A 2,6-bis(phenylamino)pyridinato titanium catalyst for the highly regioselective hydroaminoalkylation of styrenes and 1,3-butadienes

Article abstract of DOI:10.1002/anie.201403203

The C-C bond forming catalytic hydroaminoalkylation of terminal alkenes, 1,3-dienes, or styrenes allows a direct and highly atom efficient (100 %) synthesis of amines which can result in the formation of two regioisomers, the linear and the branched product. We present a new titanium catalyst with 2,6-bis(phenylamino)pyridinato ligands for intermolecular hydroaminoalkylation reactions of styrenes and 1-phenyl-1,3-butadienes that delivers the corresponding linear hydroaminoalkylation products with excellent regioselectivities. Linear progress: A new Ti complex with 2,6-bis(phenylamino) pyridinato ligands catalyzes highly regioselective hydroaminoalkylation reactions of styrenes. The process that directly gives access to the corresponding linear hydroaminoalkylation products offers a new and flexible synthetic approach towards pharmaceutically important 3-arylpropylamines. It is also possible to convert (E)-1-phenyl-1,3-butadienes into the corresponding linear products.

Full text of DOI:10.1002/anie.201403203

Angewandte
Chemie
DOI: 10.1002/anie.201403203
À
C H Activation
A 2,6-Bis(phenylamino)pyridinato Titanium Catalyst for the
Highly Regioselective Hydroaminoalkylation of Styrenes and
1,3-Butadienes**
Jaika Dçrfler, Till Preuß, Alexandra Schischko, Marc Schmidtmann, and Sven Doye*
À
Abstract: The C C bond forming catalytic hydroaminoalky-
lation of terminal alkenes, 1,3-dienes, or styrenes allows a direct
and highly atom efficient (100%) synthesis of amines which
can result in the formation of two regioisomers, the linear and
the branched product. We present a new titanium catalyst with
2,6-bis(phenylamino)pyridinato ligands for intermolecular
hydroaminoalkylation reactions of styrenes and 1-phenyl-1,3-
butadienes that delivers the corresponding linear hydroami-
noalkylation products with excellent regioselectivities.
substructure which does not lead to the formation of any side
products is shown in Scheme 1. The corresponding retrosyn-
thetic approach relies on a metal-catalyzed hydroaminoalky-
lation[4–9] of widely available vinyl arenes with easily acces-
À
sible N-methylamines that takes place under C H bond
activation in the position a to a nitrogen atom. However, in
this case, it is essential that the starting materials react
regioselectively to form the desired linear hydroaminoalky-
lation product. Hydroaminoalkylation reactions of alkenes
and styrenes can be achieved in the presence of ruthenium,[5]
iridium,[6] Group 5 metal,[7] zirconium,[8] or titanium cata-
lysts[9] but the use of ruthenium and iridium catalysts is limited
to amine substrates with a directing 2-pyridinyl substituent
bound to the nitrogen atom of the amine. While in the
presence of tantalum or titanium catalysts, terminal alkenes,
such as 1-octene (4) or styrene (6), could already be converted
into the branched hydroaminoalkylation products 5a or 7a
with high regioselectivities (Scheme 2),[7,9d] corresponding
O
wing to the fact that nitrogen-containing molecules often
possess highly important biological activities, amines are
undoubtedly among the most important synthetic target
molecules in the agrochemical, fine chemical, and pharma-
ceutical industries.[1] As a consequence, the development of
efficient synthetic methods for the production of amines is
a research area of general importance. Although the struc-
tural diversity of amines is immense, it is at least partly
possible to identify privileged substructures which often cause
high biological activity. For example, the calcimimetic agent
cinacalcet (1)[2] and the calcium channel blocker fendiline
(2)[3] shown in Scheme 1 both contain a 3-phenylpropylamine
unit as a joint structural element. A highly attractive strategy
for the synthesis of amines possessing a 3-arylpropylamine
Scheme 2. Regioselectivity of the intermolecular hydroaminoalkylation
of 1-octene (4) and styrene (6) with N-methylaniline (3) achieved with
selected Group 4 and 5 metal catalysts (Ind=h5-indenyl).[7c,l,9d,g]
attempts to selectively synthesize the linear regioisomers
have only met with limited success. However, very recently,
we presented the aminopyridinato titanium complex [(2-
MeN-Py)2Ti(NMe2)2] (Py = pyridyl)[9g] as the first example of
a catalyst that favors the formation of linear hydroaminoal-
kylation products. For example, with this catalyst, the hydro-
aminoalkylation of styrene (6) with N-methylaniline (3) takes
place with a regioselectivity of 67:33 in favor of the
biologically interesting linear 3-phenylpropylamine product
7b.
