Titanium-catalyzed hydroaminoalkylation of alkenes by C-H bond activation at sp3 centers in the α-position to a nitrogen atom

Article abstract of DOI:10.1002/anie.200805169

(Chemical Equation Presented) Good for primary and secondary amines: Hydroaminoalkylations of alkenes, which take place by C-H bond activation in the α-position to nitrogen atoms, are catalyzed by various neutral titanium complexes (see scheme). Primary a

Full text of DOI:10.1002/anie.200805169

Angewandte
Chemie
DOI: 10.1002/anie.200805169
À
C H Activation
À
Titanium-Catalyzed Hydroaminoalkylation of Alkenes by C H Bond
Activation at sp3 Centers in the a-Position to a Nitrogen Atom**
Raphael Kubiak, Insa Prochnow, and Sven Doye*
Hydroaminations of alkynes and alkenes[1] have attracted
much attention during the past few years. Both transforma-
tions allow the synthesis of nitrogen-containing molecules in a
single step with 100% atom efficiency. Besides other metal
catalysts,[1] titanium complexes have been used extensively for
these reactions.[2–4] Recently, we recognized during a study of
the Ti-catalyzed intramolecular hydroamination of alkenes
that the cyclization of 1-amino-5-hexenes to piperidines
(Scheme 1) performed with the catalysts [Ti(NMe2)4] or
analogy to the formation of aminocyclopentane side products
during Ti-catalyzed hydroaminations is obvious. For this
reason, we became interested in whether Ti complexes such as
[Ti(NMe2)4] and [Ind2TiMe2] can generally be used as
catalysts for selective hydroaminoalkylations of alkenes. To
our knowledge and with the exception of the mentioned side
reaction,[4d] corresponding Ti-catalyzed reactions have never
been reported.[10]
One possibility to suppress the intramolecular hydro-
À
amination that competes with the desired C H activation
process is to use a 1-amino-6-heptene as the substrate. In this
case, the hydroamination would lead to an unfavorable seven-
À
membered ring, while the C H bond activation reaction
would give a favored six-membered ring. Correspondingly, it
can be expected that the desired aminocyclohexane will be
formed selectively. Initial studies carried out with 1-amino-
2,2-dimethyl-6-heptene (1, Scheme 2) and 5 mol%
À
Scheme 1. Formation of an aminocyclopentane side product by C H
bond activation during a Ti-catalyzed hydroamination of a 1-amino-5-
hexene. [a] Two diastereomers, cis/trans=4:1. Ts=toluene-4-sulfonyl.
[Ind2TiMe2] (Ind = indenyl) takes place along with the
formation of aminocyclopentane side products.[4d] Interest-
ingly, a corresponding catalytic C H bond activation[5] at the
À
sp3 center in the a-position to a primary amino group has
never been observed before during a Ti-catalyzed hydro-
amination.[6] However, this reaction would represent a very
useful chemical transformation if it can be achieved selec-
tively, because it offers a direct and highly atom-efficient
conversion of simple amines to more complex molecules
Scheme 2. Selective formation of an aminocyclohexane from a
1-amino-6-heptene. [a] Two diastereomers, cis/trans=2:5.
[Ti(NMe2)4] or [Ind2TiMe2] revealed that the formation of
the desired aminocyclohexane 2 is slow at 1058C (less than
10% conversion in 24 h, as determined by GC). However,
when [Ti(NMe2)4] was used as the catalyst, an increase of the
reaction temperature (1608C) and a longer reaction time
À
through C C bond formation.
A related example of C H bond activation[5] at sp3 centers
À
in the a-position to nitrogen atoms[7,8] is the [Ta(NMe2)5]-
catalyzed intermolecular hydroaminoalkylation of alkenes
described by Hartwig and Herzon.[9] Although only secondary
N-arylated alkyl amines have been used for this reaction and
[Zr(NMe2)4] was found to be catalytically inactive, the
À
(72 h) resulted in the formation of the C H activation
product 2, which could be isolated after conversion to the
corresponding p-toluenesulfonamide derivative
3 (46%
yield). Particularly interesting is the fact that the formation
of the hydroamination product, an azepane, has not been
observed during the entire study performed with substrate 1.
