Aminopyridinato titanium catalysts for the hydroaminoalkylation of alkenes and styrenes

Article abstract of DOI:10.1002/anie.201206027

The linear product is formed as the major product when in situ generated titanium complexes with aminopyridinato ligands are used as catalysts for hydroaminoalkylation reactions of styrenes (see scheme). The reaction is not limited to the use of N-methyla

Full text of DOI:10.1002/anie.201206027

Angewandte
Chemie
DOI: 10.1002/anie.201206027
Hydroaminoalkylation
Aminopyridinato Titanium Catalysts for the Hydroaminoalkylation of
Alkenes and Styrenes**
Jaika Dçrfler and Sven Doye*
Dedicated to Professor Ekkehard Winterfeldt on the occasion of his 80th Birthday
The hydroaminoalkylation of alkenes[1] is a highly atom
a single additional example of a successful hydroaminome-
thylation of a styrene has been reported.[4i] In this case, the
branched product was again the exclusive product of the
reaction. Interestingly, linear side products could also be
obtained from hydroaminoalkylation reactions of 1-alkenes
performed with [Ti(NMe2)4][6b] or [TiBn4][6c] (Bn = benzyl) as
the catalysts. However, to our knowledge, up to now, no early
transition-metal-catalyzed hydroaminoalkylation of an
alkene or a styrene that leads to the formation of the
industrially important linear product as the major product of
the reaction has been reported.[7] In addition, hydroaminoal-
kylation reactions of styrenes with dialkylamines or N-
alkylanilines possessing alkyl groups larger than a methyl
group have never been achieved.
À
efficient (100%) reaction that allows the addition of the a-C
À
H bond of an amine across a C C double bond (Scheme 1).
To expand the substrate scope of the hydroaminoalkyla-
tion of alkenes, we recently performed a number of corre-
sponding transformations with N-methylated aminoheteroar-
omatics as substrates in the presence of the precatalyst
[Ti(NMe2)4]. During these unsuccessful attempts we observed
that the addition of 2-(methylamino)pyridine (2-MeAP-H) to
a bright yellow solution of the alkene and the precatalyst
[Ti(NMe2)4] in toluene results in a significant color change to
dark red which suggests a fast formation of titanium
complexes with 2-aminopyridinato ligands,[8] such as [(2-
MeAP)2Ti(NMe2)2] or [(2-MeAP)Ti(NMe2)3] (Scheme 2). In
this context, it must be noted that Kempe has already
synthesized the complex [(2-MeAP)2Ti(NMe2)2] by amine
Scheme 1. [Ind2TiMe2]-catalyzed hydroaminoalkylation.[6d]
As the formed a-alkylated amines are of great industrial
importance it is not surprising that a number of hydro-
aminoalkylation catalysts have already been identified.[2–6]
Successful hydroaminoalkylation reactions of alkenes can be
achieved in the presence of ruthenium,[2] iridium,[3] Group 5
metals,[4] zirconium,[5] or titanium catalysts[6] but the use of
ruthenium and iridium catalysts is limited to amine substrates
possessing a directing 2-pyridinyl substituent bound to the
nitrogen atom of the amine.[2,3] While in the presence of
Group 5 metal catalysts or [Ind2TiMe2] (Ind = h5-indenyl), the
hydroaminoalkylation of 1-alkenes, such as 1-octene (2), with
secondary amines, such as N-methylaniline (1), always gives
the branched product 3a exclusively (Scheme 1), the corre-
sponding [Ind2TiMe2]-catalyzed reaction of styrene (4) also
leads to the formation of the linear product 5b as a side
product.[6d] Unfortunately, successful [Ind2TiMe2]-catalyzed
hydroaminoalkylation reactions could only be achieved with
N-methylanilines and in this context, it must also be
mentioned that by using Group 5 metal catalysts only
[*] J. Dçrfler, Prof. S. Doye
Institut fꢀr Reine und Angewandte 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. We further thank Jessica Reimer for her
great experimental help.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206027.
