Enantiomerically pure amines as substrates for the Ti-catalyzed hydroamination of alkynes

Article abstract of DOI:10.1002/ejoc.200300522

For two representative reactions employing enantiomerically pure (S)-1-phenylethylamine and (S)-1-cyclohexylethylamine it is shown that Ti-catalyzed hydroamination reactions of alkynes do not generally take place without partial racemization at the chiral center adjacent to the nitrogen atom. However, identified from a selection of nine Ti catalysts, CP* ₂TiMe₂ and at least two other catalysts can be used for racemization-free hydroamination reactions of alkynes. Furthermore, the amount of racemization can be reduced significantly by the addition of pyridine to the reaction mixture. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300522

FULL PAPER
Enantiomerically Pure Amines as Substrates for the Ti-Catalyzed
Hydroamination of Alkynes
Frauke Pohlki,[a] Igor Bytschkov,[b] Holger Siebeneicher,[b] Andreas Heutling,[a]
Wilfried A. König,*[c] and Sven Doye*[a]
Keywords: Alkynes / Aminations / Asymmetric synthesis / Homogeneous catalysis / Titanium
For two representative reactions employing enantiomerically
pure (S)-1-phenylethylamine and (S)-1-cyclohexylethyl- racemization-free hydroamination reactions of alkynes. Fur-
amine it is shown that Ti-catalyzed hydroamination reactions thermore, the amount of racemization can be reduced signi-
of alkynes do not generally take place without partial race- ficantly by the addition of pyridine to the reaction mixture.
Cp*2TiMe2 and at least two other catalysts can be used for
mization at the chiral center adjacent to the nitrogen atom.
However, identified from a selection of nine Ti catalysts,
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
cause the resulting imines are known to be suitable sub-
strates for a diastereoselective reduction[17] giving access to
secondary amines with two stereogenic centers in enantio-
merically pure form (Scheme 1).
During the last few years, the development of catalytic
methods for the hydroamination of unsaturated organic
compounds has attracted much attention.[1] While most
catalytic hydroamination methods for alkenes are still lim-
ited to certain classes of substrates, more general catalytic
hydroamination procedures have been developed for
alkynes.[2] Among the various catalysts identified for hy-
droamination reactions of alkynes,[3Ϫ5] group IV metal
complexes play an outstanding role.[6] Based on
Bergman’s[7] and Livinghouse’s[8] early studies and boosted
[10]
by our report[9] that the well-known reagent Cp2TiMe2
Scheme 1. Approach towards the synthesis of enantiomerically
pure secondary amines by stepwise Ti-catalyzed hydroamination of
alkynes with enantiomerically pure amines and subsequent dia-
stereoselective imine reduction
and related Ti complexes can be used as catalysts for the
intermolecular hydroamination of alkynes, it has been dem-
onstrated in many subsequent publications that the Ti-cata-
lyzed hydroamination of alkynes is a remarkable new tool
in organic synthesis.[11Ϫ16]
Since the enantioselective synthesis of nitrogen-contain-
ing products from simple and commercially available start-
ing materials is a major goal of modern organic synthesis, it
would be highly desirable to employ enantiomerically pure
amines possessing a chiral center adjacent to the nitrogen
atom for the Ti-catalyzed hydroamination of alkynes be-
However, to realize a corresponding synthetic strategy it
is indispensable that the initial hydroamination reactions
take place without racemization at the chiral centers adja-
cent to the nitrogen atoms of the employed enantio-
merically pure amines. In this report, we would like to show
that some Ti complexes catalyze hydroamination reactions
of alkynes without a corresponding racemization while the
use of other catalysts leads to partial racemization at the
chiral centers of the employed amines.
