An ammonia equivalent for the dimethyltitanocene-catalyzed intermolecular hydroamination of alkynes

Article abstract of DOI:10.1021/ol006011e

(Equation presented) Commercially available α-aminodiphenylmethane 1 (benzhydrylamine) serves as a convenient ammonia equivalent in the dimethyltitanocene-catalyzed intermolecular hydroamination of alkynes. The primary formed imines can be hydrogenated and cleaved directly to the corresponding primary amines by catalytic hydrogenation using Pd/C as catalyst.

Full text of DOI:10.1021/ol006011e

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1935-1937
An Ammonia Equivalent for the
Dimethyltitanocene-Catalyzed
Intermolecular Hydroamination of
Alkynes
Edgar Haak, Holger Siebeneicher, and Sven Doye*
Institut fu¨r Organische Chemie der UniVersita¨t HannoVer,Schneiderberg 1B,
D-30167 HannoVer, Germany
sVen.doye@oci.uni-hannoVer.de
Received May 3, 2000
ABSTRACT
Commercially available r-aminodiphenylmethane 1 (benzhydrylamine) serves as a convenient ammonia equivalent in the dimethyltitanocene-
catalyzed intermolecular hydroamination of alkynes. The primary formed imines can be hydrogenated and cleaved directly to the corresponding
primary amines by catalytic hydrogenation using Pd/C as catalyst.
The direct addition of ammonia or amines to carbon-carbon
double and triple bonds, the so-called hydroamination of
alkenes and alkynes, is of fundamental interest in organic
chemistry. It represents the most atom economic synthesis
of amines, imines, and enamines which are important
building blocks for organic products, e.g., pharmaceuticals,
detergents, technical additives, and dyes. However, at the
moment no general hydroamination procedure for a wide
variety of substrates is known.1,2
for the preparation of primary amines using our hydroami-
nation strategy has yet been found. Herein we report on a
procedure that uses commercially available R-aminodiphen-
ylmethane 1 (benzhydrylamine) as a convenient ammonia
equivalent in the dimethyltitanocene-catalyzed intermolecular
hydroamination of alkynes.
Initial experiments to convert alkynes into primary amines
using benzylamine as an ammonia equivalent in the hydro-
amination step followed by hydrogenation of the resulting
imine have met with only limited success because benzyl-
amine shows a very low reactivity in dimethyltitanocene-
Recently we reported on the dimethyltitanocene-catalyzed
intermolecular hydroamination of alkynes.3 While this pro-
cedure combined with a subsequent reduction of the initially
formed imines is effective for the preparation of secondary
amines, the direct use of ammonia, giving access to primary
amines, has not been successful. Therefore, no simple means
(2) For catalytic intermolecular hydroaminations of alkynes, see: (a)
Barluenga, J.; Aznar, F. Synthesis 1977, 195-196. (b) Barluenga, J.; Aznar,
F.; Liz, R.; Rodes, R. J. Chem. Soc., Perkin Trans. 1 1980, 2732-2737.
(c) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992,
114, 1708-1719. (d) Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J.
Am. Chem. Soc. 1993, 115, 2753-2763. (e) Li, Y.; Marks, T. J.
Organometallics 1996, 15, 3770-3772. (f) Haskel, A.; Straub, T.; Eisen,
M. S. Organometallics 1996, 15, 3773-3775. (g) Tokunaga, M.; Eckert,
M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1999, 38, 3222-3225. (h) Tzalis,
D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40, 6193-6195. (i)
See also ref 3.
(1) For reviews, see: (a) Taube, R. In Applied Homogeneous Catalysis
with Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.;
VCH: Weinheim, 1996; Vol. 1, pp 507-520. (b) Mu¨ller, T. E.; Beller, M.
Chem. ReV. 1998, 98, 675-703. (c) Mu¨ller, T. E.; Beller, M. In Transition
Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, 1998; Vol. 2, pp 316-330. (d) Haak, E.; Doye, S. Chem. Unserer
Zeit 1999, 33, 296-303.
(3) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 1999, 38,
3389-3391.
10.1021/ol006011e CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/01/2000