This result indicates that Ti catalysts are able to convert
1-amino-6-heptenes at elevated temperatures selectively to
aminocyclohexanes and that for this purpose no protection of
the primary amino group is necessary.
Because secondary amines usually do not undergo Ti-
catalyzed hydroamination,[3,4a] an alternative possibility to
suppress the hydroamination that competes with the desired
[*] 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
E-mail: doye@uni-oldenburg.de
[**] We thank the Deutsche Forschungsgemeinschaft (DFG) and the
Fonds der Chemischen Industrie for financial support of our
research. We further thank Kerstin Grꢁbe for the preparation of
[{(h5-C5H4)(Me2Si)NtBu}Ti(NMe2)2].
À
C H activation process is the conversion of the primary
amino group to a secondary amino group. For that reason and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805169.
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because N-arylated alkyl amines have been found to be
and styrene (15; Table 1, entries 4, 5) did not show any
conversion, a significantly improved yield was obtained for
the addition of N-methylaniline (8) to 1-octene (12) when the
reaction was run in the absence of a solvent and with a larger
excess of the alkene (six equivalents, Table 1, entries 1, 2).
Subsequently, we investigated the addition of the slightly
modified N-alkyl anilines 9–11 to the representative alkenes
1-octene (12) and 3-phenylpropene (13, Table 1, entries 7–
12). Interestingly, even small alterations of the N-alkyl
substituent (Table 1, entries 7–10) strongly influence the
particularly good substrates for the hydroaminoalkylations
described by Hartwig et al., we tried to convert the
N-arylated aminoalkenes 4 and 6 (Scheme 3) to the amino-
À
efficiency of the C H activation process, while changes at
the N-aryl substituent (Table 1, entries 1, 3, 7, 8) are less
significant. Correspondingly, successful hydroaminoalkyla-
tions could only be achieved with N-methyl- and N-benzyl-
substituted aryl amines (8, 9, 11). On the other hand, reactions
of N-propylaniline 10 as well as experiments with dialkyl
amines (e.g. piperidine) have not been successful yet. Addi-
tionally, and in contrast to the intramolecular reaction
(Scheme 2), intermolecular hydroaminoalkylations with pri-
mary amines could not be achieved so far.
Scheme 3. Formation of aminocyclopentanes and aminocyclohexanes
from N-aryl aminoalkenes.
Finally, we investigated the catalytic properties of various
other titanium complexes. For this purpose, we chose the
hydroaminoalkylation of 1-octene (12) with N-methylaniline
(8) as a test reaction (Table 2). Surprisingly, and in contrast to
the generally accepted view that Ti complexes do not catalyze
corresponding reactions,[10] we found that many neutral Ti
complexes are suitable catalysts for intermolecular hydro-
cyclopentane and aminocyclohexane derivatives 5 and 7.
Unfortunately, it turned out that reactions performed with
10 mol% [Ti(NMe2)4] give the desired products in only poor
yields (not more than 26%). Furthermore, an isomerization
À
aminoalkylations of alkenes, which take place by C H bond
À
of the C C double bond that results in the formation of the
activation. Particularly promising for future studies is the fact
that not only the yield but also the regioselectivity of the
reaction is strongly influenced by the nature of the Ti catalyst.
For example, the use of the ansa complex [{(h5-C5H4)-
(Me2Si)NtBu}Ti(NMe2)2] (Table 2, entry 4) results in a sig-
corresponding internal alkene takes place almost exclusively
when [Ind2TiMe2] is used as the catalyst. Additionally, it was
found that N-arylated aminoalkenes that are geminally
disubstituted in the b-position to the nitrogen atom do not
undergo the desired hydroaminoal-
kylation reaction at all.