Scheme 2. Detection of in situ generated 2-aminopyridinato titanium
complexes by 1H NMR spectroscopy.[10]
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elimination from [Ti(NMe2)4] and 2 equivalents of 2-MeAP-
H.[9] In agreement with Kempeꢀs result, we were able to detect
by H NMR spectroscopy that stirring of a 1:2 mixture of
is almost identical to the result of a control experiment
performed with 10 mol% [(2-MeAP)2Ti(NMe2)2][9] which was
synthesized according to Kempeꢀs procedure (Table 1,
entry 9).[11]
1
[Ti(NMe2)4] und 2-MeAP-H in toluene or n-hexane at room
temperature results in the selective formation of the complex
[(2-MeAP)2Ti(NMe2)2] (Scheme 2).[10] In contrast, an analo-
gous experiment performed with a 1:1 mixture of [Ti(NMe2)4]
und 2-MeAP-H did not give the expected complex [(2-
MeAP)Ti(NMe2)3] selectively. In this case, a statistical mix-
ture of [(2-MeAP)Ti(NMe2)3], [(2-MeAP)2Ti(NMe2)2], and
the precursor [Ti(NMe2)4] in a ratio of approximately 1:1:1
was formed.
Because 2-aminopyridinato Ti-complexes have never
been used as catalysts for hydroaminoalkylation reactions of
alkenes, we investigated whether the in situ generated com-
plexes are able to catalyze the hydroaminoalkylation of
styrene (4) with N-methylaniline (1). For that purpose,
mixtures of [Ti(NMe2)4] (10 mol%) and 2-MeAP-H (10 or
20 mol%) in toluene were stirred at 258C for 15 h and after
addition of N-methylaniline and styrene, the mixtures were
heated to 1058C for 96 h (Table 1, entries 2 and 3). Fortu-
nately and in contrast to a corresponding reaction performed
in the absence of 2-MeAP-H (Table 1, entry 1), it was possible
to isolate the desired products 5a and 5b in combined yields
of 55 and 10%. Particularly important is that these two
experiments represent the first examples of a hydroaminoal-
kylation performed with N-methylaniline in which the linear
product 5b is formed in larger quantities than the branched
product 5a. A brief optimization study then revealed that
a simple elevation of the reaction temperature to 1408C and
a change of the solvent to n-hexane significantly improve the
combined yields to 79 and 76% (Table 1, entries 8 and 9). In
this context, it is of note that the result obtained with
a mixture of 10 mol% [Ti(NMe2)4] and 20 mol% 2-MeAP-H
A comparison of the results obtained with 10 and
20 mol% 2-MeAP-H in Table 1 leads to the conclusion that
the use of 20 mol% 2-MeAP-H mostly results in a better
regioselectivity in favor of the linear product 5b but a reduced
overall yield of the reaction. In addition, it becomes clear that
with increasing temperature, the regioselectivity of the
reaction decreases while the yield increases. Under optimized
conditions (Table 1, entry 8), it was finally possible to obtain
the products 5a and 5b in 79% combined yield with
a regioselectivity of 32:68 in favor of the linear product 5b.
The control experiments performed in the absence of 2-
MeAP-H which are also presented in Table 1 (entries 1,4,7)
impressively show that in comparison with [Ti(NMe2)4], the
in situ generated 2-aminopyridinato titanium catalysts have
a significantly improved catalytic activity.
We next turned our attention towards hydroaminoalkyla-
tion reactions of styrene (4) with various other amines
(Table 2). All corresponding reactions were performed in
sealed Schlenk tubes at 1408C for 96 h with n-hexane as the
solvent and the catalysts were generated in situ from
10 mol% [Ti(NMe2)4] and 10 or 20 mol% 2-MeAP-H.
