Controlling selectivity: From Markovnikov to anti-Markovnikov hydroamination of alkynes

Article abstract of DOI:10.1016/j.tetlet.2004.09.168

A remarkable control of regioselectivity is achieved for the titanium-catalyzed intermolecular hydroamination of various alkynes. Proper choice of the ligand enables a selectivity switch from the Markovnikov to the anti-Markovnikov products from M:anti-M = > 90:10 to >10:90. Depending on the catalyst a remarkable control of regioselectivity is achieved for the titanium-catalyzed intermolecular hydroamination of various alkynes. Proper choice of sterically hindered phenol ligands such as 1 and 4 enables a selectivity switch from the Markovnikov to the anti-Markovnikov products from M:anti-M = > 90:10 to > 10:90.

Full text of DOI:10.1016/j.tetlet.2004.09.168

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8875–8878
Controlling selectivity: from Markovnikov to anti-Markovnikov
hydroamination of alkynes
Annegret Tillack, Vivek Khedkar and Matthias Beller*
Leibniz-Institut fu¨r Organische Katalyse (IfOK) an der Universita¨t Rostock e.V., Buchbinderstr. 5-6, D-18055 Rostock, Germany
Received 27 September 2004;revised 28 September 2004;accepted 28 September 2004
Available online 14 October 2004
Abstract—Depending on the catalyst a remarkable control of regioselectivity is achieved for the titanium-catalyzed intermolecular
hydroamination of various alkynes. Proper choice of sterically hindered phenol ligands such as 1 and 4 enables a selectivity switch
from the Markovnikov to the anti-Markovnikov products from M:anti-M = > 90:10 to > 10:90.
Ó 2004 Elsevier Ltd. All rights reserved.
The addition of nitrogen and oxygen compounds across
carbon–carbon multiple bonds continues to be an
important subject for organic synthesis and catalysis.1
In general, these processes are perfectly suited to fulfill
todayÕs need of green chemistry because of availability
of substrates, and 100% atom efficiency. By using
unsymmetrical olefins or alkynes the addition reaction
can lead to two isomeric products. Typically, most of
the electrophilic addition reactions follow the Markov-
nikov rule, in which the branched compound is
mainly produced. However, often the linear isomer is a
desired product for industrial applications, which needs
an anti-Markovnikov functionalization. Although
major advances have been made in the last decades in
a number of functionalization reactions, for example,
hydroformylation, hydrocarboxylation, hydrocyana-
tion, by the introduction of tailor-made transition metal
complexes, still significant challenges exist with respect
to control of selectivity. Clearly, control of selectivity
is an important basis for application and further innova-
tions in organic synthesis.
ity. Important progress in the intermolecular hydroami-
nation of alkynes with titanium complexes has been
reported by Bergman and co-workers,4 Doye and co-
workers,5 Odom and co-workers,6 us,7 and others.8
Here, we report that by addition of different phenol lig-
ands to Ti(NEt2)4 the regio- and chemo-selectivity of
hydroaminations of terminal alkynes can be controlled.
A remarkable selectivity switch from the usual Mark-
ovnikov to the anti-Markovnikov product is obtained
by slightly varying the ligand structure.
Recently, we have discovered that bis(2,6-di-tert-butyl-
4-methylphenoxo)-bis(dimethylamido)titanium
cata-
lyzes the selective Markovnikov hydroamination of
terminal alkynes.9 The easy handling, stability, and
generality of the catalyst system stimulated further work
using other aryloxotitanium complexes for this type of
reaction. With regard to practicability we formed the
corresponding aryloxotitanium complexes in situ from
commercially available Ti(NEt2)4 and phenols 1–4
(Scheme 1).
For some time we have been involved in the develop-
ment and exploration of new methods for selective ami-
nation of olefins and alkynes. Apart from carbonylative
amination (hydroaminomethylations) of olefins,2 the di-
rect hydroamination of alkynes attracted our interest.
Among the different catalysts3 known for alkyne hydro-
aminations, especially titanium complexes have found
widespread interest due to their reactivity and availabil-
OH
OH
OH
OH
3
4
1
2
*
Scheme 1. Aryloxo ligands for titanium-catalyzed amination of
alkynes.
Corresponding author. Tel.: +49 0381 4669313;fax: +49 0381
4669324;e-mail: matthias.beller@ifok.uni-rostock.de
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.168

