[Ind2TiMe2]: A catalyst for the hydroaminomethylation of alkenes and styrenes

Article abstract of DOI:10.1002/anie.200906557

(Chemical Equation Presentation) Metal-catalyzed hydroaminomethylations of styrenes, which take place by C-H bond activation, can be achieved in the presence of the catalyst [Ind₂TiMe₂] (Ind = η⁵-indenyl). Corresponding reactions of l-alkenes with N-methylanilines performed at temperatures between 80°C and 105°C usually take place with regioselectivities of better than 99:1 in favor of the branched product.

Full text of DOI:10.1002/anie.200906557

Communications
DOI: 10.1002/anie.200906557
Titanium Catalysis
[Ind2TiMe2]: A Catalyst for the Hydroaminomethylation of Alkenes
and Styrenes**
Raphael Kubiak, Insa Prochnow, and Sven Doye*
Owing to the great biological and industrial importance of
nitrogen-containing molecules, much research has focused on
the development of efficient methods for the synthesis of
amines for a long time. Among various synthetic strategies,
the hydroamination of alkenes and alkynes[1] and the hydro-
aminoalkylation of alkenes[2–7] must be regarded as partic-
ularly promising because both processes offer a direct and
highly atom-efficient (100%) conversion of simple starting
À
À
materials into more complex molecules by C N or C C bond
formation. During a hydroaminoalkylation reaction of an
Scheme 1. Formation of regioisomers during intermolecular hydroami-
nomethylation reactions of alkenes performed with titanium or tanta-
lum catalysts.
À
alkene, the a-C H bond of a primary or a secondary amine
undergoes an addition across a C C double bond, which
À
results in an alkylation of the amine in the a position to the
nitrogen atom. Whilst simple tantalum catalysts[3,4] were
reactions and the results with styrenes may be improved by
performing the reactions under milder conditions, we rein-
vestigated the catalytic performance of [Ti(NMe2)4] and
[Ind2TiMe2] (Ind = h5-indenyl), because with these two cata-
lysts, the initially observed titanium-catalyzed hydroaminoal-
kylation reactions took place as side reactions during
attempted intramolecular hydroaminations at a temperature
of only 1058C.[10]
Initial intermolecular hydroaminoalkylation reactions of
1-octene (2) with N-methylaniline (1) performed in toluene[11]
at temperatures of 1608C or 1058C for 96 h in the presence of
10 mol% of [Ti(NMe2)4] or [Ind2TiMe2] revealed that only
[Ind2TiMe2] is catalytically active at 1058C (Table 1,
entries 1–4). Surprisingly, it was also found that with
[Ind2TiMe2] as the catalyst, the branched isomer 3a is
À
initially used for this C H activation process, corresponding
enantioselective reactions could recently be achieved in the
presence of chiral tantalum amidate complexes.[5] An addi-
tional class of suitable catalysts for hydroaminoalkylation
reactions of alkenes are complexes of the Group 4 metals.[6,7]
However, it must be noted that zirconium catalysts can only
be used for intramolecular reactions of primary aminoal-
kenes,[7] whereas titanium catalysts, such as [Ti(NMe2)4] or
[TiBn4], catalyze intra- and intermolecular reactions,[6] and
furthermore, titanium complexes show a higher catalytic
activity than their zirconium counterparts. Upon inspection of
intermolecular hydroaminoalkylation reactions of 1-alkenes
reported in the literature, it becomes clear that the use of
titanium catalysts usually results in the formation of two
regioisomeric products (branched and linear; Scheme 1),
whereas the branched regioisomer is formed exclusively in
the presence of tantalum catalysts. Another interesting point
is that efficient intermolecular hydroaminoalkylation reac-
tions of styrenes have not been reported to date.[8] A possible
explanation for this fact could be that hydroaminoalkylation
reactions are usually performed under harsh reaction con-
ditions (temperatures of 130–1658C)[9] under which styrenes
tend to undergo polymerization reactions.
Table 1: Intermolecular titanium-catalyzed hydroaminomethylation of
1-octene (2) with N-methylaniline (1).
Entry Catalyst
mol%
10
T
t
Yield 3a+3b
Selectivity 3a/
[8C] [h] [%][a]
3b[b]
1
[Ti(NMe2)4] 10
160 96 32
105 96 <5
93:7
n.d.