During these studies, it was recognized that the hydro-
aminoalkylation of styrene (4) can not only be achieved with
N-methylanilines (Table 2, entries 1–8) but also with N-ethyl-,
N-propyl-, and N-benzylaniline (Table 2, entries 9–14) as well
as with dialkylamines (Table 2, entries 15–24). A comparison
of the regioselectivities observed with the N-alkylanilines 1, 9,
10, and 11 reveals that the regioselectivity in favor of the
linear product increases with increasing size of the N-alkyl
substituent. Correspondingly, the best selectivities of ꢀ 91:9 in
favor of the linear product were observed with N-propyl- (10)
and N-benzylaniline (11). In these cases, moderate to good
yields of 48% and 85% could be achieved (Table 2, entries 11
and 13). In contrast to the strong influence of the N-alkyl
substituent on the regioselectivity of the reaction, ortho-
substitution or donor- and acceptor substituents on the
benzene ring of the N-methylanilines are less important for
the regioselectivity but on the other hand, strongly influence
the reactivity of the amine (Table 2, entries 1–8). Particularly
interesting is the fact that for the first time, hydroaminoalky-
lation reactions of styrene (4) could also be achieved with
dialkylamines (Table 2, entries 15–24). As observed before
with the N-alkylanilines, preferred formation of the linear
product (up to 93:7) took place in all cases and at least some
reactions gave good yields (up to 71%). However, it must be
mentioned that prior to isolation, the products obtained from
dialkylamines were converted into para-toluenesulfonamides.
Interestingly, reactions of the unsymmetrically substituted
amines N-methylcyclohexylamine (12) and N-methylhexyl-
amine (13) took place at the methyl group of the amine
selectively while the alkylation of N-methylbenzylamine (14)
only occurred in the benzyl position. These findings are in
good agreement with results described by Schafer et al.[4e]
Finally, analogous hydroaminoalkylation reactions using
N-methylaniline (1) were performed with various other
Table 1: Hydroaminoalkylation of styrene (4) with N-methylaniline (1).[10]
Entry
2-MeAP-H
[mol%]
Solvent
T [8C]
Yield
Selectivity
5a+5b [%][a]
5a/5b[b]
1
2
3
4
5
6
7
8
9
–
toluene
toluene
toluene
toluene
toluene
toluene
n-hexane
n-hexane
n-hexane
105
105
105
140
140
140
140
140
140
–
55
10
11
78
41
6
–
10
20
–
10
20
–
39:61
23:77
39:61
46:54
34:66
42:58
32:68
34:66
10
20
79
76[c]
[a] Reaction conditions: N-methylaniline (1, 2.0 mmol), styrene (4,
3.0 mmol), [Ti(NMe2)4] (0.2 mmol, 10 mol%), 2-MeAP-H (0.2 mmol,
10 mol% or 0.4 mmol, 20 mol%), solvent (1.0 mL), T, 96 h. Yields refer
to the total yield of isolated product (5a+5b). [b] GC analysis prior to
chromatography. [c] A control experiment performed with 10 mol% [(2-
MeAP)2Ti(NMe2)2] gave a comparable result (76%, 5a/5b=33:67).
2
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Table 2: Hydroaminoalkylation of styrene (4).[10]
Table 3: Hydroaminoalkylation of various alkenes.[10]
Entry
Alkene
2-MeAP-H
[mol%]
Yield
Selectivity
a+b [%][a]
a/b[b]
Entry
Amine
2-MeAP-H
[mol%]
Yield
Selectivity
1
2
10
20
49 (37a/b)
43 (37a/b)
44:56
45:55
a+b [%][a]
a/b[b]
1
2
10
20
79 (5a/b)
76 (5a/b)
32:68
34:66
3
4
10
20
31 (38a/b)
9 (38a/b)
19:81
4:96
3
4
10
20
31 (17a/b)[c]
4 (17a/b)
32:68
33:67
5
6
10
20
– (39a/b)
– (39a/b)
–
–
5
6
10
20
31 (18a/b)
2 (18a/b)
43:57
30:70
7
8
10
20
69 (40a/b)
21 (40a/b)
89:11
93:7
7
8
10
20
50 (19a/b)
15 (19a/b)
35:65
25:75
9
10
20
10
20
91 (41a/b)
15 (41a/b)
85 (42a/b)
30 (42a/b)
90:10
81:19
93:7
10
11
12
9
10
10
20
61 (20a/b)
21:79
21:79
32 (20a/b)[d]
93:7
13
14
10
20
99 (3a/b)
90 (3a/b)
70 (43)[c]
97:3
94:6
11
12
10
20
48 (21a/b)
4 (21a/b)
9:91
1:99
15
16
10
20
–
–
91 (43)
13
14
10
20
85 (22a/b)
30 (22a/b)
8:92
7:93
17
18
10
20
– (44)
– (44)
–
–
19
20
10
20
16 (45a)
6 (45a)
>99:1
>99:1
15
16
10
20
71 (23a/b)[e,f]
60 (23a/b)[e,f,g]
42:58
27:73
[a] Reaction conditions: N-methylaniline (1, 2.0 mmol), alkene
(3.0 mmol), [Ti(NMe2)4] (0.2 mmol, 10 mol%), 2-MeAP-H (0.2 mmol,
10 mol% or 0.4 mmol, 20 mol%), n-hexane (1.0 mL), 1408C, 96 h.