Scheme 1. Calcimimetic agent cinacalcet (1), calcium channel blocker
fendiline (2), and retrosynthetic analysis of 3-arylpropylamines.
[*] J. Dçrfler, T. Preuß, A. Schischko, Dr. M. Schmidtmann,
Prof. Dr. S. Doye
Institut fꢀr Chemie, Universitꢁt Oldenburg
Carl-von-Ossietzky-Strasse 9–11, 26111 Oldenburg (Germany)
E-mail: doye@uni-oldenburg.de
[**] We thank the Deutsche Forschungsgemeinschaft for financial
support of our research and Jessica Reimer for experimental
assistance.
To achieve hydroaminoalkylation reactions of styrenes
with improved regioselectivities in favor of the biologically
interesting linear products we subsequently performed
a study directed towards a structural optimization of the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403203.
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Table 1: Hydroaminoalkylation of styrene (6) with various secondary
aminopyridinato ligands of the titanium catalyst. During this
investigation, we found that the easily accessible titanium
complex 10 (Scheme 3) with two 2,6-bis(phenylamino)pyr-
idinato ligands is an outstandingly suitable catalyst for the
amines.[13]
Entry Amine
10
[mol%]
Product
Yield
[%][a]
Selectivity
a/b[b]
1
2
3
4
5
5
5
5
81 (7b) 6:94
73
5:95
(24b)
74
5:95
(25b)
72
6:94
(26b)
31
5
6
7
5
5
5
6:94
(27b)
Scheme 3. Synthesis (top) and X-ray crystal structure (bottom) of com-
plex 10.[11] Selected bond lengths [ꢂ] and angles [8]: Ti1-N1 2.1405(14),
Ti1-N2 2.2193(14), Ti1-N4 2.0963(14), Ti1-N5 2.112(15), Ti1-N7
1.8970(14), Ti1-N8 1.9260(15); N1-Ti1-N2 60.89(5), N4-Ti-N5 61.42(5),
C7-N1-Ti1 96.22(10), C7-N2-Ti1 92.78(10), C24-N4-Ti1 97.89(10), C24-
N5-Ti1 93.36(10).
23
5:95
(28b)
74
5:95
(29b)
46
highly regioselective conversion of styrenes into the linear
hydroaminoalkylation products, a transformation that has
never been reported before with simple amines.
8
10
10
10
6:94
(30b)
33
9
1:99
(31b)
The new catalyst 10 was synthesized in 80% yield as an
orange solid by treatment of [Ti(NMe2)4] (9) with the easily
accessible ligand precursor 8 in diethyl ether.[10] Subsequently,
orange-red crystals of 10 suitable for X-ray single-crystal
analysis were obtained by fast evaporation of a diluted
solution of 10 in diethyl ether. The solid-state structure of 10
(Scheme 3)[11] reveals a distorted octahedral geometry around
the titanium center and shows that the phenyl groups of both
ligands are twisted differently out of the corresponding
87
10
5:95
(32b)
39
11
12
10
10
1:99
(33b)
65
4:96
(34b)[c,d]
À
pyridine plane. In addition, the Ti N bonds to the pyridine
nitrogen atoms were found to be significantly longer than
those to the aniline nitrogen atoms.