Based on the simple assumption that the regioselectivity
of titanium-catalyzed intermolecular hydroaminoalkylation
2
3
4
5
6
7
8
9
[Ind2TiMe2] 10
160 96
105 96
105 24
105 24
90 24
84
97
96
96
81
86
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
n.d.
10
10
5
5
5
[*] R. Kubiak, I. Prochnow, Prof. Dr. S. Doye
Institut fꢀr Reine und Angewandte Chemie, Universitꢁt Oldenburg
Carl-von-Ossietzky-Strasse 9–11, 26111 Oldenburg (Germany)
Fax: (+49)441-798-3329
80 24
70 24 <5
5
10
11
2
1
105 24
105 24
90
6
>99:1
n.d.
E-mail: doye@uni-oldenburg.de
[**] We thank the Deutsche Forschungsgemeinschaft (DFG) and the
Fonds der Chemischen Industrie for financial support of our
research. Ind=h5-indenyl.
[a] Reaction conditions: amine (2.0 mmol), alkene (3.0 mmol), catalyst,
toluene (1 mL), T, t. Yields refer to the total yield of isolated product
(3a+3b). [b] GC analysis prior to chromatography under conditions
where a ratio of 99.5:0.5 could be detected. n.d.=not determined.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906557.
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Angew. Chem. Int. Ed. 2010, 49, 2626 –2629

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Chemie
Table 2: Intermolecular hydroaminomethylation of 1-octene (2) with
N-methylanilines.
formed with a regioselectivity of better than 99:1 at both
1608C and at 1058C. These promising results inspired us to
perform a number of additional experiments with reduced
reaction time, temperature, and catalyst loading, which led to
the finding that the product 3a is still formed in 86% yield
and with unchanged regioselectivity when the reaction is
performed for 24 h with 5 mol% [Ind2TiMe2] at a temper-
ature of only 808C (Table 1, entry 8). To the best of our
knowledge, a corresponding metal-catalyzed hydroaminoal-
kylation of an alkene has never been reported to occur at such
a low temperature.[9] However, a subsequent experiment
performed at 708C revealed that the reaction no longer takes
place at this temperature. On the other hand, it was possible
to reduce the catalyst loading to only 2 mol% in a corre-
sponding experiment performed at 1058C. After a reaction
time of 24 h, 3a was still obtained in 90% yield (Table 1,
entry 10). Although almost identical results (96%) were
obtained in corresponding experiments with 5 mol% and
10 mol% [Ind2TiMe2], a further reduction of the catalyst
loading to 1 mol% resulted in low conversion and a yield of
only 6% (Table 1, entry 11). In general, all the reactions took
place smoothly, and we were not able to detect the formation
of any side products by GC.
With these results in hand, we then tried to react a number
of amines with 1-octene (1) under the convenient conditions
that are shown in Table 1, entry 6 (5 mol% [Ind2TiMe2],
1058C, 24 h). However, at an early stage of this investigation,
it became clear that successful reactions can only be achieved
with N-methylanilines (Table 2). No conversion was observed
with primary amines, dialkylamines, and N-ethyl- or N-
propylanilines[12] under the chosen reaction conditions.
Among the various N-methylanilines investigated, best
results were obtained with substrates that possess methyl or
fluoro substituents on the benzene ring. In these cases, yields
of at least 84% and regioselectivities of more than 99:1 in
favor of the branched product were always achieved. How-
ever, an ortho-methyl substituent of the aniline is not
tolerated, and similar behavior was found for a strong
electron acceptor (CF3) and an electron donor (OMe) in the
para position. In contrast, the para-chloro-substituted N-
methylaniline 8 underwent a slow reaction under the chosen
reaction conditions, which finally gave access to the branched
product 15a in 16% yield (Table 2, entry 6). This yield could
easily be improved to 43% by performing the reaction with an
increased catalyst loading of 10 mol% and a reaction time of
96 h. Interestingly an identical observation was made during
the reaction between styrene (18) and N-methylaniline (1;
Table 3, entries 1–3). Although a corresponding reaction
performed at 1058C for 24 h in the presence of 5 mol%
[Ind2TiMe2] gave a yield of only 13%, a simple extension of
the reaction time to 96 h led to an increased yield of 71%. An
additional increase in yield to 91% could be achieved by
increasing the catalyst loading to 10 mol%. With regard to the
reactions performed with 1-octene (2), the regioselectivity of
the hydroaminoalkylation of styrene (18) slightly drops to
only 85:15 in favor of the branched product 30a. Again, the
reactions took place smoothly, and it was not possible to
detect any side products in the crude reaction mixtures. In all
cases, only the desired hydroaminomethylation products 30a
Entry Amine
Branched product
Yield
a+b
[%][a]
Selectivity
a/b[b]
1
2
96
95
>99:1
>99:1
3
84
>99:1
4
5
6
7
8
<5
96
n.d.