Table 1: Intermolecular hydroaminoalkylation of alkenes in the presence of [Ti(NMe2)4].[a]
To clarify whether N-arylated
secondary amines are generally
poor substrates for the Ti-catalyzed
À
C H activation reaction, we inves-
tigated the addition of N-methylani-
line (8) to 1-octene (12), 3-phenyl-
propene (13), methylenecyclohex-
ane (14), styrene (15), and norbor-
nene (16, Table 1, entries 1–6) in the
presence of 10 mol% [Ti(NMe2)4].
Surprisingly, we found that the
desired hydroaminoalkylation prod-
ucts are formed in modest to good
yields (up to 94%) in reactions that
employ 1-octene (12), 3-phenylpro-
pene (13), and norbornene (16;
Table 1, entries 1–3, 6). In case of
the terminal alkenes 12 and 13, two
regioisomers were formed, and the
branched product (a) was always
obtained as the major product with
high selectivity (90:10). While cor-
responding reactions performed
Entry Amine R1
R2
Alkene R3
R4 Product Yield a+b [%][b] Selectivity a/b[c]
1
2
8
8
H
H
H
H
H
H
H
H
H
H
12
12
13
14
15
n-C6H13
n-C6H13
Bn
-(CH2)5-
Ph
H
H
H
17a/b
17a/b
18a/b
19a/b
20a/b
21
22a/b
23a/b
24a/b
25a/b
26a/b
27a/b
32
62[d]
94
–
90:10
90:10
90:10
–
–
–
95:5
95:5
–
3
8
H
4
8
H
5
8
H
H
–
6
8
H
norbornene (16)
78
20
80
–
7
8
9
9
Me
Me
12
13
12
13
n-C6H13
Bn
n-C6H13
Bn
H
H
H
H
H
H
9
10
10
11
11
Me Et
Me Et
H
H
10
11
12
–
–
Ph 12
Ph 13
n-C6H13
Bn
75
84
1:1
1:1
[a] Reaction conditions: amine (2.0 mmol), alkene (3.0 mmol), [Ti(NMe2)4] (0.2 mmol, 10 mol%),
toluene (1 mL), 1608C, 96 h, Bn=benzyl. [b] Yields refer to the total yield of isolated product (a+b).
[c] GC analysis prior to chromatography. [d] Reaction conditions: amine (1.0 mmol), alkene (6.0 mmol),
with methylenecyclohexane (14) [Ti(NMe2)4] (0.04 mmol, 4 mol%), 1608C, 72 h.
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Table 2: Hydroaminoalkylation of 1-octene (12) with N-methylaniline (8)
in the presence of various Ti-catalysts.[a]
[1] For recent reviews on hydroamination of alkenes and alkynes,
see: a) T. E. Mꢀller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada,
Chem. Rev. 2008, 108, 3795 – 3892; b) J.-J. Brunet, N.-C. Chu, M.
Rodriguez-Zubiri, Eur. J. Inorg. Chem. 2007, 4711 – 4722; c) R.
Severin, S. Doye, Chem. Soc. Rev. 2007, 36, 1407 – 1420; d) R. A.
Widenhoefer, X. Han, Eur. J. Org. Chem. 2006, 4555 – 4563.
[2] For reviews on Ti-catalyzed hydroamination of alkenes and
alkynes, see: a) A. V. Lee, L. L. Schafer, Eur. J. Inorg. Chem.
2007, 2243 – 2255; b) A. Odom, Dalton Trans. 2005, 225 – 233;
c) S. Doye, Synlett 2004, 1653 – 1672; d) I. Bytschkov, S. Doye,
Eur. J. Org. Chem. 2003, 935 – 946.
[3] For selected examples of Ti-catalyzed hydroaminations of
alkynes, see: a) E. Haak, I. Bytschkov, S. Doye, Angew. Chem.
