[Ind2TiMe2]: A general catalyst for the intermolecular hydroamination of alkynes

Article abstract of DOI:10.1002/chem.200305771

[Ind₂TiMe₂] (Ind=indenyl) is a highly active and general catalyst for the intermolecular hydroamination of alkynes. It catalyzes the reaction of primary aryl-, tert-alkyl-, sec-alkyl-, and nalkylamines with internal and terminal alkynes. In the case of unsymmetrically substituted 1-phenyl-2-alkylalkynes, the reactions occur with modest to excellent regioselectivities, whereby formation of the anti-Markovnikov regioisomers is favored. While the major product of hydroamination reactions of terminal arylalkynes is always the anti-Markovnikov isomer, alkylalkynes react with arylamines to preferably give the Markovnikov products. To achieve reasonable rates for the addition of sterically less hindered n-alkyland benzylamines to alkynes, these amines must be added slowly to the reaction mixtures. This behavior is explained by the fact that the catalytic cycle proposed on the basis of an initial kinetic investigation includes the possibility that the rate of the reaction increases with decreasing concentration of the employed amine. Furthermore, no dimerization of the catalytically active imido complex is observed in the hydroamination of 1-phenylpropyne with 4-methylaniline in the presence of [Ind₂TiMe₂] as catalyst. In general, a combination of [Ind₂TiMe₂]-catalyzed hydroamination of alkynes with subsequent reduction leads to the formation of secondary amines with good to excellent yields. Particularly impressive is that [Ind ₂TiMe₂] makes it possible for the first time to perform the reactions of n-alkyl- and benzylamines with 1-phenylpropyne in a highly regioselective fashion.

Full text of DOI:10.1002/chem.200305771

FULL PAPER
[Ind2TiMe2]: A General Catalyst for the Intermolecular Hydroamination of
Alkynes
Andreas Heutling, Frauke Pohlki, and Sven Doye*[a]
Abstract: [Ind2TiMe2] (Ind=indenyl) is
a highly active and general catalyst for
the intermolecular hydroamination of
alkynes. It catalyzes the reaction of pri-
mary aryl-, tert-alkyl-, sec-alkyl-, and n-
alkylamines with internal and terminal
alkynes. In the case of unsymmetrically
substituted 1-phenyl-2-alkylalkynes, the
reactions occur with modest to excel-
lent regioselectivities, whereby forma-
tion of the anti-Markovnikov re-
gioisomers is favored. While the major
product of hydroamination reactions of
terminal arylalkynes is always the anti-
Markovnikov isomer, alkylalkynes
react with arylamines to preferably
give the Markovnikov products. To
achieve reasonable rates for the addi-
tion of sterically less hindered n-alkyl-
and benzylamines to alkynes, these
amines must be added slowly to the re-
action mixtures. This behavior is ex-
plained by the fact that the catalytic
cycle proposed on the basis of an initial
kinetic investigation includes the possi-
bility that the rate of the reaction in-
creases with decreasing concentration
of the employed amine. Furthermore,
no dimerization of the catalytically
active imido complex is observed in
the hydroamination of 1-phenylpro-
pyne with 4-methylaniline in the pres-
ence of [Ind2TiMe2] as catalyst. In gen-
eral, a combination of [Ind2TiMe2]-cat-
alyzed hydroamination of alkynes with
subsequent reduction leads to the for-
mation of secondary amines with good
to excellent yields. Particularly impres-
sive is that [Ind2TiMe2] makes it possi-
ble for the first time to perform the re-
actions of n-alkyl- and benzylamines
with 1-phenylpropyne in a highly regio-
selective fashion.