66
13
14
10
10
1:99
(35b)[c,e]
Fortunately, complex 10 could already be used success-
fully in an initial hydroaminoalkylation experiment as a cata-
lyst for the alkylation of N-methylaniline (3) with styrene (6)
performed under usually applied conditions (5 mol% 10,
hexanes (mixture of isomers), 1408C, 96 h, sealed Schlenk
tube, Table 1, entry 1).[12,13] Most importantly, in this case, the
linear regioisomer 7b was obtained as the sole product in
81% yield after a typical work-up procedure. In addition, GC
analysis performed prior to chromatographic purification of
the reaction mixture confirmed the excellent regioselectivity
of the hydroaminoalkylation in favor of the linear product 7b
(selectivity 7a/7b = 6:94).
28
15:85
(36b)[c,d]
[a] Reaction conditions: amine (2.0 mmol), styrene (6, 313 mg, 3.0 mmol),
10 (66 mg, 0.1 mmol, 5 mol% or 131 mg, 0.2 mmol, 10 mol%), hexanes
(1.0 mL), 1408C, 96 h. Yields refer to the yield of the isolated linear product b.
[b] GC analysis prior to chromatography. [c] The product was isolated after
derivatization as the corresponding para-toluenesulfonamide. [d] The reac-
tion took place at the methyl group of the amine exclusively. [e] The reaction
took place at the benzyl position of the amine exclusively.
To investigate the scope of the new process, we sub-
sequently performed additional hydroaminoalkylation reac-
2
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tions of styrene (6) with various secondary amines (Table 1).
These experiments revealed that the efficiency of the reaction
catalyzed by 10 is strongly influenced by the steric bulk of the
amine. While the sterically less-hindered para- and meta-
substituted N-methyltoluidines 11 and 12 selectively gave the
desired linear hydroaminoalkylation products 24b and 25b in
yields of 73% and 74%, respectively (Table 1, entries 2 and
3), N-methyl-ortho-toluidine was found to be completely
unreactive under the reaction conditions. In analogy, N-
ethylaniline (18) which is sterically more demanding than N-
methylaniline (3) gave the corresponding linear product 31b
only in decreased yield of 33% (Table 1, entry 9). Although
for this result it was necessary to increase the catalyst loading
to 10 mol% it should be noted that the regioselectivity in
favor of the linear isomer 31b was excellent (99:1). In contrast
to the modest reactivity of 18, the N-benzyl-substituted
aniline 19 delivered the linear product 32b in very good yield
(87%, Table 1, entry 10). This improved result can probably
yields were achieved. In this context, note that besides the
catalyst [(2-MeN-Py)2Ti(NMe2)2][9g] which was recently iden-
tified by our group, 10 is only the second titanium complex
that catalyzes corresponding reactions of dialkylamines, and
fortunately better regioselectivities are achieved with 10. As
observed before, reactions of the unsymmetrically substituted
amines N-methylcyclohexylamine (21) and N-methylhexyl-
amine (23) took place at the methyl group of the amine
exclusively while the alkylation of N-methylbenzylamine (22)
only occurred in the benzyl position.[7e,9g] During an addi-
tional experiment performed with N-methyl-1-(1-naphthyl)-
ethylamine it was also possible to detect the selective
formation of a Cinacalcet analogue (GC/MS, NMR spectros-
copy) but in this case, large amounts of unconsumed starting
materials prevented the isolation of the pure product.