8876
A. Tillack et al. / Tetrahedron Letters 45 (2004) 8875–8878
Table 1. Intermolecular hydroamination of 1-octyne with sec-butyl-
amine using (Et2N)4Ti and ligand 1–4a
Table 2. Intermolecular hydroamination of 1-octyne with different
amines using (Et2N)4Ti and ligand 1 in comparison with ligand 4a
10 mol% (Et2N)4Ti
10 mol% (Et2N)4Ti
NsBu
nHex
anti-Markovnikov Markovnikov
(anti-M) (M)
NsBu
NR'
NR'
/ 20 mol% L
/ 20 mol% L
nHex
+
sBuNH2
+
H
nHex
+
R'NH2
nHex
+
H
nHex
toluene, 100 °C
toluene ,100 °C
H
nHex
H
Markovnikov
(M)
anti-Markovnikov
(anti-M)
R' = Bn, nBu, sBu, cyclo-C8H15, tBu, Ph
Entry Ligand Conversion (%) Yieldb (%) Anti-M:M ratioc
Entry Ligand Amine
Conv. Yieldb Anti-M:M
(%)
(%)
ratioc
1
2
3
4
1
2
3
4
100
100
100
100
98
97
88
97
10:90
49:51
72:28
94:6
1
1
4
1
4
1
4
4
4
1
4
1
1
4
1
1
4
Benzylamine
Benzylamine
100
100
100
100
100
100
100
97
99
72
99
82
98
97
98
95
99
94
50
58
44
99
96
86
20:80
86:14
25:75
92:8
2
3
n-Butylamine
n-Butylamine
sec-Butylamine
sec-Butylamine
sec-Butylamine
sec-Butylamine
a Reaction conditions: 1.5mmol 1-octyne, 1.8mmol amine, 10mol%
catalyst, Ti/L = 1:2, 2mL toluene, 100°C, 24h.
4
5
10:90
94:6
94:6
b Yield is determined by GC analysis with dodecane or hexadecane as
internal standard, reaction conditions are not optimized.
c GC analysis is used to determine the ratio of regioisomers.
6
7d
8e
9
94:6
14:86
94:6
Cyclooctylamine 100
Cyclooctylamine 100
10
11
12f
13
14
15f
16
tert-Butylamine
tert-Butylamine
tert-Butylamine
Aniline
50
75
74:26
88:12
99:1
In the first experiments, the addition of sec-butylamine
to 1-octyne was studied as a model reaction (Table
1).10 In general, the hydroamination was run in toluene
at 100°C in the presence of 10mol% of Ti(NEt2)4, and
20mol% of the corresponding phenol. It is important
to note that only sterically hindered phenols show signif-
icant catalyst activity. By employing simple phenol or
cresols as ligand no activity is observed due to the for-
mation of stable tris- and tetrakisphenoxy titanium
complexes. However, in agreement with our previous
studies the use of bulky 2,6-di-tert-butyl-4-methylphenol
1 gave an excellent yield (98%) and a high Markovnikov
selectivity (anti-M/M = 10:90). When using 2,6-diphe-
nylphenol 2 to our surprise the selectivity significantly
dropped and a 1:1-mixture of regioisomers is obtained.
In the presence of 4,6-dimethyl-2-tert-butylphenol 3
the anti-Markovnikov product becomes the major
regioisomer (anti-M/M = 72:28), and an excellent anti-
Markovnikov selectivity (94:6) is obtained using 2,6-
diisopropylphenol 4 as ligand. Apparently, it is possible
by slight changes of the ligand structure to reverse the
regioselectivity of the amination reaction, a phenome-
non which has been rarely observed until today. Because
of the very similar steric and electronic nature of 1 and 4
the origin of this unusual selectivity shift is not yet clear.
54
100
100
100
22:78
20:80
34:66
Aniline
Aniline
a Reaction conditions: 1.5mmol 1-octyne, 1.8mmol amine, 10mol%
catalyst, Ti/L = 1:2, 2mL toluene, 100°C, 24h, reaction conditions
are not optimized.
b Yield is determined by GC analysis with dodecane or hexadecane as
internal standard.
c GC analysis is used to determine regioisomers.
d 85°C.
e 5mol% catalyst, 1mL toluene.
f Ti:L = 1:1.
On the other hand the use of ligand 1 led preferentially
to the formation of Markovnikov imines, albeit with
somewhat lower selectivity. Applying aniline, both in
the presence of 1 and 4 the Markovnikov isomer is
obtained preferentially. In this respect it is interesting
to note that recent theoretical investigations demon-
strated, that electrostatic stabilization favors the
Markovnikov performance for aromatic amines.7a
Furthermore we explored the scope of ligands 1 and 4 in
hydroaminations of other alkynes. Here, we have tested
the reaction of various aliphatic, aromatic, and func-
tionalized terminal alkynes with different aryl and alkyl
amines (Table 3). In most cases high conversion of the
alkyne and good yield of the imines are observed. Again,
except for sterically very hindered substrates, ligands 1
and 4 gave the corresponding products in opposite
regioselectivity.
Next, we were interested in the generality of the
observed effect (Tables 2 and 3). Hence, the behavior
of ligands 1 and 4 was tested in the reaction of 1-octyne
with other aromatic (aniline) and aliphatic amines
(benzylamine, n-butylamine, sec-butylamine, tert-butyl-
amine, cyclooctylamine). In all catalytic reactions a
slight excess of amine (1.2equiv) was employed in order
to suppress oligomerization and polymerization of the
alkynes. Nevertheless, in some cases small amounts of
aminated dimers, oligomers, and polymers of the alkyne
are observed. As shown in Table 2 the hydroamination
of 1-octyne proceeds in all cases with good to excellent
yield (72–99%), except for tert-butylamine, which is
less reactive because of the steric hindrance. With
aliphatic amines ligand 4 gave the corresponding anti-
Markovnikov imines in good to very good regioselectiv-
ity (anti-Markovnikov/Markovnikov = 86:14 up to
99:1).
For example, good yield and excellent anti-Mark-
ovnikov selectivity are obtained in the reaction of
1-phenyl-3-propyne or 3-cyclopentyl-1-propyne with
benzylamine and sec-butylamine using 4 (Table 3, en-
tries 1–4). Sterically hindered tert-butylamine reacted
only slowly with N,N-dimethylpropargylamine to give
exclusively the anti-Markovnikov product using both
ligands 1 and 4 (Table 3, entry 5). However, sterically
less hindered amines such as sec-butylamine reacted fas-