Keywords: alkynes
¥ amination ¥
homogeneous catalysis ¥ metallo-
cenes ¥ titanium
Introduction
and therefore useless from a synthetic point of view. As a
result, the term ™general∫ seems to be inappropriate for de-
scribing the performance of [Cp2TiMe2] as a hydroamination
catalyst. Later, it was found that transformations employing
sterically less demanding n-alkyl- and benzylamines are
better performed in the presence of catalytic amounts of
The development of catalytic methods for the hydroamina-
tion of unsaturated organic compounds can be regarded as
one of the most challenging goals in synthetic organic
chemistry.[1] While corresponding hydroamination methods
for alkenes are still limited to activated substrates, more
general catalytic hydroamination procedures have been de-
veloped for alkynes.[2] Among the steadily growing class of
Group 4 metal catalysts for the hydroamination of al-
kynes,[3,4] the well-known reagent [Cp2TiMe2][5] has been
5
[8]
*
[Cp2 TiMe2] (Cp*=h -C5Me5). Unfortunately, the regiose-
lectivities observed for corresponding additions to unsym-
metrically substituted alkynes such as 1-phenylpropyne are
*
poor when [Cp2 TiMe2] is used as catalyst. Furthermore, this
catalyst cannot be used for the hydroamination of terminal
[6]
alkynes.[8] Therefore, [Cp2 TiMe2] cannot be regarded as a
*
used most extensively in the last fewyears. In the presence
of this catalyst, primary aryl-, tert-alkyl-, and sec-alkylamines
react with symmetrically and unsymmetrically substituted in-
ternal and terminal alkynes. In the case of unsymmetrically
substituted 1-aryl-2-alkylalkynes, the reactions occur with
high regioselectivity to give the anti-Markovnikov isomers
as major products.[6,7] However, reactions with sterically less
demanding n-alkyl- and benzylamines are extremely slow
™general∫ catalyst either. However, inspired by the great
success achieved with [Cp2TiMe2], many other titanium
complexes have been identified as catalysts for the hydroa-
14]
mination of alkynes by us[9] and others.[10
These catalysts
allowalkynes to be converted to secondary amines in effi-
cient one-pot hydroamination/reduction
sequences[8]
(Scheme 1). A fewother examples of efficient hydroamina-
[a] A. Heutling, F. Pohlki, Prof. Dr. S. Doye
Organisch-Chemisches Institut, Universit‰t Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221/54-4205
Scheme 1. Hydroamination/reduction sequence for the synthesis of secon-
dary amines.
E-mail: sven.doye@urz.uni-heidelberg.de
Chem. Eur. J. 2004, 10, 3059 3071
DOI: 10.1002/chem.200305771
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPER
tion reactions of sterically less hindered amines have been
reported,[11b,12c,14] but these experiments were only per-
formed with terminal alkynes.
lyst. After subsequent reduction with NaBH3CN in the pres-
ence of ZnCl2,[8] the desired secondary amines were isolated
in pure form by chromatography (Table 1).
Although the scope and limitations are not well docu-
mented for most Ti catalysts, we recognized that the catalyt-
ic activities of the titanium complexes usually strongly
depend on the properties of the employed substrates.[9] Re-
cently, we compared 13 titanium complexes in two selected
hydroamination/reduction test reaction sequences.[9] We
found that, in contrast to other catalysts, the known complex
[Ind2TiMe2] (Ind=indenyl)[15] gave good results in both test
reactions. Therefore, we decided to investigate the catalytic
performance of this catalyst in more detail, and we present
the results here.
Table 1. [Ind2TiMe2]-catalyzed hydroamination of diphenylacetylene (1)
with various amines and subsequent reduction.[a]
Entry
1
Amine
t [h]
Yield[a,b] [%]
24
98 (8)
Results and Discussion
2
3
5
3
84 (9)
To get an impression of the activity of [Ind2TiMe2] as a hy-
droamination catalyst we first performed hydroamination
reactions of diphenylacetylene (1) with various amines at
1058C in toluene in the presence of 5.0 mol% of the cata-
91 (10)
4
5
90 (11)
Abstract in German: Die vorliegende Studie zeigt, dass der
kommerziell erh‰ltliche Komplex [Ind2TiMe2] ein hoch aktiv-
er und generell einsetzbarer Katalysator f¸r die intermoleku-
lare Hydroaminierung von Alkinen ist. Mit diesem Katalysa-
tor kˆnnen prim‰re Aryl-, tert-Alkyl-, sec-Alkyl- und n-Al-
kylamine erfolgreich an interne und terminale Alkine addiert
werden. Im Fall von unsymmetrisch substituierten 1-Phenyl-
2-alkylalkinen verlaufen die Reaktionen mit guten bis exzel-
lenten Regioselektivit‰ten, wobei sich bevorzugt die Anti-
Markovnikov-Regioisomere bilden. W‰hrend terminale Aryl-
alkine mit allen Aminen bevorzugt zu den entsprechenden
Anti-Markovnikov-Produkten reagieren, stellen bei Umset-
zungen von terminalen Alkylalkinen mit Arylaminen die
Markovnikov-Produkte die Hauptprodukte der Reaktionen
dar. Um akzeptable Reaktionsgeschwindigkeiten f¸r die Ad-
dition von sterisch wenig gehinderten Aminen wie n-Alkyl-
und Benzylaminen an Alkine zu erreichen, m¸ssen diese
Amine langsam zur Reaktionsmischung zugetropft werden.