[a]
Organisch-Chemisches Institut, Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: (internat.) ϩ 49-(0)6221/54-4205
E-mail: sven.doye@urz.uni-heidelberg.de
Results and Discussion
[b]
Institut für Organische Chemie, Universität Hannover
Schneiderberg 1B, 30167 Hannover, Germany
During a study directed toward the application of micro-
wave heating in Ti-catalyzed hydroamination reactions of
alkynes,[11b] we found that a one-pot hydroamination/re-
duction sequence starting from diphenylacetylene (1) and
Fax: (internat.) ϩ 49-(0)511/762-3011
[c]
Institut für Organische Chemie, Universität Hamburg
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax: (internat.) ϩ 49-(0)40/42838 2893
E-mail: wkoenig@chemie.uni-hamburg.de
Eur. J. Org. Chem. 2004, 1967Ϫ1972
DOI: 10.1002/ejoc.200300522
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1967

F. Pohlki, I. Bytschkov, H. Siebeneicher, A. Heutling, W. A. König, S. Doye
FULL PAPER
enantiomerically pure (S)-1-phenylethylamine (2) (ee ϭ
99%) gave access to two diastereomers of the secondary am-
ine 4 in a 5:2 ratio (Scheme 2). Interestingly, GC analysis
showed that the ee values for the two diastereomers were
only 87%. In an additional hydroamination experiment be-
tween 1 and 2, the amine 2 could be reisolated after hy-
drolysis (SiO2) of the initially formed imine 3. GC analysis
of reisolated amine 2 showed that the ee value had de-
creased to 86% which is almost identical to the 87% ob-
tained for the diastereomers of 4. It is therefore clear that
the hydroamination step and not the subsequent reduction
is responsible for the partial racemization observed. This
interpretation is in good agreement with the fact that dia-
stereoselective reductions of imines synthesized from en-
antiomerically pure 2 and ketones usually take place with-
out partial racemization.[17]
Table 1. (S)-1-Phenylethylamine (2) as substrate for the Ti-cata-
lyzed hydroamination of alkynes
[a] Reaction conditions: 1) alkyne 1 (1.0 mmol), amine 2 (1.0 mmol),
toluene (0.1 mL), catalyst (0.05 mmol), 105 °C, 48 h; 2) SiO2
(0.5 g), technical toluene (6.0 mL), 25 °C, 12 h; yields represent iso-
lated yields of pure compounds; reaction times have not been mini-
Scheme 2. Comparison between hydroamination/reduction and hy-
droamination/hydrolysis sequences
[b]
[c]
mized.
Determined by gas chromatography (Method A).
[d]
Experiment in the absence of alkyne 1.
Experiment in the ab-
sence of alkyne 1 and Ti catalyst.
Since the ee values determined for the two diastereomers
of 4 and reisolated 2 are almost identical we chose the hy-
droamination/hydrolysis sequence for all further investi-
gations because the determination of ee values for reisolated by GC. First of all, it can be seen from Table 1 that
commercially available amines is easier than the analysis of only the hydroamination reactions employing Cp2TiMe2,
secondary amines like 4.
Cp*2TiMe2, Ind2TiMe2, 9, and 10 (Entries 1, 4, 5, 9, 10)
In order to compare the behaviour of various Ti catalysts went to completion within 48 h. Interestingly, the reisolated
with the behaviour of Cp2TiMe2, we first synthesized amine 2 was still enantiomerically pure if Cp*2TiMe2 or 10
Cp*2TiMe2,[18] Ind2TiMe2,[19] 6,[20] 7,[20] 8,[20] 9,[21] and had been used as catalysts (Entries 4, 10). These results also
10[22] (Table 1) according to literature procedures. These prove that the hydrolysis of the imine intermediate in the
catalysts, which have already been investigated as hydro- presence of SiO2 obviously takes place without any race-
amination catalysts in our laboratories,[11d][11h] as well as mization. In comparison, 2 was obtained with only 80%,
[13a]
commercially available Ti(NMe2)4
were then used for a 64%, and 87% ee employing Cp2TiMe2, Ind2TiMe2, and 9
standard hydroamination/hydrolysis reaction sequence em- (Entries 1, 5, 9), respectively, indicating that these com-
ploying diphenylacetylene (1) and (S)-1-phenylethylamine plexes cannot be used for racemization-free hydroamination
(2) as substrates (Table 1). In all cases 5.0 mol % of the reactions. To obtain a first impression about the mechan-
catalyst was used and the hydroamination was performed istic details of the racemization, we performed a control
at 105° for 48 h (reaction times have not been minimized). experiment under identical conditions in the absence of al-