Yields refer to the total yield of isolated product (a+b). The reaction
conditions were not separately optimized for each substrate. [b] GC
analysis prior to chromatography. [c] In addition, double alkylation of the
amine occurred in the a-position to the nitrogen atom in 26% yield.
17
18
10
20
22 (24a/b)[e,f]
5 (24a/b)[e,f]
20:80
12:88
19
20
21
22
10
20
10
20
69 (25a/b)[e,h]
40 (25a/b)[e,h]
5 (26a/b)[e]
7:93
35:65
12:88
12:88
17 (26a/b)[e]
23
24
10
20
26 (27a/b)[e]
8 (27a/b)[e]
15:85
12:88
the yield of the hydroaminoalkylation reaction strongly
depends on the electronic and steric properties of the styrene
substrate. Whereas the electron-donating para-methoxy
group of the styrene 30 totally prevents the hydroaminoalky-
lation reaction, the electron-withdrawing para-CF3 group of
29 seems to result in a preferred formation of the linear
product 38b. In contrast to the reactions of styrenes, all
experiments performed with 1-alkenes (Table 3, entries 7–14)
delivered the branched products in large excess and good to
very good yields could always be achieved. Of the disubsti-
tuted alkenes investigated (34–36), only norbornene (34) gave
a satisfactory result (91% yield).
In summary, our studies have shown that 2-aminopyridi-
nato titanium complexes generated in situ from [Ti(NMe2)4]
and 2-(methylamino)pyridine are efficient catalysts for the
hydroaminoalkylation of alkenes and styrenes. With these
catalysts, it is possible for the first time to achieve transition-
metal-catalyzed hydroaminoalkylation reactions of styrenes
[a] Reaction conditions: amine (2.0 mmol), styrene (4, 3.0 mmol),
[Ti(NMe2)4] (0.2 mmol, 10 mol%), 2-MeAP-H (0.2 mmol, 10 mol% or
0.4 mmol, 20 mol%), n-hexane (1.0 mL), 1408C, 96 h. Yields refer to the
total yield of isolated product (a+b). The reaction conditions were not
separately optimized for each substrate. [b] GC analysis prior to
chromatography. [c] In addition, double alkylation of the amine occurred
in the a-position to the nitrogen atom in 5% yield. [d] A control
experiment performed with 10 mol% [(2-MeAP)2Ti(NMe2)2] gave a com-
parable result (33%, 20a/20b=20:80). [e] The products were isolated
after derivatization as the corresponding para-toluenesulfonamides.
[f] The reaction took place at the methyl group of the amine exclusively.
[g] A control experiment performed with 10 mol% [(2-MeAP)2Ti(NMe2)2]
gave a comparable result (57%, 23a/23b=25:75). [h] The reaction took
place at the benzyl position of the amine exclusively.
styrenes and alkenes (Table 3). As can be seen from the
results of the experiments performed with the electronically
and sterically modified styrenes 28–30 (Table 3, entries 1–6),
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2010, 82, 1503 – 1515; g) G. Zi, F. Zhang, H. Song, Chem.
Commun. 2010, 46, 6296 – 6298; h) A. L. Reznichenko, T. J.
Emge, S. Audçrsch, E. G. Klauber, K. C. Hultzsch, B. Schmidt,
Organometallics 2011, 30, 921 – 924; i) A. L. Reznichenko, K. C.
Hultzsch, J. Am. Chem. Soc. 2012, 134, 3300 – 3311.
with dialkylamines or N-alkylanilines bearing alkyl groups
larger than a methyl group. Particularly noteworthy is that the
industrially important linear hydroaminoalkylation products
can be obtained as the major products of the reactions.