Diese Tatsache kann dadurch erkl‰rt werden, dass der in
einer ersten kinetischen Studie ermittelte Katalysezyklus die
Mˆglichkeit beinhaltet, dass die Reaktionsgeschwindigkeit
minus erster Ordnung bez¸glich des Amins ist. Dar¸ber
hinaus wurde festgestellt, dass es bei der Verwendung von
[Ind2TiMe2] als Katalysator f¸r die Umsetzung von 1-Phenyl-
propin mit 4-Methylanilin zu keiner reversiblen Dimerisie-
rung der unter den Reaktionsbedingungen gebildeten kataly-
tisch aktiven Spezies kommt. Insgesamt liefern die durchge-
f¸hrten Sequenzen aus [Ind2TiMe2]-katalysierter Hydroami-
nierung von Alkinen und nachfolgender Reduktion sekun-
d‰re Amine in guten bis exzellenten Ausbeuten. Besonders
vorteilhaft ist die Tatsache, dass es unter Verwendung von
[Ind2TiMe2] als Katalysator erstmals gelingt, sterisch wenig
gehinderte n-Alkyl- und Benzylamine mit hoher Regioselekti-
vit‰t an 1-Phenylpropin zu addieren.
5
6
3
89 (12)
48
30[c] (13)
[a] Reaction conditions: 1) Alkyne 1 (2.40 mmol), amine (2.64 mmol),
[Ind2TiMe2] (0.12 mmol, 5.0 mol%), toluene (1.0 mL), 1058C, 3 48 h;
2) NaBH3CN (4.80 mmol), ZnCl2 (2.40 mmol), MeOH (10 mL), 258C,
20 h. [b] Yields refer to isolated pure compounds. [c] 62% of 1 was recov-
ered.
While the hydroamination reaction between 1 and the ar-
omatic amine 4-methylaniline (2) needed 24 h to reach
100% conversion (entry 1, Table 1), corresponding reactions
with tert-butylamine (3), cyclopentylamine (4), benzhydryla-
mine (5), and n-propylamine (6) went to completion within
3 5 h (entries 2 5, Table 1). The yields of the secondary
amines 8 12 obtained after subsequent reduction were good
to excellent (84 98%) for all reactions (entries 1 5,
Table 1). While the result obtained with 4-methylaniline (2)
is comparable to earlier results obtained with [Cp2TiMe2],[16]
the short reaction times for reactions of the alkylamines 3 6
indicate that [Ind2TiMe2] is a far more reactive catalyst than
[Cp2TiMe2] for these substrates. This conclusion is illustrated
most impressively by the fact that, after reduction, the yield
of 12 was only 10% when [Cp2TiMe2] (6.0 mol%) was used
at 1148C in toluene to convert diphenylacetylene (1) and n-
propylamine (6) to 12.[8] The results presented in Table 1
showthat [Ind TiMe2] is clearly a suitable catalyst for the
2
addition of aromatic amines as well as tert-, sec-, and n-al-
kylamines to diphenylacetylene (1). The result obtained
with benzhydrylamine (5) shows that [Ind2TiMe2] also seems
to be suitable for the conversion of alkynes to primary
amines, because 5 has already been used as an ammonia
equivalent for Ti-catalyzed hydroamination reactions.[7a]
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Catalytic Hydroamination of Alkynes
3059 3071
However, a disappointing result was obtained for the hydro-
amination of 1 with benzylamine (7). The reaction did not
reach 100% conversion over 48 h. After subsequent reduc-
tion, only 30% of the desired product 13 was isolated, and
62% of unconverted starting material 1 was recovered
(entry 6, Table 1). Since benzylamines are already known to
be poor substrates for [Cp2TiMe2]-catalyzed hydroamina-
tions we were not totally surprised by this finding. Hence,
we initially continued our study without performing further
experiments with other benzylamine derivatives. However,
later on in this paper, we present a reinvestigation of the be-
havior of benzylamine derivatives in [Ind2TiMe2]-catalyzed
hydroamination reactions.
