Hydroamination/hydrosilylation sequence catalyzed by titanium complexes

Article abstract of DOI:10.1002/anie.200462250

(Chemical Equation Presented) A single precatalyst is used for the sequential combination of the Ti-catalyzed hydroamination of alkynes with the Ti-catalyzed hydrosilylation of imines. In this way alkynes and primary amines are converted efficiently into

Full text of DOI:10.1002/anie.200462250

Angewandte
Chemie
Homogeneous Catalysis
Hydroamination/Hydrosilylation Sequence
Catalyzed by Titanium Complexes**
Andreas Heutling, Frauke Pohlki, Igor Bytschkov, and
Sven Doye*
Over the past few years, strategies for the one-pot synthesis of
interesting target molecules that require more than one
chemical transformation have gained increasing attention. In
this context, the use of a single catalyst for a combination of
different catalytic reactions (multifunctional catalysis) is one
of the most promising approaches.[1] One way to realize a
corresponding strategy is the combination of different
transitions-metal-catalyzed reactions into a sequence. In this
case, a single catalyst that mediates several consecutive
reactions is used for the one-pot process. Each individual
reaction is initiated by a change of the reaction conditions or
the addition of a new reagent.[2]
During the last few years, we have been intensively
involved in the development of the Ti-catalyzed hydroami-
nation of alkynes, which converts alkynes and primary amines
into imines in the presence of TiIV catalysts.[3] The corre-
sponding imine products were usually reduced with stoichio-
metric amounts of NaBH3CN to give secondary amines.
Herein, for the first time, we describe a sequential combina-
tion of the Ti-catalyzed hydroamination of alkynes with the
Ti-catalyzed reduction of imines.[4] By this new reaction
sequence, alkynes and primary amines can be converted into
secondary amines in a fully catalytic one-pot protocol
employing a single Ti-precatalyst (Scheme 1).[5]
Scheme 1. Ti-catalyzed hydroamination/hydrosilylation sequence.
The catalytically active species involved in the Ti-cata-
lyzed reduction (hydrogenation, hydrosilylation) of imines is
presumed to be a TiIII hydride.[4b] This species is generated in
situ immediately prior to the reaction from a TiIV precursor
[*] Dr. A. Heutling, Dr. F. Pohlki, Dr. I. Bytschkov, Prof. Dr. S. Doye
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)6221-54-4205
E-mail: sven.doye@urz.uni-heidelberg.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft,
the Fonds der Chemischen Industrie, and the Dr. Otto Rꢁhm
Gedꢀchtnisstiftung, Darmstadt. We thank Professor E. Winterfeldt
for his generous support of our research.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 2951 –2954
DOI: 10.1002/anie.200462250
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2951

