this substrate based regioselectivity is
the use of amine substrates with substituents R1 larger than a
hydrogen atom, because corresponding reactions with N-
methylaniline would not deliver the linear hydroaminoalkylation
product as the major isomer. In order to solve this problem, we
assumed that linear hydroaminoalkylation products could formally
be obtained from alkyl-substituted alkenes and N-methylaniline, if
the employed amine substrate possesses
a
removable
substituent R1, such as a trimethylsilyl group, which can be
removed by a subsequent protodesilylation step after the
hydroaminoalkylation reaction (Scheme 3).
Figure 1. Selected titanium catalysts for the hydroaminoalkylation of alkenes.
DIPP = 2,6-diisopropylphenyl.
Table 1. Catalyst screening for the hydroaminoalkylation of allylbenzene (2)
with N-((trimethylsilyl)methyl)aniline (4).[a]
Scheme 3. Retrosynthetic analysis for the formal conversion of alkyl-substituted
alkenes with N-methylaniline to linear hydroaminoalklylation products.
We started our investigation with a few control reactions to check,
whether the α-TMS-substituted N-methylaniline 4 (Scheme 3) is a
suitable substrate for hydroaminoalkylation reactions. For that
purpose, we reacted N-((trimethylsilyl)methyl)aniline (4) with
allylbenzene (2) in the presence of the selected titanium
complexes I,[3] II,[10,11] or III[12] (Figure 1), that have already been
identified to be active hydroaminoalkylation catalysts. As
expected, the corresponding reactions performed with I, II, or III
delivered the hydroaminoalkylation products 5a and 5b with a
promising regioselectivity of up to 18:82 in favor of the linear
isomer 5b (Table 1, entries 1-3), but only disappointing combined
yields (≤ 34 %) were obtained. Due to the fact, that the α-C-H
activation at methylene groups is quite more challenging when
Entry
Catalyst
Catalyst
loading [mol%]
T [°C]
Yield
a+b
Sel.
5a/5b[c]
[%][b]
1
I
10
10
10
140
160
160
8
18:82
24:76
18:82
2
3
II
traces
34
III
2
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10.1002/chem.202003223
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substituents of the ligand of catalyst VIII did not undergo
desilylation reaction under the applied conditions. This finding
could be of high interest for large scale reactions because it offers
the possibility of recycling the ligand.
4
IV
10
10
10
10
10
10
5
140
140
140
140
140
140
140
140
24
65
81
81
89
78
85
24
24:76
16:84
13:87
12:88
7:93
5
V
6
VI
7
VII
VIII
IX
Table 2. One-pot procedure for the formal conversion of N-methylaniline with
various alkyl-substituted alkenes into linear hydroaminoalkylation products.[a]
8
9
13:87
7:93
10
11
VIII
VIII
2.5
7:93
[a] Reaction conditions: N-((trimethylsilyl)methyl)aniline (4, 179 mg, 1.00 mmol),
allylbenzene (2, 177 mg, 1.50 mmol), catalyst (0.10 mmol, 10 mol% or 0.05
mmol, 5 mol% or 0.025 mmol, 2.5 mol%), toluene (1.0 mL), T, 24 h. [b] Isolated
Yield of 5a+5b. [c] Product ratios were determined by GC analysis prior to flash
chromatography.
Entry
Alkene
substrate
Major product
Yield
[%][b]
Sel.