>99:1
>99:1
n.d.
16[c]
<5
<5
n.d.
[a] Reaction conditions: amine (2.0 mmol), alkene (3.0 mmol),
[Ind2TiMe2] (0.1 mmol, 5 mol%), toluene (1 mL), 1058C, 24 h. Yields
refer to the total yield of isolated product (a+b). [b] GC analysis prior to
chromatography under conditions where a ratio of 99.5:0.5 could be
detected. n.d.=not determined. [c] A yield of 43% was obtained with
10 mol% [Ind2TiMe2] after a reaction time of 96 h.
and 30b were detected by GC together with unconsumed
styrene (18). Overall, this reaction is the first example of an
efficient metal-catalyzed hydroaminomethylation of a sty-
rene. Additional transformations of the styrenes 19–25 with
N-methylaniline (1, Table 3, entries 4–10) performed under
identical reaction conditions revealed that many styrenes
undergo successful hydroaminomethylation reactions in the
presence of [Ind2TiMe2]. Only the reactions of the ortho-
ortho-disubstituted styrene 23 and the CF3-substituted sty-
rene 25 gave yields of less than 5%. In contrast, the para-
alkyl-, para-aryl-, and para-methoxy-substituted styrenes 19–
21 and 24 underwent successful hydroaminomethylation
reactions with high yields (95–99%) and regioselectivities of
82:18 or more in favor of the respective branched product
(Table 3, entries 4–6, 9). Even the ortho-methyl-substituted
styrene 22 gave the desired products 34a and 34b with a
regioselectivity of 75:25 in 94% yield (Table 3, entry 7). If this
regioselectivity is compared with the regioselectivity
observed with the comparable ortho-unsubstituted substrate
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Communications
Table 3: Intermolecular hydroaminomethylation of alkenes with N-meth-
ylaniline (1).
conditions, corresponding reactions of the 1-alkenes 26 and 27
gave the desired branched products 38a and 39a with
excellent yields of 93% and 92%, respectively (Table 3,
entries 11, 12). In particular, the regioselectivity of more than
99:1 observed with alkene 27 that can be seen as a
“tetrahydrostyrene” is worthy of attention because this
result is much better than the selectivity observed (85:15)
with the corresponding styrene 18. From these data, one can
draw the conclusion that electronic reasons are responsible
for the decreased regioselectivity observed with styrenes.
Experiments performed with norbornene (28) and allylben-
zene (29) clearly indicated that better yields (83% and 94%)
have already been reported for these substrates.[6]
Entry Alkene
mol%
t
[h]
Branched product
Yield Selectivity
a+b
a/b[b]
[%][a]
1
2
3
5
5
10
24
96
96
13
71
91
85:15
85:15
85:15
Further attempted intramolecular reactions of secondary
aminoalkenes performed at 1058C in the presence of the
catalyst [Ind2TiMe2] (Scheme 2) did not give access to the
4
5
10
10
96
96
99
97
90:10
87:13
6
7
8
9
10
10
10
10
96
96
96
96
97
94
82:18
75:25
n.d.
<5
95
Scheme 2. Double-bond migration during attempted intramolecular
hydroaminoalkylation reactions performed in the presence of
[Ind2TiMe2].
92:8
10
11
12
10
10
10
96
96
96
<5
n.d.
desired cyclopentyl- or cyclohexylamines. Instead of a hydro-
À
aminoalkylation reaction, an isomerization of the C C
À
double bond, which is probably caused by a competing C H
93
>99:1
bond activation in the allylic position, always occurred.
