Anti-Markovnikov hydroamination of terminal alkynes

Article abstract of DOI:10.1002/1521-3773(20020715)41:14<2541::AID-ANIE2541>3.0.CO;2-7

Titanocene-η-alkyne complexes such as 1 are efficient catalysts for the hydro-amination of terminal alkynes to imines (see scheme; R = alkyl, R′ = SiMe₃ or Ph). Excellent yields of imines and good to excellent regioselectivities for the anti-Markovnikov products were obtained.

Full text of DOI:10.1002/1521-3773(20020715)41:14<2541::AID-ANIE2541>3.0.CO;2-7

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product. Hence, various domino reactions (e.g. direct nucle-
ophilic addition of organometallic reagents) are possible,
which do not work in the presence of water.
The homogeneously catalyzed intermolecular hydroamina-
tion of alkynes is known to proceed in the presence of Hg and
Tl salts,[2] alkali metals (Cs),[3] Ti,[4] Zr,[5] Nd,[6] U, and Th[7]
complexes. In addition, complexes of late-transition metals
(such as Ru, Pd,[8] and Rh[9]) have been used as catalysts for
this transformation. Clearly, catalysts based on cheap and
easily available titanium and zirconium complexes offer
significant advantages compared to those based on toxic metals
(Hg, Tl) or more expensive (U, Th, Ru, Pd, and Rh) complexes.
Recently, important progress in the intermolecular hydro-
amination of alkynes with titanium complexes was made by
Johnson and Bergman[10] and by Doye and co-workers.[4]
While the former group developed the modified titanium
ˆ
complex [Cp(ArNH)(py)Ti NAr] (Cp ˆ cyclopentadienyl,
[28] Parameters: water: dipole moment 1.854 D,[30] polarizability 1.45 Â
10À24 cm3,[30] relative ion gauge sensitivity 0.97;[31] hexafluoroacetone:
dipole moment 0.395 D,[32] polarizability 7.5 Â 10À24 cm3 (estimation
based on the data for acetone and fluorinated methanes CHnF4Àn[30]),
relative ion gauge sensitivity 2.59.[31]
[29] J. N. Harvey, D. Schrˆder, W. Koch, D. Danovich, S. Shaik, H.
Schwarz, Chem. Phys. Lett. 1997, 273, 164 170.
[30] CRC Handbook of Chemistry and Physics, 79th ed. (Ed.: D. R. Lide),
CRC Press, Boca Raton, FL, 1998.
py ˆ pyridyl) and used it for the reaction of 2,6-dimethylani-
line and diphenylacetylene, the latter group described an
efficient and general method for the hydroamination of
various internal alkynes using dimethyltitanocene as a cata-
lyst. Bytschkov and Doye showed that the turnover frequency
of this catalyst can be enhanced by using microwaves.[4c]
Kinetic measurements by Bergman[10] and Doye[11] also
established a general mechanism of the dimethyltitanocene-
catalyzed intermolecular hydroamination of alkynes. Surpris-
ingly little attention was paid to the hydroamination of
terminal alkynes using titanium catalysts,[12] although the
regioselective, sequential amination and hydroxylation of
compounds that are unsaturated at the terminal position is
one of the most challenging goals for industrial catalysis. Herein
we report the first example of a titanocene-catalyzed anti-
Markovnikov hydroamination of terminal aliphatic alkynes.
Some time ago we started a program on catalytic amination
reactions of olefins and alkynes.[13, 9] Inspired by the work of
Doye and Bergman, we also recently looked for easily
available and stable titanocene complexes. Here, titanocene
[31] J. E. Bartmess, R. M. Georgiadis, Vacuum 1983, 33, 149 153.
[32] J. U. Grabow, N. Heineking, W. Stahl, Z. Naturforsch. A 1991, 46,
229 232.
[33] Note added in proof (June 3, 2002): Since the submission of this paper
À
several publications have appeared on C F bond activation; see for
example: K. Uneyama, H. Amii, J. Fluorine Chem. 2002, 114, 12 7
¬
131; K. Guennou de Cadenet, R. Rumin, F. Y. Petillon, D. S. Yufit,
K. W. Muir, Eur. J. Inorg. Chem. 2002, 639 657; D. Zhang, C. Liu, S.
Bi, J. Phys. Chem. A 2002, 106, 4153 4157.
Anti-Markovnikov Hydroamination of
Terminal Alkynes**
2
ꢀ
alkyne complexes of the type [Cp2Ti(h -Me3SiC CR)]
Annegret Tillack, Ivette Garcia Castro,
Christian G. Hartung, and Matthias Beller*
(Rosenthal×s catalyst)[14] appeared to be suited as amination
catalysts.[15] These complexes ([Cp2Ti(h -Me3SiC CSiMe3)]
2
ꢀ
Dedicated to Professor Dr. Lutz F. Tietze
on the occasion of his 60th birthday
1[14a] and [Cp2Ti(h -Me3SiC CPh] 2[14b]) are easily synthesized
2
ꢀ
by reaction of titanocene dichloride with the corresponding
silylated alkyne.
Imines are of significant importance as intermediates for
the synthesis of various amines and carbonyl compounds. In
general, the synthesis of imines includes amination of a
suitable aldehyde or ketone. A more atom-efficient route is
the direct hydroamination of alkynes.[1] This method has the
additional advantage that no water is produced as a by-
Compared to previously used titanocene precatalysts, the
titanacyclopropene complexes 1 and 2 are safe and stable
under argon at room temperature for many months in
German version. Indeed, hydroamination of internal alkynes
(diphenylacetylene, 1-phenylpropyne) with aniline or tert-
butylamine proceeds in excellent yields in the presence of 1