a/b[c]
a
b
With an optimized catalyst in hand, we then investigated the
scope of the hydroaminoalkylation of various alkyl-substituted
alkenes with amine 4 (Table 2). For that purpose, we additionally
combined the hydroaminoalkylation reaction with a subsequent
protodesilylation step into a simple one-pot process to get direct
access to the desired desilylated amine products. During our
optimization, we found 3.0 equivalents of TBAF trihydrate and 15
h stirring at 110 °C without any solvent to be the best conditions
for the protodesilylation reaction (for further details see the
Supporting Information). In this context, it must be mentioned that
for a successful outcome of the desilylation reaction, it is essential
that the solvent is removed after the hydroaminoalkylation step
and that the vessel remains open during the protodesilylation, so
that the emerging trimethylsilyl fluoride can escape; otherwise the
conversion will remain poor. First, we performed the one-pot
process with allylbenzene (2) and in good agreement with the
result of the catalyst screening (Table 1, entry 8) the desired linear
product 3b could be isolated in good yield of 71 % and excellent
regioselectivity of 7:93 in favor of the linear isomer (Table 2, entry
1). Performing the corresponding reaction sequence with the
sterically more demanding dimethyl-substituted allylbenzene
derivative 6 delivered the linear product 12b exclusively in nearly
the same yield (Table 2, entry 2). By employing the sterically less
hindered homoallylbenzene (7), a reduced regioselectivity of
18:82 resulted in a decreased yield of 55 % of the linear product
13b (Table 2, entry 3). In comparison, the functionalized alkenes
8 and 9 bearing a phenoxy or morpholine substituent at the
homoallylic position instead of the phenyl group, showed an
enhanced regioselectivity of 10:90 with good yields of 60-61 % of
the linear products 14b and 15b (Table 2, entries 4-5). In the case
of 4-vinylcyclohexene (10), the regioselectivity enhanced to 3:97
but unfortunately, the linear isomer 16b could only be isolated in
47 % yield (Table 2, entry 6), probably caused by the more difficult
insertion of the sterically more hindered alkene into the
titanaaziridine. In contrast, the less hindered substrate 1-octene
(11) delivered the products 17a and 17b as a mixture in better
yield (65 %) but with a reduced regioselectivity of only 19:81
(Table 2, entry 7). Finally, it should be noted that in all cases, the
desilylation of the initial hydroaminoalkylation products occurred
with 100 % conversion. In contrast, the tert-butyldimethylsilyl
1
2
7
71
7:93
-
68
0:100
3
11
5
55
60
61
18:82
10:90
10:90
4
5[d]
7
6
7
-
47
3:97
65 (a+b)
19:81
[a] Reaction conditions: 1) N-((trimethylsilyl)methyl)aniline (4, 179 mg, 1.00
mmol), alkene (1.50 mmol), VIII (157 mg, 0.10 mmol, 10 mol%), toluene (1.0
mL), 140 °C, 24 h; 2) TBAF ⋅ 3 H2O (947 mg, 3.00 mmol), no solvent, 110 °C,
15 h. [b] Isolated yields. [c] Product ratios were determined by GC analysis prior
to flash chromatography. [d] Pure 15a and pure 15b were obtained in 5 % and
47 % yield, respectively. Additionally, a mixture of 15a and 15b (15a/15b =
11:89) was obtained in 16 % yield.
To further investigate how the alkyl-substituent of the amine
substrate influences the regioselectivity of the reaction, we
performed additional hydroaminoalkylation reactions of
allylbenzene (2) and 2-allyl-1,3-dimethylbenzene (6) with various
secondary amines (Table 3). First of all, corresponding reactions
of allylbenzene (2) with N-ethylaniline (18), N-propylaniline (19),
and N-isobutylaniline (20) revealed that as expected, the
regioselectivity is shifted towards the linear isomers 23b, 24b and
25b (up to 4:96) with increasing size of the alkyl substituent of the
amine and interestingly, the isolated yields (21-66 %) also
increase with increasing size of the substituent (Table 3, entries
1-3). Although an additional reaction with N-benzylaniline (21)
gave access to the linear product 26b in good isolated yield of
59 %, only a surprisingly modest regioselectivity of 34:66 towards
the linear isomer was observed in this case (Table 3, entry 4).
3
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1,2,3,4-Tetrahydroquinoline (22) as an example for a bicyclic
amine gave the linear product 27b only in disappointing isolated
yield of 13 % and again a poor regioselectivity of only 41:59
towards the linear product was observed (Table 3, entry 5).
Interestingly, by employing VI as the catalyst (Scheme 4), an
improved yield of 55 % of 27b and a better regioselectivity of
29:71 (a/b+c) in favor for the linear isomers was obtained.
Surprisingly, the dihydroaminoalkylation product 27c could also
be isolated in 8 % yield in this case. To the best of our knowledge,
this reaction represents the first example of an alkene
hydroaminoalkylation, in which the α-C-H activation takes place
at a tertiary carbon atom. Finally, amines 20-22 were reacted with
the sterically more demanding 2-allyl-1,3-dimethylbenzene (6)
and as expected, better regioselectivities of up to 0:100 towards
the linear isomer as well as good yields could be observed (Table
3, entries 6-8). The corresponding reaction of 22 was also
performed with catalyst VI which again gave improved results
(Table 3, entry 9), but in this case, no dihydroaminoalkylation
product was observed. The latter fact can easily be explained by
the increased steric bulk of alkene 6 compared to 2.
