Titanium-catalyzed intermolecular hydroamination of vinylarenes

Article abstract of DOI:10.1002/anie.200501423

(Chemical Equation Presented) The Lewis acid TiCl₄ allows the intermolecular hydroamination of vinylarenes (see scheme). Some of the hydroamination products undergo rearrangements to give ortho-alkylated compounds. The catalyst tolerates a rang

Full text of DOI:10.1002/anie.200501423

Communications
Hydroamination
simple Brønsted acid mediated reaction is not operative
(entries 3 and 4). These results are in agreement with
observations made by Hartwiget al., who found that even
the intramolecular addition of amines, not bearingan
electron-withdrawinggroup, does not occur in the presence
of concentrated sulfuric acid.[33,34]
DOI: 10.1002/anie.200501423
Titanium-Catalyzed Intermolecular
Hydroamination of Vinylarenes**
Under the above reaction conditions, mixtures of hydro-
amination and ortho-hydroarylation products were obtained.
While the reaction time for quantitative conversion could be
reduced significantly with microwave irradiation, the amount
Ludwig T. Kaspar, Benjamin Fingerhut, and
Lutz Ackermann*
Table 1: Hydroamination of vinylarenes 1 with 4-chloroaniline (2a).[a]
Most substituted amines are made
today by multistep syntheses.
Therefore, addition reactions of
simple amines onto unsaturated
carbon–carbon multiple bonds,
hydroamination reactions,[1–6] are
of considerable importance for
industry and academia. Transforma-
tions of alkynes and allenes can be
catalyzed by a variety of reagents.[7]
However, protocols for intermolec-
ular hydroamination reactions of
more readily available olefins have
thus far proven limited. Various
lanthanide complexes catalyze
Entry
Reagent
R
t [h]
3/4[b]
Yield 3
Yield 4
[%][c]
[%][c]
1
2
3
4
5
6
7
8
9
TiCl4
–
H2SO4
4-ClC6H4NH3Cl
Cp2TiCl2
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
Me (1b)
Me (1b)
F (1c)
22
22
22
22
61:39
–
30 (3a)
–
–
–
–
–
–
40 (3b)
–
29 (3c)
32 (4a)
–
–
–
–
61 (4a)
52 (4a)
40 (4b)
68 (4b)
37 (4c)
–
–
–
22
4[d]
22[e]
22
13:87
16:84
41:59
7:93
42:68
hydroamination
reactions
of
alkenes, but they lack compatibility
with a number of important func-
2[d]
6[d]
tional
groups.[8,9]
Significant
10
research activity has focused on
the use of late-transition-metal
[a] Reaction conditions: 1 (1 mmol), 2a (4 mmol), toluene (2 mL), 1308C. [b] By GC analysis. [c] Yields
of isolated product. [d] With microwave irridiation. [e] 1.0 equiv TiCl4.
complexes
for
intermolecular
hydroamination reactions of olefins,
[10–12]
featuringiridium,
rhodium,[13–18] nickel,[19,20] palla-
of hydroarylation product increased (entries 6, 9, and 10). As
the ortho-alkylated product was also predominantly formed
when stoichiometric amounts of the Lewis acid TiCl4 were
employed (entry 7), we wondered if a rearrangement of the
hydroamination product occurs. Accordingly, we synthesized
secondary amine 3a independently through a palladium-
catalyzed amination reaction[35] and subjected it to the
hydroamination reaction conditions [Eq. (1)]. Indeed, the
secondary amine 3a was quantitatively converted, while the
primary amine 4a remained unchanged under the reaction
conditions [Eq. (2)].
dium,[21–24] platinum,[25,26] and ruthenium.[27,28] The high cost
of these complexes, their stabilizingligands, or the additives
constitute a limitation of these protocols. Recently, we
reported a Group 4 metal catalyzed[29] intermolecular[30]
hydroamination of norbornene.[31] Herein we present tita-
nium-catalyzed[32] hydroamination reactions of vinylarenes as
well as an application of this procedure to the synthesis of a
tetrahydroisoquinoline.
Initial experiments showed that catalytic amounts of the
Lewis acid TiCl4 converted styrene (1a) in the presence of
four equivalents of 4-chloroaniline (2a) efficiently at 1308C
(Table 1, entry 1). Control experiments indicated that a
[*] Dipl.-Chem. L. T. Kaspar, B. Fingerhut, Dr. L. Ackermann
Ludwig-Maximilians-Universität München
Department of Chemistry and Biochemistry
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)089-2180-77425