1999, 111, 3584 – 3586; Angew. Chem. Int. Ed. 1999, 38, 3389 –
3391; b) I. Bytschkov, S. Doye, Tetrahedron Lett. 2002, 43, 3715 –
3718; c) D. Mujahidin, S. Doye, Eur. J. Org. Chem. 2005, 2689 –
2693; d) K. Marcsekovꢁ, B. Wegener, S. Doye, Eur. J. Org. Chem.
2005, 4843 – 4851; e) K. Grꢂbe, F. Pohlki, S. Doye, Eur. J. Org.
Chem. 2008, 4815 – 4823; f) C. Cao, J. T. Ciszewski, A. L. Odom,
Organometallics 2001, 20, 5011 – 5013; g) D. L. Swartz II, A. L.
Odom, Organometallics 2006, 25, 6125 – 6133; h) A. Tillack, H.
Jiao, I. Garcia Castro, C. G. Hartung, M. Beller, Chem. Eur. J.
2004, 10, 2409 – 2420; i) A. Tillack, V. Khedkar, H. Jiao, M.
Beller, Eur. J. Org. Chem. 2005, 5001 – 5012; j) L. Ackermann,
R. G. Bergman, R. N. Loy, J. Am. Chem. Soc. 2003, 125, 11956 –
11963; k) M. L. Buil, M. A. Esteruelas, A. M. Lꢃpez, A. C.
Mateo, E. Oꢄate, Organometallics 2007, 26, 554 – 565; l) C. Li,
R. K. Thomson, B. Gillon, B. O. Patrick, L. L. Schafer, Chem.
Commun. 2003, 2462 – 2463; m) Z. Zhang, L. L. Schafer, Org.
Lett. 2003, 5, 4733 – 4736.
Entry Catalyst
Yield
Selectivity
17a/
17a+17b
[%][b]
17b[c]
1
2
3
4
[Ti(NMe2)4]
[Cp2TiMe2]
[Ind2TiMe2]
62
3
16
77
90:10
n.d.[d]
n.d.[d]
[{(h5-C5H4)(Me2Si)NtBu}Ti-
(NMe2)2]
>99:1
5
6
[{(h5-C5H4)(Me2Si)NtBu}TiMe2]
[(ebthi)TiMe2]
75
–
>99:1
–
[a] Reaction conditions: amine 8 (1 mmol), alkene 12 (6 mmol), catalyst
(0.04 mmol, 4 mol%), 1608C, 72 h. Cp=cyclopentadienyl, ebthi=
ethylen-1,2-bis(h5-4,5,6,7-tetrahydro-1-indenyl). [b] Yields refer to the
total yield of isolated product (17a+17b). [c] GC analysis prior to
chromatography. [d] Not determined.
nificantly increased yield (77%) compared to the result
obtained with [Ti(NMe2)4] (62%). Fortunately, this improve-
ment is accompanied by an increased regioselectivity of
greater than 99:1 in favor of the branched product 17a. Both
findings suggest a great potential for further optimization.
Although no mechanistic studies have been carried out to
[4] For recent examples of Ti-catalyzed hydroaminations of alkenes,
see: a) M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak, L. L.
Schafer, Angew. Chem. 2007, 119, 358 – 362; Angew. Chem. Int.
Ed. 2007, 46, 354 – 358; b) K. Marcsekovꢁ, S. Doye, Synlett 2007,
2564 – 2568; c) J. A. Bexrud, C. Li, L. L. Schafer, Organometal-
lics 2007, 26, 6366 – 6372; d) C. Mꢀller, W. Saak, S. Doye, Eur. J.
Org. Chem. 2008, 2731 – 2739; e) S. Majumder, A. L. Odom,
Organometallics 2008, 27, 1174 – 1177; f) A. L. Gott, A. J.
Clarke, G. J. Clarkeson, P. Scott, Chem. Commun. 2008, 1422 –
1424.