(81 98% yield after hydrolysis with HCl, Table 1). As shown
in Table 2, different terminal aliphatic alkynes react with tert-
butylamine with extremely high regioselectivity (>98%), in
high yields (84 98%), and within a short time (2 24 h), by
using 0.5 2.5 mol% of catalyst 1, to give the imines 4a e and
5. Although the reactions proceed smoothly with 0.5 mol% of
catalyst, we used 2.5 mol% in general because of the shorter
reaction time.
[*] Prof. Dr. M. Beller, Dr. A. Tillack, Dr. I. Garcia Castro,
Dr. C. G. Hartung
Institut f¸r Organische Katalyseforschung (IfOK)
Universit‰t Rostock e.V.
Buchbinderstrasse 5 6, 18055 Rostock (Germany)
Fax : (‡49)381-466-9324
E-mail: matthias.beller@ifok.uni-rostock.de
[**] We acknowledge financial support of this project from the Deutsche
Forschungsgemeinschaft (DFG) and the state of Mecklenburg-West
Pommerania. C. Mewes, Dr. C. Fischer, H. Baudisch, and S. Buchholz
are thanked for their excellent technical support.
Pleasingly, only the anti-Markovnikov products were ob-
tained, which is explained by the selective formation of the
Angew. Chem. Int. Ed. 2002, 41, No. 14
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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Table 1. Intermolecular hydroamination of internal alkynes in the pres-
selectively with anti-Markovnikov regiochemistry to yield the
1,8-bisimine 5. Phenylacetylene also reacts with high regiose-
lectivity to give the anti-Markovnikov product. Unfortunate-
ly, a preparative isolation of the corresponding linear imine
was not possible because of side reactions during distillation
of this product.
Apart from tert-butylamine, other aliphatic (sec-butyl-
amine, 3,3-dimethyl-2-butylamine), benzylic amines (a-meth-
ylbenzylamine), and aniline react with 1-hexyne to give
imines in high yields (Table 3). Except when using aniline, the
ence of 1.[a]
Alkyne
R
Amine
R'
Mole%
cat.
T
[8C]
Conversion
[%]
Yield
[%][b]
Ph
Ph
CH3
CH3
tBu
Ph
tBu
Ph
3.0
3.0
3.0
2.0
100
140
100
140
100
95
100
100
84 (3a)
92( 3b)
81 (3c)
98 (3d)
[a] Toluene, 24 h, amine/alkyne ˆ 1.5:1. [b] Determination of yield of the
corresponding ketone after hydrolysis of the imine (5% HCl) was by gas
chromatography with an internal standard.
Table 3. Hydroamination of 1-hexyne with different amines in the
presence of 1.
Table 2. Hydroamination of terminal aliphatic alkynes with tert-butylamine in
the presence of 1.
Amine
Mole%
cat.
T [8C]
85
t [h]
2
Amine/
Alkyne
Yield [%]
(anti-M:M)[a]
2.5
5.0
1.5:1
1.5:1
90 (>99:1) 4a
86 (3:1) 4 f
85
24
Entry Alkyne
Mole%
cat.
T
t
Amine/ Yield [%]
2.5
85
24
1.5:1
96 (4:1) 4g
[8C] [h] Alkyne (anti-M/M)[a]
1
2
3
4
5
6
2.5
2.5
1.0
0.5
2.5
2.5
85
85
2
2
1.5:1
1.5:1
90 (>99:1) 4a
97 (87:1) 4b
98 (89:1) 4b
60 (75:1) 4b
92 (83:1) 4b
93 (63:1) 4c
5.0
5.0
100
100
24
24
1.2:1
1.2:1
79 (2:1) 4h
94 (1:3) 4i
85 24 1.5:1
85 24 1.5:1
85 24 1.5:1
85 24 1.5:1
[a] GC yield determined with internal standard (hexadecane or dodecane).
anti-Markovnikov products were obtained preferentially.
However, the observed regioselectivity is lower than that
obtained with tert-butylamine, which demonstrates the im-
portance of steric factors for the selective formation of the
azatitanacyclobutene 6. Nevertheless, steric bulk is not the
only important factor influencing the regiochemical outcome
of the reaction, as shown by the hydroamination of 1-hexyne
with aniline.
7
8
2.5
2.5
85 24 1.2:1
85 24 1.5:1
84 (63:1) 4d
88 (100:0) 4e
9
5.0
100
24.0:1
9(1200:0)
5
In summary, we have introduced titanocene alkyne com-
plexes as new catalysts for the hydroamination of internal and
terminal alkynes. This class of titanium complexes is easily
available, stable, and can be used in a safe and practical
manner. The reactions of terminal alkynes with aliphatic
amines proceed highly selectively in the presence of catalyst 1
or 2, to give the corresponding primary anti-Markovnikov
functionalized imines in good to excellent yields. Even higher
selectivities for anti-Markovnikov aminations might be ex-
pected by using sterically more hindered titanocenes.
[a] GC yield determined with an internal standard (hexadecane or dodecane).
[b] 64% conversion. [c] Catalyst: 2. anti-M/Mˆ anti-Markovnikov/Markovnikov.
azatitanacyclobutene 6. Here, the ligand L
represents either another cyclopentadienyl
ligand, an amine, or an alkyne, because free
cyclopentadiene is observed in most GC
spectra of the reaction mixtures.
In agreement with the binding constant of
the different alkynes, catalyst 1 is slightly
more active than catalyst 2 (Table 2, entries 2 and 5). Inter-
estingly, the dihydroamination of diynes, for example, 1,7-
octadiyne (entry 9), proceeds smoothly. In the presence of an
excess of amine (amine/alkyne ˆ 4:1), both triple bonds react
Experimental Section
Chemicals were obtained from Aldrich, Fluka (solvents), Acros, and Strem
and, unless otherwise noted, were used without further purification.
2542
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Angew. Chem. Int. Ed. 2002, 41, No. 14