Subsequently, we studied the scope of the catalytic
intermolecular hydroamination of styrene derivatives
(Table 2). A number of vinylarenes 1 and aniline derivatives
2 were efficiently converted with catalytic amounts of TiCl4,
leadingto the functionalized products in high yields. Elec-
tron-poor amines underwent more efficient reactions
E-mail: Lutz.Ackermann@cup.uni-muenchen.de
[**] We thank Professor Paul Knochel, the DFG (Emmy Noether-
Programm), the Fonds der Chemischen Industrie, and the Ludwig-
Maximilians-Universität for generous support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Titanium-catalyzed hydroamination of vinylarenes 1.[a]
Entry
R
R’
Amine
t [h]
3/4[b]
Yield 3
Yield 4
Yield 3+4
[%][c]
[%][c]
[%][c]
1
2
3
4
5
6
7
8
9
H
Cl
F
H
H
H
H
H
H
H (1a)
H (1d)
H (1c)
H (1a)
H (1a)
H (1a)
H (1a)
Me (1e)
H (1a)
H (1 f)
H (1a)
3,5-(CF3)2C6H3NH2 (2b)
3,5-(CF3)2C6H3NH2 (2b)
3,5-(CF3)2C6H3NH2 (2b)
2-CNC6H4NH2 (2c)
2,4-Br2C6H3NH2 (2d)
4-FC6H4NH2 (2e)
3,5-(CH3)2C6H3NH2 (2 f)
2-ClC6H4NH2 (2g)
2,4,6-Cl3C6H2NH2 (2h)
2,4-Br2C6H3NH2 (2d)
3,5-(CF3)2C6H3NH2 (2b)
30
30
30
>99:1
99:1
>99:1
91:9
7:93
32:68
8:92
<1:99
–
<1:99
>99:1
87 (3d)
68 (3e)
81 (3 f)
62 (3g)
–
–
–
–
87
68
81
62
65
68
50
85
–
22[d,e]
20[d]
3[f,g]
20[g,h]
19[d]
16[g]
22
–
65 (4h)
47 (4i)
50 (4j)
85 (4k)
–
21 (3i)
–
–
–
10
11
OMe
H
–
51 (4l)
–
51
85
22[i]
85 (3d)
[a] Reaction conditions: 1 (1 mmol), 2 (4 mmol), TiCl4 (20 mol%), toluene (2 mL). [b] By GC analysis. [c] Yields of isolated product. [d] 1308C. [e] 1a
(4 mmol), 2c (1 mmol). [f] With microwave irridiation. [g] 1708C. [h] TiCl4 (1 mmol). [i] HfCl4 (20 mol%).
double bond yielded the desired tetrahydroisoquinoline 7
with excellent regioselectivity and a diastereoselectivity of
4:1.[39]
In summary, we have described a protocol for titanium-
catalyzed hydroamination reactions of styrene derivatives. A
subsequent rearrangement gives rise to ortho-alkylated
products. The catalytic system was applied to the synthesis
of a tetrahydroisoquinoline derivative.
(entries 1–6). A variety of functional groups was tolerated by
the catalyst, such as CF3 (entries 1–3), Cl (entry 2), CN
(entry 4), F (entries 3 and 6), and Br substituents (entries 5
Experimental Section
and 10). Additionally, a-methylstyrene (1e) was quantita-
tively converted into product 4k, which contains a quarter-
nary carbon center (entry 8). Interestingly, di-ortho-substi-
tuted aniline 2h was not converted (entry 9).[31] In the
reaction of aniline 2b catalytic amounts of the Lewis acid
HfCl4 led to comparable results (entry 11).
Finally, we applied the titanium-catalyzed hydroamina-
tion reaction to a regioselective synthesis of a tetrahydroiso-
quinoline (Scheme 1).[36] The highly regio- and chemoselec-
tive titanium-catalyzed hydroamination[37,38] of enyne 5 and
subsequent one-pot reduction gave aminoalkene 6 in good
yield. Intramolecular hydroamination of the remaining
Representative procedure for titanium-catalyzed hydroamination: A
sealed tube was equipped with a septum and purged with N2. The tube
was charged with dry toluene (2 mL), 3,5-bis(trifluoromethyl)aniline
(2b; 917 mg, 4.00 mmol), and styrene (1a; 104 mg, 1.00 mmol). TiCl4
(0.022 mL, 0.20 mmol, 20 mol%) was added, the tube was sealed, and
the resultingmixture was stirred for 30 h at 110 8C. CH2Cl2 (5 mL),
Et2O (60 mL), aq NH4OH (1n, 15 mL), and brine (50 mL) were
added to the cold suspension. The separated aqueous phase was
washed with Et2O (2 ” 60 mL). The combined organic phases were
dried over MgSO4 and concentrated in vacuo. Purification by column
chromatography (silica gel, n-pentane/Et2O 100:1) yielded N-1-
phenylethyl-3,5-bis(trifluoromethyl)aniline (3d) as
a yellow oil
(290 mg, 87%).
Received: April 25, 2005
Published online: August 12, 2005
Keywords: alkenes · catalysis · heterocycles · hydroamination ·
.
titanium
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Scheme 1. Titanium-catalyzed synthesis of tetrahydroisoquinoline 7.
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5973

Communications
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