Communications
and a reducing agent. Since a TiIV species remains in the
reaction mixture obtained after a successful hydroamination
of an alkyne, we assumed that this TiIV compound can also be
converted into a TiIII-species, which then catalyzes the
reduction of the generated imine. To verify this assumption,
a mixture of 1-phenylpropyne (1) and aniline (2) in toluene
was heated to 1058C for 24 h in the presence of 10 mol%
[Cp2TiMe2].[6] Subsequently, phenylsilane (3 equiv), piperi-
dine (40 mol%), and MeOH (40 mol%)[4d] were added, and
the resulting mixture was heated to 1058C for additional
24 h.[6] After aqueous workup (decomposition of NSi com-
pounds), the corresponding secondary amine 12a was isolated
in 85% yield [Eq. (1), Table 1, entry 1].
Table 1: Intermolecular Ti-catalyzed hydroamination/hydrosilylation
With this promising result in hand, we performed a
number of hydroamination/hydrosilylation sequences under
identical reaction conditions employing 1-phenylpropyne (1)
and various amines [Eq. (1), Table 1]. We found that aromatic
amines (entries 1–8) gave comparable good results as long as
they do not possess an ortho substituent. While the hydro-
silylation reaction still proceeded slowly in the case of 2-
methylaniline (7; 57% yield after a hydrosilylation reaction
time of 48 h), no successful reduction was observed when the
sterically very demanding 2,6-dimethylaniline (8) was used.
However, worse results were obtained with alkyl amines
(entries 9–12). In these cases, under the employed reaction
conditions, the desired secondary amines could be isolated in
only modest to poor yields, even when the reaction time for
the hydrosilylation was extended to 48 h.[7] Since the regio-
selectivity of the reaction sequence is generally determined
during the hydroamination step, the ratios of the regioiso-
meric secondary amines are very good to excellent, as
expected.[3] Additionally, two reaction sequences were per-
formed with the ansa complex 22[8] as the precatalyst
(entries 5, 11). Both reactions also led to the formation of
the desired secondary amines.
We also investigated the performance of various alkynes
in Ti-catalyzed hydroamination/hydrosilylation sequences.
For that purpose, we compared several reaction sequences
employing 4-methylaniline (5) and the alkynes 1 and 23–29
[Eq. (2), Table 2]. We found that 1-phenylpropyne derivatives
(1, 23, 24) and terminal alkynes (25–27) were very good
substrates, while sterically more demanding alkynes such as
diphenylacetylene (28) and 3-hexyne (29) gave worse results.
In the case of highly reactive terminal alkynes, very good
results were obtained in the presence of only 5 mol% of the
catalyst. Furthermore, only short reaction times (3 h) were
necessary for the hydroamination step. The observed regio-
selectivities were again in the expected ranges for the various
substrates.[3]
sequence employing various amines [Eq. (1)].
Entry
1
Amine
Cat.
Yield [%][a]
Sel. a/b[b]
[Cp2TiMe2]
85 (12a)
99:1
2
3
4
5
[Cp2TiMe2]
[Cp2TiMe2]
[Cp2TiMe2]
22
83 (13a)
86 (14a)
85 (15a)
99[c] (15a)
99:1
99:1
99:1
99:1
6
7
8
[Cp2TiMe2]
[Cp2TiMe2]
[Cp2TiMe2]
71 (16a)
99:1
99:1
35 (17a),
57[d] (17a)
[d]
–
(18a)
9
[Cp2TiMe2]
[Cp2TiMe2]
22
6[d] (19a)
99:1
95:5
95:5
92:8
10
11
12
39[d] (20a/b)
44[c,d] (20a/b)
11[d] (21a/b)
Finally, we focused on intramolecular reaction sequences
of aminoalkynes 37 and 38 [Eq. (3), Table 3]. In addition to
[Cp2TiMe2] and 22 we also employed the chiral catalysts
[(S,S)-(ebthi)TiMe2] (41)[4] and (R,R)-42[9] (ebthi = ethylene-
1,2-bis(h2-4,5,6,7-tetrahydro-1-indenyl). The expected cyclic
secondary amines 39 and 40 were obtained in modest to good
yields in all cases, and the products were generated in
enantiomerically enriched form (up to 66% ee) when [(S,S)-
(ebthi)TiMe2] (41) and (R,R)-42 were used as precata-
lysts.[10,11]
[Cp2TiMe2]
[a] Reaction conditions: 1) alkyne 1 (2.40 mmol), amine (2.64 mmol),
[Cp2TiMe2] (0.33 molLÀ1 in toluene, 0.24 mmol, 10 mol%), toluene
(0.28 mL), 1058C, 24 h; 2) PhSiH3 (7.20 mmol), piperidine (0.96 mmol,
40 mol%), MeOH (0.96 mmol, 40 mol%), 1058C, 24 h. Yields refer to
isolated compounds. Reaction times have not been minimized. All
hydroamination reactions reached 100% conversion. [b] GC–MS analy-
sis prior to chromatography. [c] 22 (0.24 mmol, 10 mol%), toluene
(1.0 mL). [d] The reaction time of the hydrosilylation step was 48 h.
2952
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 2951 –2954