During additional hydroaminoalkylation experiments
performed with N-methylaniline (3) and various other
styrenes (Table 2) it was found that in the presence of
10 mol% of 10, many styrenes undergo highly regioselective
hydroaminoalkylation reactions although the yield and the
regioselectivity are strongly influenced by the steric proper-
ties of the styrene (Table 2, entries 1 and 2). While the
reaction of para-methylstyrene (37) gave the linear product
45b in good yield (74%) and with high regioselectivity (45a/
45b = 9:91), a lower yield of only 42% of the linear product
was obtained with the ortho-methyl-substituted styrene 38
and most importantly, in this case, the regioselectivity
dropped dramatically to 46a/46b = 33:67. Following this
downward trend in reactivity, a successful reaction of a steri-
cally more demanding ortho,ortho-dimethyl-substituted sty-
rene could not be achieved. In contrast, the presence of a tert-
butyl group in the para-position of the styrene 39 was
tolerated without any problems and even the annelated
benzene ring in 2-vinylnaphthalene (44) only resulted in
a slightly reduced yield (Table 2, entries 3 and 8). Importantly,
in these cases, the regioselectivities remained very high (ꢀ
93:7) and the linear products were isolated exclusively. The
results obtained with the donor- and acceptor-substituted
styrenes 40–43 (Table 2, entries 4–7) show that both classes of
substituents are generally tolerated and good yields of the
corresponding linear products (48b–51b, 63–71%) can be
achieved. With regard to the regioselectivity of the reaction,
the electron-withdrawing CF3 and Cl substituents lead to
improved results while the electron-donating para-methoxy
group has a negative effect. Particularly interesting is the
selective formation of the linear hydroaminoalkylation prod-
uct 49b from 41 because this product contains the core
structure of cinacalcet (1). In contrast to the behavior of
styrenes, the corresponding reaction of 1-octene (4, Table 2,
entry 9) favored the formation of the branched regioisomer
5a and only a modest yield could be achieved. However, it
must be noted that even in this case, significant amounts of
the linear product 5b were formed, a finding that is in sharp
contrast to observations made with other titanium catalysts.[9d]
Because no significant polymerization of styrenes had
been observed during the reactions performed with 10, we
additionally attempted hydroaminoalkylation reactions of 1-
aryl-substituted (E)-1,3-dienes which are known to possess
limited stability under harsh reaction conditions. During these
À
be explained by the increased reactivity of the benzylic C H
bond which becomes activated during the course of the
reaction. Fortunately, the first titanium-catalyzed hydroami-
noalkylation of styrene (6) with 1,2,3,4-tetrahydroquinoline
(20, Table 1, entry 11) could also be achieved in the presence
of 10 mol% of 10 and again, the corresponding linear product
33b was formed exclusively. Although some of the yields
obtained with 18, 19 and 20 were only modest, the corre-
sponding results clearly underline the fact that hydroami-
noalkylation reactions can deliver products which are not
accessible by hydroformylation of a styrene and a subsequent
reductive amination. Reactions performed with additional
para- and meta-substituted N-methylanilines then showed
that a number of heteroatom substituents are tolerated
(Table 1, entries 4–8). For example, thioether 17 as well as
the electron-rich para-methoxy substituted substrate 16 and
the electron-poor para-fluoro derivative 13 reacted with
styrene in good to modest yields and in all cases, high
regioselectivities (ꢀ 94:6) in favor of the linear hydroami-
noalkylation products were observed (Table 1, entries 4, 7,
and 8). From a synthetic point of view, the linear product 29b
which was formed in 74% yield is particularly interesting
because the para-methoxyphenyl group bound to the nitrogen
atom is a well-established protecting group. Simple cleavage
under oxidative conditions would deliver the corresponding
primary amine. While the good result obtained with 13 shows
that fluoro substituents are tolerated without any problems,
the other halogenated substrates para-chloro-N-methylani-
line (14) and meta-bromo-N-methylaniline (15) gave the
linear products 27b and 28b only in lower yields of 31% and
23%, respectively, even though the regioselectivities
remained high (Table 1, entries 5 and 6). However, despite
the lower yields these results clearly demonstrate the
suitability of halogenated substrates which offer the possibil-
ity of subsequent functionalization reactions. Finally, it was
found that with 10 as the catalyst, even dialkylamines, such as
21–23, undergo regioselective hydroaminoalkylation reac-
tions with styrene (6, Table 1, entries 12–14). In these cases,
the linear products which were again formed in large excess
could be isolated after derivatization as the corresponding
para-toluenesulfonamides (34b–36b) and sometimes, good
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Table 2: Hydroaminoalkylation of various styrenes and alkenes with N-
methylaniline (3).[13]
Table 3: Hydroaminoalkylation of (E)-1,3-butadienes performed in the
presence of catalyst 10.[13]
Entry Alkene
Product
Yield [%][a] Selectivity
a/b[b]
Entry
R
Yield [%][a]
Selectivity a/b[b]
1
2
3
4
C6H5 (53)
40 (57a/57b)
33 (58a/58b)
34 (59a/59b)
37 (60a/60b)
61:39
65:35
71:29
54:46
1
2
74 (45b)
42 (46b)
9:91
p-Me-C6H4 (54)
p-MeO-C6H4 (55)
p-Cl-C6H4 (56)
33:67
[a] Reaction conditions: 1) N-methylaniline (3, 214 mg, 2.0 mmol), 1,3-
diene (3.0 mmol), 10 (131 mg, 0.2 mmol, 10 mol%), hexanes (1.0 mL),
1208C, 48 h; 2) acetyl chloride (1m in CH2Cl2, 4.0 mmol), NEt3
(4.0 mmol), CH2Cl2 (30 mL), 258C, 16 h. Yields refer to the total yield of
isolated product (a+b). [b] GC analysis prior to acetylation and
chromatography.