We converted the dialkylalkynes 3-hexyne (14) and 4-
octyne (17) to secondary amines by hydroamination/reduc-
tion sequences (Scheme 2). The hydroamination reactions of
14 and 17 were performed in the presence of 5.0 mol%
[Ind2TiMe2] under standard con-
Scheme 2. [Ind2TiMe2]-catalyzed hydroamination of dialkylalkynes and
subsequent reduction.
ditions with (ꢀ)-1-phenylethyl-
Table 2. [Ind2TiMe2]-catalyzed hydroamination of unsymmetrically substituted 1-phenyl-2-alkylalkynes with
various amines and subsequent reduction.
amine (15) and 2,6-dimethyl-
aniline (18), respectively. After
reaction times of 24 h for the
hydroamination step (not mini-
mized) and subsequent reduc-
tion the yields of 16 and 19
were 81 and 92%, respectively.
These results in combination
Entry
1
Alkyne
Amine
Yield [%][a]
Ratio a:b
with the study employing
1
99 (23a/b)
49:1
clearly indicate that [Ind2TiMe2]
is a suitable catalyst for the in-
termolecular hydroamination of
symmetrical diaryl- and dialkyl-
alkynes.
2
90 (24a/b)
>99:1
With these results in hand,
we focused on [Ind2TiMe2]-cat-
alyzed hydroaminiation reac-
tions of unsymmetrically substi-
tuted 1-phenyl-2-alkylalkynes
with various amines (Table 2).
The corresponding hydroamina-
tion/reduction sequences were
all performed under standard
3
4
80 (25a/b)
89 (26a/b)
>99:1
18:1
5
6
84 (27a/b)
76 (28a/b)
11:1
6:1
conditions
with
5.0 mol%
[Ind2TiMe2]. The reaction time
of the hydroamination step was
always 24 h (not minimized).
All reaction sequences gave the
desired secondary amines in
good to excellent yields (76
99%). Interestingly, the anti-
Markovnikov regioisomer (23
31a) is the major product in all
cases. However, the regiosele-
lectivity is influenced by the
nature of the alkyl substituent
of the 1-phenyl-2-alkylalkyne
7
8
92 (29a/b)
80 (30a/b)
11:1
3:1
9
87 (31a/b)
3:1
[a] Reaction conditions: 1) Alkyne (2.40 mmol), amine (2.64 mmol), [Ind2TiMe2] (0.12 mmol, 5.0 mol%), tolu-
ene (1.0 mL), 1058C, 24 h; 2) NaBH3CN (4.80 mmol), ZnCl2 (2.40 mmol), MeOH (10 mL), 258C, 20 h. Yields
refer to isolated compounds. Reaction times have not been minimized.
and the bulkiness of the primary amine. Increasing regiose-
lectivity is observed with increasing size of the amine (en-
tries 1 4, Table 2). Furthermore, 1-phenyl-2-alkylalkynes
with small alkyl substituents such as 20 are hydroaminated
much more regioselectively than substrates with a bulky
substituent, such as 22 (entries 3 and 9, Table 2). However,
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S. Doye et al.
FULL PAPER
in 22 the phenyl and the 1-cyclohexenyl substituents can be
regarded as sterically and electronically comparable. As ex-
pected, a medium-sized alkyl substituent like the cycloprop-
yl group in 21 results in modest to good regioselectivities
(entries 5 8, Table 2). Correspondingly, the reaction be-
tween the bulky amine 4-methylaniline (2) and 20 gave a
mixture of 23a and 23b in an excellent ratio of 49:1
(entry 1, Table 2), while the regioselectivity for the addition
of sterically less demanding n-propylamine (6) to 21 is only
3:1 (entry 8, Table 2).
(entries 2 and 3, Table 3). An explanation for this observa-
tion is that the formation of alkyne polymers decreases with
decreasing temperature. In general, Table 3 shows that
alkyl- (32, 33) and arylalkynes (34 36) are suitable sub-
strates for [Ind2TiMe2]-catalyzed hydroamination reactions.