COMMUNICATIONS
Amines were distilled from CaH2. Alkynes were degassed, flushed with
argon, and stored over molecular sieves (4 ä). All experiments were
carried out under an argon atmosphere.
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Fluka.
Catalysts 1 and 2 were synthesized according to a literature procedure.[14a,b]
Imines 4b h and 5 were isolated after distillation of the crude hydro-
amination mixtures and were characterized by NMR spectroscopy, MS, IR
spectroscopy, and elemental analyses. Identification of all other products
was performed by comparison with authentic products. Compounds 4a and
4i were synthesized according to the procedures in references [16] and [9],
respectively.
Example of a typical hydroamination experiment (4b, Table 2, entry 2): A
solution of 1-octyne (3.2 mL, 2.4 g, 21.5 mmol) and tert-butylamine
(3.5 mL, 2.4 g, 32.2 mmol) was treated with
1 (0.15 g, 0.43 mmol,
2mol%) in toluene (6 mL). This mixture was heated to 85 8C and distilled
under vacuum after 24 h. Product 4b was obtained at 48 498C (0.1 mbar);
yield: 2.9 g (75%, >98% (GC) anti-Markovnikov product); 1H NMR
(400 MHz, CDCl3): d ˆ 0.85 (t, 3H, CH3), 1.14 (s, 9H, C-CH3), 1.21 1.34
(m, 8H, CH2), 1.46 (m, 2H, CH2), 2.20 (m, 2H, CH2), 7.56 ppm (t, 3J ˆ
5.35 Hz, 1H, CH); 13C NMR (100 MHz, CDCl3): d ˆ 14.0 (CH3), 22.6, 26.4,
29.1, 29.2 (CH2), 29.6 (C-CH3), 31.7, 36.4 (CH2), 56.4 (Cq), 159.3 ppm (CH);
‡
‡
IR (neat): nÄC N: 1671 cmÀ1; MS (EI, 70 eV): m/z ˆ 184 [M ‡1], 183 [M ],
ˆ
‡
‡
‡
‡
168 [M À CH3], 99 [C7H15 ], 84 [C4H9NCH ], 57 [C4H9 ]; elemental
analysis C12H25N calcd (%) C 78.62, H 13.74, N 7.64; found C 78.19, H 13.99,
N 7.42.
Received: December 21, 2001 [Z18425]
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[*] Prof. Dr. G. Erker, Dipl.-Chem. J. W. Strauch, Dr. G. Kehr,
Dr. R. Frˆhlich[‡]
Organisch-Chemisches Institut der Universit‰t
Westf‰lische Wilhelms-Universit‰t M¸nster
Corrensstrasse 40, 48149 M¸nster (Germany)
Fax : (‡49)251-833-36503
[9] C. G. Hartung, A. Tillack, H. Trauthwein, M. Beller, J. Org. Chem.
2001, 66, 6339 6343.
[10] J. S. Johnson, R. G. Bergman, J. Am. Chem. Soc. 2001, 123, 2 92 3
2924.
E-mail: erker@uni-muenster.de
‡
[ ] X-ray crystal structure analysis.
[**] This work was supported by the Fonds der Chemischen Industrie (and
the BMBF) and the Deutsche Forschungsgemeinschaft.
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Angew. Chem. Int. Ed. 2002, 41, No. 14
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4114-2543 $ 20.00+.50/0
2543