3
4
5
77 (47b)
69 (48b)
63 (49b)
6:94
2:98
2:98
In summary, the new titanium complex 10 was identified
to be a highly efficient catalyst for the intermolecular
hydroaminoalkylation of styrenes and (E)-1-phenyl-1,3-buta-
dienes. With this catalyst, it is possible to obtain the
corresponding linear hydroaminoalkylation products with
excellent regioselectivities. This finding establishes a new
and flexible synthetic approach towards the pharmaceutically
important class of 3-arylpropylamines.
6
7
8
71 (50b)
67 (51b)
64 (52b)
4:96
11:89
7:93
Received: March 11, 2014
Published online: && &&, &&&&
59
À
9
89:11
Keywords: 1,3-dienes · amines · C H activation · styrenes ·
titanium
(5a+5b)[c]
.
[a] Reaction conditions: N-methylaniline (3, 214 mg, 2.0 mmol), alkene
(3.0 mmol), 10 (131 mg, 0.2 mmol, 10 mol%), hexanes (1.0 mL), 1408C,
96 h. Yields refer to the yield of the isolated linear product b. [b] GC
analysis prior to chromatography. [c] The yield refers to the total yield of
isolated product (a+b).
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À
of 10, successful hydroaminoalkylation of the terminal C C
double bond of the dienes 53–56 (Table 3) can be achieved
with modest yields. This finding strongly underlines the high
catalytic activity of 10 because to date [Ind2TiMe2] was the
only catalyst suitable for hydroaminoalkylation reactions of
1,3-dienes.[9h] Note that in contrast to [Ind2TiMe2], the new
catalyst 10 produces linear regioisomers almost exclusively
and that the corresponding hydroaminoalkylation products
were obtained as mixtures of two compounds, one with an
À
isomerized and one with a non-isomerized C C double bond.
On the other hand, the corresponding branched products
could only be detected in trace amounts by GC analysis.
Owing to their better separation from residual starting
materials, the products with isomerized and non-isomerized
C C double bonds[14] were isolated after conversion into their
À
corresponding acetamides.
4
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ccdc.cam.ac.uk/data_request/cif.
[12] A detailed optimization study of the reaction conditions can be
found in the Supporting Information.
[13] For experimental details, see the Supporting Information.
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product.
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Communications
À
C H Activation
J. Dçrfler, T. Preuß, A. Schischko,
M. Schmidtmann,
S. Doye*
&&&& — &&&&
A 2,6-Bis(phenylamino)pyridinato
Titanium Catalyst for the Highly
Regioselective Hydroaminoalkylation of
Styrenes and 1,3-Butadienes
Linear progress: A new Ti complex with
2,6-bis(phenylamino)pyridinato ligands
catalyzes highly regioselective hydroami-
noalkylation reactions of styrenes. The
process that directly gives access to the
corresponding linear hydroaminoalkyla-
tion products offers a new and flexible
synthetic approach towards pharmaceut-
ically important 3-arylpropylamines. It is
also possible to convert (E)-1-phenyl-1,3-
butadienes into the corresponding linear
products.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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