Subsequent hydrolysis employing SiO2 in technical toluene kyne 1 employing 2 and Cp2TiMe2 as the catalyst (Entry
at room temperature gave access to ketone 5, regenerated 2). After 48 h of reaction time, the ee value of 2 had de-
amine 2 and in some cases unchanged alkyne 1. For all creased from 99% to 47%. Therefore, it is clear that the
reactions, the ee values for reisolated 2 were determined presence of an alkyne is not necessary for the racemization
1968
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 1967Ϫ1972

Enantiomerically Pure Amines as Substrates for the Ti-Catalyzed Hydroamination of Alkynes
FULL PAPER
of an enantiomerically pure amine in the presence of a Ti alkyl analogue of 2, (S)-1-cyclohexylethylamine (11)
catalyst. A further control experiment under identical con- (Table 2). As can be seen from Table 2, all hydroamination
ditions in the absence of alkyne 1 and Cp2TiMe2 at 105 °C reactions employing 11 went to completion within 48 h in
did not lead to any racemization of 2 (Entry 3). Although the presence of the mentioned catalysts. Fortunately, the re-
reactions employing the pyridine-containing (imido)- isolated amine 11 was again enantiomerically pure if
titanium complexes 6, 7, and 8 as catalysts (Entries 6, 7, 8) Cp*2TiMe2 or 10 had been used as catalysts (Entries 3, 5).
did not reach 100% conversion within 48 h, the ee values Therefore, these Ti complexes can be regarded as suitable
determined for reisolated 2 are promising (96%, 99%, 99%) catalysts for a racemization-free intermolecular hydroamin-
in these cases. However, in this context, one should keep in ation of alkynes. In addition, partial racemization (93% ee
mind that the catalytic activity of a certain titanium com- of reisolated 11) was observed for the catalysts Cp2TiMe2
plex is strongly dependant on the properties of the em- and Ind2TiMe2 (Entries 1, 4). Since in these cases the
ployed substrates.[11h] For that reason, imido complexes 6, amount of racemization is small compared to the results
7, and 8 deserve further investigations with other substrates. obtained with benzylamine derivative 2 it is remarkable that
A common and probably important structural property of a control experiment under identical conditions in the ab-
6, 7, and 8 is the presence of at least one pyridine ligand. sence of alkyne 1 employing 11 and Cp2TiMe2 as the cata-
Since the result obtained with 6 (96% ee, Entry 6) is much lyst (Entry 2) resulted in the reisolation of 11 with only 32%
better than the result obtained with the structurally related ee. Anyway, these results clearly indicate that the partial ra-
complex Cp2TiMe2 (80% ee, Entry 1) it is possible that the cemization observed during Ti-catalyzed hydroamination
addition of small amounts of pyridine to hydroamination reactions of alkynes is not limited to benzylamine deriva-
reaction mixtures can generally suppress the undesired tives.
partial racemization. Finally, the worst result was obtained
In addition, we performed some standard hydroamin-
with commercially available Ti(NMe2)4 (Entry 11). With ation/hydrolysis experiments employing other alkynes (12,
this catalyst, the reaction reaches approximately 50% con- 14) and (S)-1-phenylethylamine (2) (Scheme 3). As catalysts
version and the ee value of reisolated 2 was found to be we used Ind2TiMe2 and the bridged complex 10. While the
only 24%.
results obtained for catalyst 10 again prove that racemi-
With these results in hand, we wanted to find out zation does not represent a significant problem for hydro-
whether the racemization during the Ti-catalyzed hydro- aminations employing this catalyst the result obtained for
amination is restricted to benzylamine derivatives or not. Ind2TiMe2 in the hydroamination of 1-dodecyne (14)
For that reason, we performed identical hydroamination/ clearly indicates that Ind2TiMe2 cannot be regarded as a
hydrolysis sequences in the presence of 5.0 mol % general catalyst for a racemization-free addition of enant-
Cp2TiMe2, Cp*2TiMe2, Ind2TiMe2, and 10 employing the iomerically pure amines to alkynes. In this context, it is
worth mentioning that all hydroamination reactions shown
in Scheme 3 went to completion within the standard reac-
tion time of 48 h for the hydroamination reaction.