In summary, it was shown for the first time that efficient
metal-catalyzed hydroaminomethylation reactions of styr-
enes can be achieved in the presence of titanium catalysts.
Furthermore, [Ind2TiMe2] was identified as a catalyst that is
catalytically active at temperatures as low as 808C. With this
catalyst, 1-alkenes react with N-methylanilines to give the
corresponding branched hydroaminomethylation products
with very high regioselectivity.
92[c] >99:1
13
14
10
10
96
96
12
40
n.d.
92:8
[a] Reaction conditions: amine (2.0 mmol), alkene (3.0 mmol),
[Ind2TiMe2], toluene (1 mL), 1058C, t. Yields refer to the total yield of
isolated product (a+b). [b] GC analysis prior to chromatography under
conditions where a ratio of 99.5:0.5 could be detected. n.d.=not
determined. [c] Two diastereomers in a ratio of 85:15.
Received: November 20, 2009
Revised: December 18, 2009
Published online: March 2, 2010
À
Keywords: alkenes · amines · C H activation ·
.
homogeneous catalysis · titanium
19 (90:10), it becomes clear that an increasing steric demand
of the aryl ring of the styrene supports the formation of the
linear product. However, the finding that the regioselectiv-
ities of hydroaminomethylation reactions of the para-substi-
tuted styrenes 19–21 and 24 also vary significantly (from 92:8
to 82:18) clearly indicates that not only pure steric effects but
also electronic factors influence the regioselectivity of the
reaction.
[1] For a recent review on hydroamination of alkenes and alkynes,
see: T. E. Mꢀller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada,
Chem. Rev. 2008, 108, 3795 – 3892.
[2] Review: P. W. Roesky, Angew. Chem. 2009, 121, 4988 – 4991;
Angew. Chem. Int. Ed. 2009, 48, 4892 – 4894.
[3] 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.
Although successful transformations of a- and b-methyl-
styrene and indene could not be achieved under analogous
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[4] a) S. B. Herzon, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129,
6690 – 6691; b) S. B. Herzon, J. F. Hartwig, J. Am. Chem. Soc.
2008, 130, 14940 – 14941.
[5] P. Eisenberger, R. O. Ayinla, J. M. P. Lauzon, L. L. Schafer,
Angew. Chem. 2009, 121, 8511 – 8515; Angew. Chem. Int. Ed.
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[6] a) R. Kubiak, I. Prochnow, S. Doye, Angew. Chem. 2009, 121,
1173 – 1176; Angew. Chem. Int. Ed. 2009, 48, 1153 – 1156; b) I.
Prochnow, R. Kubiak, O. N. Frey, R. Beckhaus, S. Doye,
ChemCatChem 2009, 1, 162 – 172.
[9] With [{Cl3Ta(NMePh)2}2] as the catalyst, a successful hydro-
aminoalkylation (1-ocetene + N-methylaniline) could be ach-
ieved at a temperature of only 908C; see Ref. [4b].
[10] C. Mꢀller, W. Saak, S. Doye, Eur. J. Org. Chem. 2008, 2731 –
2739.
[11] For the corresponding reaction between allylbenzene and
N-methylaniline, comparable yields are obtained in various
solvents, such as toluene, xylenes, 1,4-dioxane, n-heptane or
diphenyl ether: N. Bruns, BSc Thesis, Universitꢁt Oldenburg,
2009.
[12] A possible explanation for the fact that, among the substance
class of N-alkylamines, only N-methylamines undergo successful
reactions could be that a sterically more demanding N-alkyl
substituent prevents alkene insertion into the carbon–titanium
bond of a titanaaziridine, which is assumed to be the catalytically
active species. For plausible suggestions regarding the mecha-
nism of the hydroaminoalkylation reaction, see Refs [4–7].
[7] J. A. Bexrud, P. Eisenberger, D. C. Leitch, P. R. Payne, L. L.
Schafer, J. Am. Chem. Soc. 2009, 131, 2116 – 2118.
[8] The general feasibility of a titanium-catalyzed hydroaminoalky-
lation of styrene has already been demonstrated using [TiBn4] as
the catalyst; see Ref. [6b].
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