Angewandte
Chemie
We have shown that a sequential combination of the Ti-
catalyzed hydroamination of alkynes with the Ti-catalyzed
hydrosilylation of imines, which employs simple precatalysts,
is an efficient and fully catalytic one-pot process for the
conversion of alkynes and primary amines into secondary
amines. The application of related Ti precatalysts is presently
under investigation in our laboratories.
Table 3: Intramolecular Ti-catalyzed hydroamination/hydrosilylation
sequence employing various aminoalkynes [Eq. (3)].
Entry
n
Cat.
t1 [h]
t2 [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
1
1
1
1
2
2
2
[Cp2TiMe2]
6
6
15
6
6
15
6
22
22
36
36
22
36
36
62 (39)
82 (39)
46 (39)
68 (39)
68 (40)
50 (40)
68 (40)
–
–
22
41
42
22
41
42
66
25
–
60
55
Table 2: Intermolecular Ti-catalyzed hydroamination/hydrosilylation
sequence employing various alkynes [Eq. (2)].
Entry Alkyne
Cat.
Yield [%][a]
Sel. a/b[b]
99:1
[a] Reaction conditions: 1) aminoalkyne (1.0 mmol), cat. (0.1 mmol,
10 mol%), toluene (0.42 mL), 1058C; 2) PhSiH3 (3.0 mmol), piperidine
(0.4 mmol, 40 mol%), MeOH (0.4 mmol, 40 mol%), 1058C. Yields refer
to isolated compounds. Reaction times have not been minimized. All
hydroamination reactions reached >95% conversion (TLC). [b] GC–MS
analysis of the corresponding (S)-(À)-N-(trifluoroacetyl)-prolyl amides.
1
2
[Cp2TiMe2] 85 (15a)
[Cp2TiMe2] 83 (30a)
[Cp2TiMe2] 86 (31a)
98:2
3
4
5
6
7
8
9
98:2
[Cp2TiMe2] 88[c,d,e] (32a/b) 31:69
[Cp2TiMe2] 65[c,d] (33a/b) 57:43
(0.72 mL, 0.33m in toluene, 0.24 mmol, 10.0 mol%), and toluene
(0.28 mL). The resulting mixture was heated to 1058C for 24 h. The
brown mixture was then cooled to room temperature, and phenyl-
silane (0.89 mL, 7.20 mmol), piperidine (95 mL, 96 mmol), and
methanol (39 mL, 0.96 mmol) were added. The mixture was heated
to 1058C for further 24 h, cooled to room temperature, diluted with
Et2O (25 mL), and poured into 1n aqueous NaOH (25 mL). After this
mixture had been stirred at 258C for 20 h, the organic layer was
separated. The aqueous layer was extracted with Et2O (4 ꢀ 30 mL),
and the combined organic layers were dried with MgSO4. After
concentration under vacuum, the residue was purified by flash
chromatography (SiO2).
22
50[c,f] (33a/b) 76:24[g]
[Cp2TiMe2] 76[c,d,e] (34a/b) 39:61
[Cp2TiMe2] 31 (35)
[Cp2TiMe2] 33 (36)
[a] Reaction conditions: 1) alkyne (2.40 mmol), amine 5 (2.64 mmol),
[Cp2TiMe2] (0.33 molLÀ1 in toluene, 0.24 mmol, 10 mol%), toluene
(0.28 mL), 1058C, 24 h; 2) PhSiH3 (7.20 mmol), piperidine (0.96 mmol,
40 mol%), MeOH (0.96 mmol, 40 mol%), 1058C, 24 h. Yields refer to
isolated compounds. Reaction times have not been minimized. All
hydroamination reactions reached 100% conversion. [b] GC—MS
analysis prior to chromatography. [c] The reaction time of the hydro-
amination step was 3 h. [d] Prior to the addition of alkyne, [Cp2TiMe2],
amine 5, and toluene were heated to 1058C for 90 min. [e] Reaction
conducted with 5 mol% [Cp2TiMe2], 20 mol% piperidine, and 20 mol%
MeOH. [f] Reaction conducted with 22 (0.24 mmol, 10 mol%) and
toluene (1.0 mL). [g] Small amounts of the imine that corresponds to
amine 33b were observed, a/b (including imine) 69:31.
Received: October 8, 2004
Publication delayed on authorsꢁ request.
Published online: April 8, 2005
Keywords: alkynes · amines · hydroamination · hydrosilylation ·
.
titanium
[1] For a review, see: A. Ajamian, J. L. Gleason, Angew. Chem.
2004, 116, 3842 – 3848; Angew. Chem. Int. Ed. 2004, 43, 3754 –
3760.
[2] a) J. Louie, C. W. Bielawski, R. H. Grubbs, J. Am. Chem. Soc.
2001, 123, 11312 – 11313; b) A. Fꢂrstner, A. Leitner, Angew.
Chem. 2003, 115, 320 – 323; Angew. Chem. Int. Ed. 2003, 42, 308 –
311; c) B. Schmidt, Eur. J. Org. Chem. 2003, 816 – 819; d) B.
Schmidt, Chem. Commun. 2004, 742 – 743; e) A. N. Thadani,
V. H. Rawal, Org. Lett. 2002, 4, 4317 – 4320; f) A. N. Thadani,
Experimental Section
A Schlenk tube equipped with a Teflon stopcock and a magnetic
stirring bar was charged with 1-phenylpropyne (1, 279 mg,
2.40 mmol), 4-methylaniline (5, 283 mg, 2.64 mmol), [Cp2TiMe2]
Angew. Chem. Int. Ed. 2005, 44, 2951 –2954
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2953