Table 2. (S)-1-Cyclohexylethylamine (11) as substrate for the Ti-
catalyzed hydroamination of alkynes
Scheme 3. Ti-catalyzed hydroaminations of 1-phenylpropyne (12)
and 1-dodecyne (14) with (S)-1-phenylethylamine (2) in the pres-
ence of Ind2TiMe2 or catalyst 10
[a]
Reaction conditions: 1) alkyne
1 (1.0 mmol), amine 11
(1.0 mmol), toluene (0.1 mL), catalyst (0.05 mmol), 105 °C, 48 h;
2) SiO2 (0.5 g), technical toluene (6.0 mL), 25 °C, 12 h; the yields
of 5 have not been determined; reaction times have not been mini-
[b]
mized.
Determined by gas chromatography (GC) of the corre-
In order to rule out the possibility that the partial race-
mization takes place at the stage of the imine products we
performed an additional standard hydroamination reaction
[c]
sponding trifluoroacetates. Experiment in the absence of alkyne
1. [d] The hydrolysis was performed with a mixture of HCl aqueous
solution (c ϭ 2.0 mol/L) and CH2Cl2.
Eur. J. Org. Chem. 2004, 1967Ϫ1972
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1969

F. Pohlki, I. Bytschkov, H. Siebeneicher, A. Heutling, W. A. König, S. Doye
FULL PAPER
in the presence of 5.0 mol % Ind2TiMe2. During this experi- antiomerically pure amines possessing a chiral center adja-
ment, we took samples from the reaction mixtures after 2 h, cent to the nitrogen atom do not generally take place with-
4 h, 6 h, 27 h, and 48 h. All samples were subsequently hy- out partial racemization. The amount of racemization at
drolyzed and analyzed (Table 3, Entries 1Ϫ5). While it was the corresponding chiral center seems to be influenced by
noticed that the Ind2TiMe2-catalyzed hydroamination reac- the structure of the amine and, fortunately, by the nature
tion went to completion within 4 h (ee of reisolated 2: 83%) of the catalyst. During our studies we were able to identify
no significant decline of the ee value of reisolated 2 (within Cp*2TiMe2 as highly active catalyst which can be used for
experimental error) was observed during the following 44 h a racemization-free hydroamination of alkynes. Further-
reaction time of the hydroamination indicating that the im- more, no racemization was observed employing the pyri-
ine product does not undergo further racemization under dine-stabilized (imido)titanium complexes 7 and 8. Further
the reaction conditions.
investigations proved that the addition of small amounts of
pyridine to hydroamination reaction mixtures can minimize
the undesired partial racemization. In addition, racemiz-
ation does not seem to represent a significant problem for
hydroaminations employing the bridged catalyst 10. Mecha-
nistic studies of the racemization are underway in our
laboratories.
Table 3. Influences of the reaction time and the presence of pyri-
dine on the ee value of reisolated amine 2
Experimental Section
General Remarks: All reactions were performed under argon in
flame-dried Duran Schlenk tubes equipped with Teflon stopcocks.
Toluene was distilled from molten sodium under argon. Cp2TiMe2
was synthesized according to ref.[10a] Cp*2TiMe2 was synthesized
according to ref.[18] Ind2TiMe2 was synthesized according to ref.[19]
Catalysts 6, 7, and 8 were synthesized according to ref.[20] Catalyst
9 was synthesized according to ref.[21] Catalyst 10 was synthesized
according to ref.[22] All other reagents were purchased from com-
mercial sources and were used without further purification. Yields
refer to isolated yields of pure compounds as gauged by 1H and
13C NMR and TLC or GC analysis. All products were identified
by comparison with authentic samples purchased from commercial
sources. PE: light petroleum ether, b.p. 40Ϫ60 °C.