[5] Zirconium catalysts: J. A. Bexrud, P. Eisenberger, D. C. Leitch,
P. R. Payne, L. L. Schafer, J. Am. Chem. Soc. 2009, 131, 2116 –
2118.
Received: July 27, 2012
Revised: September 19, 2012
Published online: && &&, &&&&
[6] Titanium catalysts: a) C. Mꢁller, W. Saak, S. Doye, Eur. J. Org.
Chem. 2008, 2731 – 2739; b) R. Kubiak, I. Prochnow, S. Doye,
Angew. Chem. 2009, 121, 1173 – 1176; Angew. Chem. Int. Ed.
2009, 48, 1153 – 1156; c) I. Prochnow, R. Kubiak, O. N. Frey, R.
Beckhaus, S. Doye, ChemCatChem 2009, 1, 162 – 172; d) R.
Kubiak, I. Prochnow, S. Doye, Angew. Chem. 2010, 122, 2683 –
2686; Angew. Chem. Int. Ed. 2010, 49, 2626 – 2629; e) I.
Prochnow, P. Zark, T. Mꢁller, S. Doye, Angew. Chem. 2011,
123, 6525 – 6529; Angew. Chem. Int. Ed. 2011, 50, 6401 – 6405;
f) D. Jaspers, W. Saak, S. Doye, Synlett 2012, 23, 2098 – 2102.
[7] In the presence of ruthenium and iridium catalysts, N-(2-
pyridinyl)alkylamines can be converted selectively into the
linear hydroaminoalkylation products (see Refs. [2] and [3]).
[8] For Reviews on metal complexes with 2-aminopyridinato
ligands, see: a) R. Kempe, Eur. J. Inorg. Chem. 2003, 791 – 803;
b) R. Kempe, N. Hoss, T. Irrgang, J. Organomet. Chem. 2002,
647, 12 – 20; c) R. Kempe, Z. Anorg. Allg. Chem. 2010, 636,
2135 – 2147.
À
Keywords: alkenes · amines · aminopyridines · C H activation ·
titanium
.
[1] For a Review on the hydroaminoalkylation of alkenes, see: P. W.
Roesky, Angew. Chem. 2009, 121, 4988 – 4991; Angew. Chem. Int.
Ed. 2009, 48, 4892 – 4894.
[2] 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.
[3] Iridium catalysts: S. Pan, K. Endo, T. Shibata, Org. Lett. 2011, 13,
4692 – 4695.
[4] Group 5 metal catalysts: a) M. G. Clerici, F. Maspero, Synthesis
1980, 305 – 306; b) W. A. Nugent, D. W. Ovenall, S. J. Holmes,
Organometallics 1983, 2, 161 – 162; c) S. B. Herzon, J. F. Hartwig,
J. Am. Chem. Soc. 2007, 129, 6690 – 6691; d) S. B. Herzon, J. F.
Hartwig, J. Am. Chem. Soc. 2008, 130, 14940 – 14941; e) P.
Eisenberger, R. O. Ayinla, J. M. P. Lauzon, L. L. Schafer, Angew.
Chem. 2009, 121, 8511 – 8515; Angew. Chem. Int. Ed. 2009, 48,
8361 – 8365; f) P. Eisenberger, L. L. Schafer, Pure Appl. Chem.
[9] R. Kempe, Z. Kristallogr. New Cryst. Struct. 1997, 212, 477 – 478.
[10] For experimental details, see the Supporting Information.
[11] Because all attempts to selectively synthesize [(2-MeAP)Ti-
(NMe2)3] failed so far, no analogous control experiment could be
performed with this complex.
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Hydroaminoalkylation
J. Dçrfler, S. Doye*
&&&& — &&&&
Aminopyridinato Titanium Catalysts for
the Hydroaminoalkylation of Alkenes and
Styrenes
The linear product is formed as the major
product when in situ generated titanium
complexes with aminopyridinato ligands
are used as catalysts for hydroaminoal-
kylation reactions of styrenes (see
the use of N-methylanilines and for the
first time can be performed with N-
alkylanilines bearing alkyl groups larger
than methyl, or even with dialkylamines.
The best selectivities in favor of a linear
product are better than 90:10.
scheme). The reaction is not limited to
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