catalyzed hydroamination reactions.3 This low reactivity
which has generally been observed for primary n-alkylamines
forced us to investigate primary s-alkylamines as ammonia
equivalents. Among this class of compounds we found that
R-aminodiphenylmethane 1 (benzhydrylamine), which offers
the possibility of a reductive cleavage of the carbon-nitrogen
bond,4 serves as an ammonia equivalent in a convenient
manner (Scheme 1).
Table 1. Synthesis of Primary Amines from Alkynes Using a
Hydroamination-Reduction Strategy5
Scheme 1. Formal Addition of Ammonia to Alkynes
First we found that hydroamination reactions between
R-aminodiphenylmethane 1 (benzhydrylamine) and various
alkynes 2 yielding the corresponding imines 3 can be realized
efficiently in the presence of 3 mol % of Cp2TiMe2 at 110-
120 °C in the absence of a solvent. The reactions are
generally very clean but, however, relatively slow. For bisaryl
alkynes and alkyl aryl alkynes, the reactions proceed to
completion within 72 h. In contrast, reactions employing
bisalkyl alkynes do not reach 100% conversion after 72 h.
As shown previously,3 for unsymmetrically substituted
alkynes such as alkyl aryl alkynes and terminal alkynes the
hydroamination reactions occur with high regioselectivity,
forming the anti-Markovnikov products exclusively.
Further investigations showed that the crude imines 3 can
be directly reduced to the desired primary amines 4 by
catalytic hydrogenation under 1 atm of H2 at 25 °C using
1.5-5 mol % of Pd/C as catalyst.5 Table 1 shows several
examples for the described hydroamination-reduction strat-
egy.
a Reaction conditions: (1) 1.0 equiv of amine, 1.2 equiv of alkyne, 3.0
mol % of Cp2TiMe2, 110 °C, 72 h; (2) 1 atm of H2, 1.5 mol % of Pd/C,
THF, 25 °C, 72 h. Reaction times have not been minimized. Yields represent
1
isolated yields of pure compounds as judged by H NMR, 13C NMR, and
TLC analysis. b 5 mol % of Pd/C was used for the reduction step. c 3.0
equiv of alkyne was used for the hydroamination step. d 20 h reaction time
for the hydroamination step.
cally substituted alkyl phenyl alkynes 1-phenyl-1-propyne
2b (entry 2), 1-phenyl-1-butyne 2c (entry 3), and 1-phenyl-
1-pentyne 2d (entry 4) were regioselectively converted into
the biologically interesting phenylethylamines 2-amino-1-
phenylpropane (amphetamine) 4b, 2-amino-1-phenylbutane
4c, and 2-amino-1-phenylpentane 4d in 79%, 67%, and 70%
yields, respectively. The use of the bisalkyl alkynes 3-hexyne
2e (entry 5) and 4-octyne 2f (entry 6) also gave access to
the corresponding primary amines. However, the hydroami-
nation reactions employing 2e and 2f did not reach 100%
conversion after 72 h. Therefore, the primary amines were
isolated in lower yields: 3-aminohexane 4e was isolated in
59% yield while 4-aminooctyne 4f was only obtained in 16%
yield. Furthermore, the terminal alkyne phenylacetylene 2g
(entry 7) was converted into 2-phenylethylamine 4g. The
obtained yield was 20% when the reaction time for the
hydroamination step was 72 h. It was also possible to isolate
a complex mixture of amine side products from the reaction
mixture. Surprisingly, the isolated yield went up to 41% when
the reaction time for the hydroamination step was only 20
h. In this case the amount of the formed amine mixture
decreased. However, the fact that the amount of the obtained
amine side products increased with increasing reaction time
for the hydroamination step indicates that the side reactions
Diphenylacetylene 2a (entry 1) could be converted into
1,2-diphenylethylamine 4a in 67% yield. The unsymmetri-
(4) Benzhydrylamines are usually cleaved more easily than benzy-
lamines: (a) Kocienski, P. J. Protecting Groups; Georg Thieme Verlag:
Stuttgart, New York, 1994; pp 220-227. (b) Overman, L. E.; Mendelson,
L. T.; Jacobsen, E. J. J. Am. Chem. Soc. 1983, 105, 6629-6637.
(5) General reaction procedure: A dry Schlenk tube equipped with a
Teflon stopcock was charged under an argon atmosphere with R-amino-
diphenylmethane 1 (367 mg, 2.0 mmol), 1-phenyl-1-pentyne 2d (346 mg,
2.4 mmol), and a solution of Cp2TiMe2 in toluene (0.18 mL, 0.33 mol/L,
0.06 mmol, 3.0 mol %). The mixture was heated to 110 °C for 72 h. The
crude reaction mixture was then dissolved in THF (14 mL). Pd/C (64 mg,
3.2 mg Pd, 0.03 mmol, 1.5 mol %) was added and the mixture was stirred
under 1 atm of H2 at 25 °C for 72 h. Filtration, concentration, and
purification by flash chromatography (CH2Cl2:CH3OH, 10:1) afforded 4d
(230 mg, 1.41 mmol, 70%) as a colorless solid.
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Org. Lett., Vol. 2, No. 13, 2000

take place during the hydroamination step, probably lowering
the yield by converting the desired product into side products.
One possible explanation for this observation which is in
contrast to the behavior of all other alkynes used in this study
is the fact that here the imine which is initially formed in
the hydroamination step is an aldimine. This aldimine can
easily undergo side reactions, e.g., aldol type reactions, under
the reaction conditions leading to various amine products.
Therefore, the obtained yield decreases if longer reaction
times are employed.
for the described reaction sequence strongly depends on the
structure of the employed alkyne. While bisaryl alkynes and
alkyl aryl alkynes react smoothly under the reaction condi-
tions, bisalkyl alkynes and terminal alkynes give lower yields.
Acknowledgment. We thank Prof. Winterfeldt for his
generous support of our research. We are grateful to the
Deutsche Forschungsgemeinschaft and the Fonds der Che-
mischen Industrie for financial support and to Bayer AG for
providing chemicals.
In summary, we have demonstrated the utility of employ-
ing R-aminodiphenylmethane 1 (benzhydrylamine) as a
substitute for ammonia in the dimethyltitanocene-catalyzed
hydroamination of alkynes. Using the presented hydroami-
nation-reduction strategy, alkynes can be easily converted
into primary amines. However, the obtained overall yield
Supporting Information Available: Characterization
data for compounds 4a-4g. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL006011E
Org. Lett., Vol. 2, No. 13, 2000
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