Entry
t [h]
Additive
ee of 2 [%][a][b]
1
2
3
4
2
4
6
27
48
48
Ϫ
Ϫ
Ϫ
Ϫ
81
83
79
82
75
95
5
Ϫ
6[c]
pyridine (5.0 mol %)
[a] Reaction conditions: 1) alkyne 1 (5.0 mmol), amine 2 (5.0 mmol),
toluene (0.5 mL), Ind2TiMe2 (0.25 mmol), 105 °C; 2) The samples
were hydrolyzed with SiO2 (0.5 g) in technical toluene (6.0 mL) at
25 °C for 12 h. [b] Determined by gas chromatography (Method B).
[c] Reaction conditions: 1) alkyne 1 (1.0 mmol), amine 2 (1.0 mmol),
toluene (0.1 mL), Ind2TiMe2 (0.05 mmol), pyridine (0.05 mmol),
105 °C, 48 h; 2) SiO2 (0.5 g), technical toluene (6.0 mL), 25 °C,
12 h.
General Procedure: A Schlenk tube containing a magnetic stirring
bar was charged with diphenylacetylene (1) (178 mg, 1.0 mmol),
amine (2 or 11) (1.0 mmol), toluene (0.1 mL), and the catalyst
(0.05 mmol). The mixture was heated to 105 °C for 48 h (TLC
monitoring). Then, SiO2 (0.5 g) and technical toluene (6.0 mL)
were added. After this had been stirred at 25 °C for 12 h, the mix-
ture was filtered and concentrated under vacuum. The formed am-
ine (2 or 11) was separated from ketone 5 by flash chromatography
on SiO2 (2: PE/EtOAc, 20:1 Ǟ EtOAc; 11: CH2Cl2/MeOH, 10:1).
Since Ind2TiMe2-catalyzed hydroaminations obviously
take place with partial racemization, we decided to choose
a corresponding reaction to verify the idea that the addition
of pyridine to the hydroamination reaction mixture could
reduce the degree of racemization. Fortunately, the ee value
of amine 2 which was reisolated from a corresponding hy-
droamination/reduction sequence performed in the presence
of 5.0 mol % pyridine was found to be 95% (Table 3, Entry
6). Since this ee value is much higher than the ee value
observed in the absence of pyridine (75%, Table 3, Entry 5)
pyridine seems to be an appropriate additive to minimize
racemization processes during Ti-catalyzed hydroamin-
ations of alkynes. Further investigations dealing with this
fact are underway in our laboratories.
Separation of the Enantiomers of 2. Method A: A sample of reiso-
lated 2 (0.05 mL) was dissolved in EtOAc (1.0 mL) and used for gas
chromatography. Gas chromatographic analysis: The separation of
the enantiomers was achieved using a 50-m FS Hydrodex-β-PM
capillary (0.25 mm i. d.) with the following temperature program:
40 min at 80 °C; 0.4 °C/min to 100 °C; 100 °C. An HP 5890 Series
II gas chromatograph with split injection and flame ionization de-
tection was used with 4.0 bar H2 as carrier gas. The order of elution
of 1-phenylethylamine (2) enantiomers was (R) before (S) with a
separation factor α ϭ 1.02. Method B: In a 1.5-mL screw-cap vial
with Teflon insert in the lid approximately 1 mg of sample (dis-
solved in EtOAc as obtained after chromatography) was dried in a
stream of N2 and taken up in CH2Cl2 (0.2 mL). Trifluoroacetic
anhydride (0.05 mL) was added and the solution was kept at room
temperature for 30 min. After removal of excess of reagent in a
stream of N2, the sample was dissolved in CH2Cl2 (0.5 mL) and
Conclusion
In summary, the study presented undoubtedly proves that
Ti-catalyzed hydroamination reactions of alkynes with en- used for gas chromatography. Gas chromatographic analysis: The
1970  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 1967Ϫ1972

Enantiomerically Pure Amines as Substrates for the Ti-Catalyzed Hydroamination of Alkynes
FULL PAPER
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stream of N2 and taken up in CH2Cl2 (0.2 mL). Trifluoroacetic
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