7
19
69
20:80
8
9
17
60
38:62
23:77
9[d]
18
[a] Reaction conditions: amine (1.00 mmol), alkene (1.50 mmol), VIII (157 mg,
0.10 mmol, 10 mol%), toluene (1.0 mL), 140 °C, 24 h. [b] Isolated yields. [c]
Product ratios were determined by GC analysis prior to flash chromatography.
[d] VI (111 mg, 0.10 mmol, 10 mol%) was used as the catalyst.
Table 3. Hydroaminoalkylation of allylbenzene (2) and 2-allyl-1,3-
dimethylbenzene (6) with various secondary amines.[a]
Scheme 4. Hydroaminoalkylation of allylbenzene (2) with 1,2,3,4-
tetrahydroquinoline (22) performed with catalyst VI.
In summary, we have presented a new one-pot procedure which
for the first time, allows to formally convert N-methylaniline with
alkyl-substituted
alkenes
regioselectively
into
linear
hydroaminoalkylation products. For that purpose, several new
titanium complexes were developed, which proved to be highly
active catalysts for the hydroaminoalkylation of alkenes with
sterically challenging amine substrates. In addition, a clear
relationship between the catalyst structure and the regioselectivity
was determined, which could be crucial for future ligand design.
Entry
Amine
substrate
Major product
Yield [%][b]
Sel.
a/b[c]
a
b
Acknowledgements
1
2
3
18
18:82
10:90
We thank the Research Training Group "Chemical Bond
Activation"
(GRK
2226)
funded
by
Deutsche
Forschungsgemeinschaft for financial support of this project and
Jessica Reimer for support of the experimental work.
52 (a+b)
66 (a+b)
Keywords: Amines • Alkenes • Hydroaminoalkylation • Titanium
3
4:96
[1]
[2]
[3]
For a review on hydroformylation reactions, see: R. Franke, D. Selent, A.
Börner, Chem. Rev. 2012, 112, 5675-5732.
For a recent review on hydroaminoalkylation reactions, see: P. M.
Edwards, L. L. Schafer, Chem. Commun. 2018, 54, 12543-12560.
J. Dörfler, T. Preuß, A. Schischko, M. Schmidtmann, S. Doye, Angew.
Chem. Int. Ed. 2014, 53, 7918–7922; Angew. Chem. 2014, 126, 8052–
8056.
4
5
40
59
34:66
41:59
8
0
13
79
[4]
[5]
L. H. Lühning, M. Rosien, S. Doye, Synlett 2017, 28, 2489–2494.
Ruthenium catalysts: a) C.-H. Jun, D.-C. Hwang, S.-J. Na, Chem.
Commun. 1998, 1405–1406; b) N. Chatani, T. Asaumi, S. Yorimitsu, T.
Ikeda, F. Kakiuchi, S. Murai, J. Am. Chem. Soc. 2001, 123, 10935–10941.
Iridium catalysts: a) S. Pan, K. Endo, T. Shibata, Org. Lett. 2011, 13,
4692–4695; b) M. A. Ashley, C. Yamauchi, J. C. K. Chu, S. Otsuka, H.
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6
0:100
[6]
[7]
A. Koperniku, P. J. Foth, G. M. Sammis, L. L. Schafer, J. Am. Chem. Soc.
2019, 141, 18944–18948.
4
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[8]
I. Prochnow, P. Zark, T. Müller, S. Doye, Angew. Chem. Int. Ed. 2011,
50, 6401–6405; Angew. Chem. 2011, 123, 6525–6529.
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[9]
[10] J. Dörfler, T. Preuß, C. Brahms, D. Scheuer, S. Doye, Dalton Trans. 2015,
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[11] Titanium Complex II was first reported by Eisen et al.: T. Elkin, N. V.
Kulkarni, B. Tumanskii, M. Botoshansky, L. J. W. Shimon, M. S. Eisen,
Organometallics 2013, 32, 6337–6352.
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5
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Entry for the Table of Contents
Linear hydroaminoalkylation products are formed from alkyl-substituted alkenes and sterically demanding α-substituted N-
methylaniline derivatives with high selectivity in the presence of a new and highly active titanium catalyst. In the case of α-TMS-
substituted N-methylaniline, a subsequent protodesilylation step gives direct access to amines with unbranched alkyl chains. A strong
dependence between the ligand structure and the observed regioselectivity is reported.
6
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