Particularly interesting are the good yields (71 77%) of the
hydroamination/reduction sequences with arylalkynes 34 36,
because in the past only a fewTi-catalyzed hydroamination
reactions of phenylacetylene (34) have been reported.
[7b,11,13a]
As observed before,[7b,11,12] the regioselectivity of
To complete the investigation of the behaviour of various
alkynes in [Ind2TiMe2]-catalyzed hydroamination reactions,
we focused on transformations of terminal alkyl- and arylal-
kynes with various amines (Table 3). All reactions were per-
amine addition to alkylalkynes such as 1-octyne (32) and 1-
dodecyne (33) is strongly influenced by the nature of the
amine. While reactions employing arylamine 2 (entries 1 3,
Table 3) favor the formation of the Markovnikov regioiso-
mers 37b and 38b, the anti-
Markovnikov products 39a and
Table 3. [Ind2TiMe2]-catalyzed hydroamination of terminal alkynes with various amines and subsequent reduc-
tion.
40a are the major products in
reactions employing the alkyla-
mines 3 and 4 (entries 4 and 5,
Table 3). In contrast, reactions
employing the arylalkynes 34
36 always favor formation of
Entry
1
Alkyne
Amine
T [8C]
t [h]
Yield [%][a]
Ratio a:b
the
anti-Markovnikov
re-
gioisomers 41 45a (entries 6
10). The best anti-Markovnikov
regioselectivities (>99:1) are
generally observed with the
sterically demanding amine tert-
butylamine (3) (entries 4, 7, and
8, Table 3), which is in agree-
ment with reports by Beller
et al.[12] However, lower regio-
selectivities (1.5 4.5:1) were ob-
served with arylamine 2 or the
sterically less demanding alkyl-
amine 4. Comparison of the 4-
methoxy- and 4-chloro-substi-
tuted phenylacetylenes 35 and
36 indicates that these substitu-
ents do not significantly change
the behavior of the alkynes.
105
1
95 (37a/b)
1:4
2
3
105
75
2
8
87 (38a/b)
99 (38a/b)
1:2.5
1:3.8
4
5
105
105
2
75 (39a/b)
81 (40a/b)
>99:1
24[b]
1.5:1
6
75
6
77 (41a/b)
4.5:1
Since at this stage of the
study benzylamine (7) was the
7
75
75
75
75
8
8
77 (42a/b)
71 (43a/b)
75 (44a/b)
73 (45a/b)
>99:1
>99:1
2.7:1
only
poor
substrate
for
[Ind2TiMe2]-catalyzed
hydro-
8
amination reactions we decided
to reinvestigate the behavior of
sterically less hindered benzyla-
mines and related compounds
in more detail (Table 4). After
reproducing the result obtained
with diphenylacetylene (1) and
9
12
12
10
2.6:1
7
(entry 1, Table 4), we ob-
[a] Reaction conditions: 1) Alkyne (2.40 mmol), amine (2.64 mmol), [Ind2TiMe2] (0.12 mmol, 5.0 mol%), tolu-
ene (1.0 mL), 75 1058C, 1 24 h; 2) NaBH3CN (4.80 mmol), ZnCl2 (2.40 mmol), MeOH (10 mL), 258C, 20 h. tained an even worse result
Yields refer to isolated compounds. [b] Reaction time has not been minimized.
with 1 and 4-methoxybenzyla-
mine (46). Under standard con-
formed under standard conditions in the presence of
5.0 mol% catalyst. Although reactions were fast at 1058C,
better yields and regioselectivities were obtained at 758C
ditions, after 48 h reaction time in the hydroamination step
and subsequent reduction, the yield was only 22% (entry 2,
Table 4). Since our initial result obtained with the sterically
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Catalytic Hydroamination of Alkynes
3059 3071
Table 4. [Ind2TiMe2]-catalyzed hydroamination of diphenylacetylene (1)
with benzyl- and n-alkylamines and subsequent reduction.
the reactions are performed in sealed Schlenk tubes at
1058C one can assume that under the reaction conditions
the majority of n-propylamine (6) is in the gas phase rather
than in the liquid phase. Therefore, the concentration of 6 in
the liquid phase, where the reaction takes place, is low.