A. Tillack et al. / Tetrahedron Letters 45 (2004) 8875–8878
8877
Table 3. Intermolecular hydroamination of functionalized terminal alkynes with different amines using (Et2N)4Ti and ligand 1 in comparison with
ligand 4a
10 mol% (Et2N)4Ti
NR'
NR'
/ 20 mol% L
+
R'NH2
+
H
R
R
toluene, 100 °C
H
R
anti-Markovnikov Markovnikov
(anti-M)
(M)
Entry
1
Alkyne
Amine
Ligand
Conversion (%)
Yieldb (%)
Anti-M:M ratioc
NH2
1
4
100
100
83
74
33:67
92:8
NH2
2
1
4
100
100
97
96
32:68
96:4
NH2
3
4
5
1
4
100
100
91
71
10:90
80:20
NH2
1
4
100
100
97
96
5:95
95:5
Me
1
4
65
100
37
66
99:1
99:1
H2N
N
Me
Me
NH2
6
1
4
100
99
90
73
36:64
98:2
N
Me
NH2
TBDMSO
TBDMSO
7
8
1
4
100
100
85
70
13:87
75:25
NH2
1
4
100
100
98
92
16:84
95:5
NH2
9
1
4
58
100
43
93
97:3
98:2
TES
TES
10
1
4
12
98
10
98
99:1
99:1
H2N
a Reaction conditions: 1.5mmol alkyne, 1.8mmol amine, 10mol% catalyst, Ti/L = 1:2, 2mL toluene, 100°C, 24h, reaction conditions are not
optimized.
b Yield is determined by GC analysis with hexadecane as internal standard.
c GC analysis is used to determine the ratio of regioisomers.
ter with N,N-dimethylpropargylamine leading to the
Markovnikov or anti-Markovnikov product depending
on the ligand (Table 3, entry 6). Also reactions of alky-
nes containing protected hydroxy groups with benzyl-
amine or sec-butylamine gave good to excellent yield
(70–98%) and regioselectivity depending on the ligand
1 (Markovnikov) and 4 (anti-Markovnikov) (Table 3,
entries 7 and 8). In addition, the hydroamination of tri-
ethylsilylacetylene with cyclooctylamine or tert-butyl-
amine in the presence of 4 proceeded with very good
anti-Markovnikov selectivity and yield (Table 3, entries
9 and 10).
different sterically hindered phenoxy ligands. The reac-
tions can be easily performed and proceed with high
yield. Depending on the ligand (1 or 4) the Mark-
ovnikov or the anti-Markovnikov regioisomer is formed
with good to excellent selectivity. Such a control of reg-
ioselectivity has been rarely observed so far and pro-
vides an important basis for further applications of
this chemistry.
Acknowledgements
This work has been supported by the State of Mecklen-
burg-Western Pommerania, the BMBF (Bundesministe-
In conclusion, we presented a general titanium-catalyzed
hydroamination of terminal alkynes in the presence of
rium fur Bildung und Forschung) and the Fonds der
¨