Communications
V. H. Rawal, Org. Lett. 2002, 4, 4321 – 4323; g) P. A. Evans, J. E.
Robinson, J. Am. Chem. Soc. 2001, 123, 4609 – 4610; h) E. Teoh,
E. M. Campi, W. R. Jackson, A. J. Robinson, Chem. Commun.
2002, 978 – 979; i) J. Tian, N. Yamagiwa, S. Matsunaga, M.
Shibasaki, Angew. Chem. 2002, 114, 3788 – 3790; Angew. Chem.
Int. Ed. 2002, 41, 3636 – 3638; j) H. Du, K. Ding, Org. Lett. 2003,
5, 1091 – 1093.
[3] For reviews, see: a) I. Bytschkov, S. Doye, Eur. J. Org. Chem.
2003, 935 – 946; b) S. Doye, Synlett 2004, 1653 – 1672.
[4] a) C. A. Willoughby, S. L. Buchwald, J. Am. Chem. Soc. 1992,
114, 7562 – 7564; b) C. A. Willoughby, S. L. Buchwald, J. Am.
Chem. Soc. 1994, 116, 8952 – 8965; c) C. A. Willoughby, S. L.
Buchwald, J. Am. Chem. Soc. 1994, 116, 11703 – 11714; d) X.
Verdaguer, U. E. W. Lange, M. T. Reding, S. L. Buchwald, J. Am.
Chem. Soc. 1996, 118, 6784 – 6785; e) X. Verdaguer, U. E. W.
Lange, S. L. Buchwald, Angew. Chem. 1998, 110, 1174 – 1178;
Angew. Chem. Int. Ed. 1998, 37, 1103 – 1107; f) M. C. Hansen,
S. L. Buchwald, Org. Lett. 2000, 2, 713 – 715; g) J. Okuda, S.
Verch, T. P. Spaniol, R. Stꢂrmer, Chem. Ber. 1996, 129, 1429 –
1431; h) A. Tillack, C. Lefeber, N. Peulecke, D. Thomas, U.
Rosenthal, Tetrahedron Lett. 1997, 38, 1533 – 1534.
[5] Recently, a hydroamination/hydrosilylation sequence catalyzed
by cationic IrI complexes was reported: L. D. Field, B. A.
Messerle, S. L. Wren, Organometallics 2003, 22, 4393 – 4395.
[6] In order to compare the various experiments, reaction times
were kept constant and were not minimized.
[7] For comparison: The [Cp2TiMe2]-catalyzed hydroamination
between 1 and 10 followed by reduction with NaBH3CN/ZnCl2
gave 20a/b in 89% yield.
[8] a) W. A. Herrmann, M. J. A. Morawietz, J. Organomet. Chem.
1994, 482, 169 – 181; b) D. W. Carpenetti, L. Kloppenburg, J. T.
Kupec, J. L. Petersen, Organometallics 1996, 15, 1572 – 1581; c) J.
Okuda, Chem. Ber. 1990, 123, 1649 – 1651.
[9] a) S. Pritchett, P. Gantzel, P. J. Walsh, Organometallics 1999, 18,
823 – 831; b) L. Ackermann, R. G. Bergman, Org. Lett. 2002, 4,
1475 – 1478; c) L. Ackermann, R. G. Bergman, R. N. Loy, J. Am.
Chem. Soc. 2003, 125, 11956 – 11963.
[10] Chiral catalysts (S,S)-41 and (R,R)-42 both favor formation of
the same enantiomers of 39 and 40. We are currently investigat-
ing which enantiomer is the main product.
[11] For recent examples of enantioselective hydroaminations of
alkenes, see: a) P. W. Roesky, T. E. Mꢂller, Angew. Chem. 2003,
115, 2812 – 2814; Angew. Chem. Int. Ed. 2003, 42, 2708 – 2710;
b) P. D. Knight, I. Munslow, P. N. OꢁShaughnessy, P. Scott, Chem.
Commun. 2004, 894 – 895.
2954
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 2951 –2954