Since the concentration of the amine in the liquid phase in-
creases with increasing boiling point of the amine, the con-
centration of n-butylamine (48) in the liquid phase is higher
under the reaction conditions than that of n-propylamine
(6). The highest amine concentrations in the liquid phase
are expected for n-pentylamine (49) and n-hexylamine (50),
because the boiling points of these amines are above or in
the range of the reaction temperature. Furthermore, the
boiling points of the other sterically less hindered amines 7
(1848C), 46 (2368C), and 47 (1598C) are also above 1058C.
Therefore, their behavior is comparable to those of 49 and
50. Since the best results in hydroamination/reduction se-
quences employing sterically less hindered amines such as n-
alkyl- and benzylamines are obtained with low-boiling
amines it is conceivable that the rates of [Ind2TiMe2]-cata-
lyzed hydroamination reactions employing these substrates
increase with decreasing amine concentration in the liquid
phase. Bergman et al. reported in 1992 that the zirconium
bisamide-catalyzed hydroamination reaction between diphe-
nylacetylene (1) and 2,6-dimethylaniline (18) is inverse first
order with respect to the concentration of the amine.[4b] Ac-
cordingly, fast, high-yield [Ind2TiMe2]-catalyzed hydroami-
nation of n-alkyl- and benzylamines should be possible if
the concentration of the amine is kept lowduring the entire
reaction.
Entry
1
Amine
t [h]
Recovered 1 [%]
Yield [%][a]
48
62
30 (13)
2
3
48
48
58
69
22 (51)
22 (52)
4
5
6
7
3
24
24
24
89 (12)
41 (53)
19 (54)
20 (55)
56
80
74
[a] Reaction conditions: 1) Alkyne 1 (2.40 mmol), amine (2.64 mmol),
[Ind2TiMe2] (0.12 mmol, 5.0 mol%), toluene (1.0 mL), 1058C, 3 48 h;
2) NaBH3CN (4.80 mmol), ZnCl2 (2.40 mmol), MeOH (10 mL), 258C,
20 h. Yields refer to isolated pure compounds.
less hindered n-propylamine (6) was much better (89%, 3 h
reaction time for the hydroamination step), we thought that
the benzylic position of the amino group might be responsi-
ble for the lack of reactivity of benzylamine derivatives. To
verify this idea, we performed a comparable hydroamination
reaction with 1 and cyclohexylmethylamine (47, entry 3,
Table 4). To our surprise, the result was as poor (22%) as
that obtained with benzylamine derivative 46. Since there is
no obvious difference between the alkylamines 47 and 6 we
additionally performed hydroamination/reduction sequences
with 1 and n-butyl- (48), n-pentyl- (49), and n-hexylamine
(50). Surprisingly, all these reactions were significantly
slower than the reaction of n-propylamine (6). After per-
forming the hydroaminations of 1 with 48, 49, and 50 for
24 h, the products 53, 54, and 55 were isolated after subse-
quent reduction in only 41, 19, and 20% yield, respectively
(entries 5 7, Table 4). In all cases, large amounts of uncon-
verted alkyne 1 were recovered. While the results obtained
with n-pentyl- (49) and n-hexylamine (50) are similar to
those obtained with benzylamines 7 and 46 and cyclohexyl-
methyl derivative 47, the 41% yield of the reaction between
1 and n-butylamine (48) is remarkable. Since the structural
differences of the n-alkylamines 6, 48, 49, and 50 are remote
from the reactive NH2 group and therefore should not be re-
sponsible for significant changes in the reactivity of these
substrates, we sought an alternative explanation for the
strange behavior of the sterically unhindered n-alkylamines
in [Ind2TiMe2]-catalyzed hydroamination reactions.
To verify this idea, we performed a slightly modified reac-
tion between 1 and 50 in the presence of 5.0 mol% of
[Ind2TiMe2] at 1058C (Scheme 3). At the beginning of the
Scheme 3. [Ind2TiMe2]-catalyzed hydroamination of diphenylacetylene
(1) with n-hexylamine (50) and subsequent reduction.
experiment we added only 15 mol% of amine 50 to the re-
action mixture. After 30 min at 1058C we added another
10 mol% of 50. The remaining 80 mol% of 50 (ꢀ=
105 mol%) was then added in eight portions of 10 mol%
over a period of 4 h at 1058C. Finally, the mixture was stir-
red for a further 2 h at 1058C. Thus, the desired product 55
was obtained with 72% yield after subsequent reduction.