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10. Preparative procedure for hydroamination: In an Ace-
pressure tube under an argon atmosphere ligand 4
(2.2mmol) was dissolved in 7.5mL toluene. To this
solution
sec-butylamine
(13.5mmol),
1-octyne
(11.3mmol), and Ti(NEt2)4 (1.1mmol) were added. The
pressure tube was fitted with a Teflon cap and heated at
100°C for 24h in an oil bath. Afterwards all volatiles were
removed in vacuo and distillation in vacuo afforded sec-
butyl-octylidene-amine as a colorless oil. Isolated yield:
1.45g (70%);bp 41–43 °C/0.1mbar. 1H NMR (CDCl3,
400MHz) d: 7.57 (t, J = 5.2Hz, 1H), 2.88 (sext, J = 6.5Hz,
1H), 2.20 (m, 2H), 1.46 (quint, J = 7.5Hz, 4H), 1.17–1.35
(m, 8H), 1.11 (d, J = 6.3Hz, 3H), 0.85 (m, 3H), 0.76 (t,
J = 7.5Hz, 3H). 13C NMR (CDCl3, 100MHz): 162.9, 67.9,
35.7, 31.7, 30.4, 29.2, 29.0, 26.4, 22.6, 22.4, 14.0, 11.0. MS
(EI, 70eV) m/z (rel. intensity): 183 (1) [M+], 154 (38)
[M+ ꢀC2H5], 112 (24), 99 (100) [C7H1þ5], 84 (44), 71 (15),
57 (50) [C4Hþ9 ]), 44 (52), 41 (75), 29 (47). FT IR (neat,
cmꢀ1): 1669 (C@N). HRMS Calcd. for C12H25N:
183.19870. Found: 183.19762.