À
date, we believe that the Ti-catalyzed C H activation takes
place by a process similar to the mechanism proposed by
Hartwig,[9] Nugent, et al.[10b] This idea is strongly supported by
the fact that enantiomerically pure amines possessing a chiral
center adjacent to the nitrogen atom racemize in the presence
of neutral Ti catalysts.[11]
In summary, we have shown that various neutral Ti
complexes are suitable catalysts for intra- and intermolecular
hydroaminoalkylations of alkenes, which take place by C H
À
[5] For reviews on C H activation, see: a) F. Kakiuchi, S. Murai, in
Activation of Unreactive Bonds and Organic Synthesis (Ed.: S.
Murai), Springer, Berlin, 1999, pp. 47 – 79; b) S.-I. Murahashi, H.
Takaya, Acc. Chem. Res. 2000, 33, 225 – 233; c) Handbook of C-
H Transformations (Ed.: G. Dyker), Wiley-VCH, Weinheim,
2005; d) A. R. Dick, M. S. Sanford, Tetrahedron 2006, 62, 2439 –
2463; e) M. Tobisu, N. Chatani, Angew. Chem. 2006, 118, 1713 –
1715; Angew. Chem. Int. Ed. 2006, 45, 1683 – 1684; f) J.-Q. Yu, R.
Giri, X. Chen, Org. Biomol. Chem. 2006, 4, 4041 – 4047; g) R. G.
Bergman, Nature 2007, 446, 391 – 393.
À
bond activation in the a-position to nitrogen atoms. Partic-
ularly interesting is the fact that primary and secondary
amines can be used as substrates.
Experimental Section
General procedure exemplified by the reaction of 8 with 13 (Table 1,
entry 3): Under an atmosphere of nitrogen,
N-methylaniline (8, 214 mg, 2.0 mmol), allylbenzene (13, 354 mg,
3.0 mmol), [Ti(NMe2)4] (44 mg, 0.2 mmol, 10 mol%), and toluene
(1 mL) was heated to 1608C for 96 h. The crude product was purified
by flash chromatography (SiO2, n-hexane/EtOAc, 20:1) to give a
mixture of the regioisomers 18a and 18b (424 mg, 94%, 18a/18b
90:10) as a clear, colorless oil.
[6] Related side reactions have been observed in base-catalyzed
hydroaminations of styrenes with amine substrates possessing
a mixture of
À
acidified a-C H bonds: P. Horrillo-Martꢅnez, K. C. Hultzsch, A.
Gil, V. Branchadell, Eur. J. Org. Chem. 2007, 3311 – 3325.
À
[7] For reviews on catalytic C H activation in the a-position to an
N atom, see: a) K. R. Campos, Chem. Soc. Rev. 2007, 36, 1069 –
1084; b) S. Doye, Angew. Chem. 2001, 113, 3455 – 3457; Angew.
Chem. Int. Ed. 2001, 40, 3351 – 3353.
[8] a) C.-H. Jun, D.-C. Hwang, S.-J. Na, Chem. Commun. 1998,
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Ishii, F. Kakiuchi, S. Murai, J. Am. Chem. Soc. 2000, 122, 12882 –
12883; c) S.-I. Murahashi, N. Komiya, H. Teraki, Angew. Chem.
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2006, 128, 14220 – 14221; e) N. Chatani, T. Asaumi, T. Ikeda, S.
Yorimitsu, Y. Ishii, F. Kakiuchi, S. Murai, J. Am. Chem. Soc.
Received: October 22, 2008
Published online: December 30, 2008
À
Keywords: alkenes · amines · C H activation ·
.
homogeneous catalysis · titanium
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Communications
2000, 122, 12882 – 12883; f) A. J. Catino, J. M. Nichols, B. J.
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[10] It was reported that [Ti(NMe2)4] does not catalyze the hydro-
aminoalkylation of 1-hexene and 1-pentene with dimethyl-
amine: 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.
[11] F. Pohlki, I. Bytschkov, H. Siebeneicher, A. Heutling, W. A.
Kꢇnig, S. Doye, Eur. J. Org. Chem. 2004, 1967 – 1972.
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