Compared to the same reaction performed without slow ad-
dition of the amine (20% yield, 24 h reaction time for the
hydroamination step) the yield is remarkably improved.
Clearly, much higher yields of [Ind2TiMe2]-catalyzed hydroa-
mination reactions of alkynes employing sterically less hin-
dered amines are obtained when the amine is added slowly
to the reaction mixture.
One difference between 6, 48, 49, and 50 is the boiling
point: n-propylamine (6), 488C; n-butylamine (48), 788C; n-
pentylamine (49), 1048C; n-hexylamine (50), 1318C. Since
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S. Doye et al.
FULL PAPER
To determine whether slow addition of the amine can also
improve the yields of other hydroaminations with sterically
less hindered amines, we performed some additional reac-
tions. In an initial set of experiments with alkyne 1, addition
of benzylamine (7) or n-hexylamine (50) to the reaction
mixture over a period of 4 h by syringe pump was followed
by reduction. The desired products 13 and 55 were both ob-
tained in 67% yield (Scheme 4).
of the amine must be regarded as the first possibility for per-
forming high-yield additions of sterically less demanding n-
alkyl- and benzylamines to unsymmetrically substituted 1-
aryl-2-alkylalkynes with high regioselectivity.
To compare the activities of [Ind2TiMe2] and [Cp2TiMe2]
and to obtain some mechanistic insight, a kinetic investiga-
tion was carried out. For this purpose, we chose the addition
of 4-methylaniline (2) to 1-phenylpropyne (20), which was
already used for a detailed kinetic investigation of the
[Cp2TiMe2]-catalyzed hydroamination of alkynes (Sche-
me 6).[7c]
Scheme 6. Kinetically investigated reaction of 1-phenylpropyne (20) and
4-methylaniline (2).
In the presence of ferrocene as internal standard, the
Scheme 4. [Ind2TiMe2]-catalyzed hydroamination of diphenylacetylene
(1) with benzyl- and n-alkylamines and subsequent reduction.
changes in the concentrations of 2, 20, and 58 (two isomers)
1
could be determined by H NMR spectroscopy. The kinetic
experiments were carried out with a ninefold excess of
Finally, we focused on two reactions of the unsymmetri-
cally substituted alkyne 1-phenylpropyne (20) with the steri-
cally less hindered amines benzylamine (7) and n-hexyla-
mine (50). In these experiments, the amines were added
over 2 h by syringe pump. After subsequent reduction, re-
gioisomeric mixtures of the products 56a/b and 57a/b were
obtained in 76 and 83% yield, respectively (Scheme 5).
amine 2 at 105ꢀ0.18C, and the concentration of alkyne 20
1
was monitored as a function of time by H NMR spectrosco-
py. All experiments in the presence of varying amounts of
[Ind2TiMe2] showed a first-order disappearance of alkyne
20; hence, the rate lawin Equation (1) ( n=reaction rate)
describes the reaction.
dcð20Þ
ð1Þ
n ¼ À
¼ kobscð20Þ
dt
A plot of the obtained kobs for different concentrations of
[Ind2TiMe2] versus c([Ind2TiMe2]) is shown in Figure 1. A
corresponding plot for [Cp2TiMe2][7c] is also included. For all
Scheme 5. [Ind2TiMe2]-catalyzed hydroamination of 1-phenylpropyne
(20) with benzyl- and n-alkylamines and subsequent reduction.
~
Figure 1. Plot of kobs versus the concentrations of [Ind2TiMe2] ( ) and
^
[Cp2TiMe2] ( ).
Most impressively, the reactions which favor the forma-
tion of the anti-Markovnikov products take place with high
regioselectivities (ꢁ16:1). In comparison, the same reactions
catalyst concentrations reactions in the presence of
[Ind2TiMe2] are much faster than reactions in the presence
of [Cp2TiMe2]. Therefore, [Ind2TiMe2] must be regarded as
a more active catalyst than [Cp2TiMe2], at least for the in-
vestigated transformation. Unfortunately, direct comparison
take place with regioselectivities of less than 3:1 in the pres-
[8]
*
ence of [Cp2 TiMe2]. Therefore, the use of [Ind2TiMe2] as
hydroamination catalyst in combination with slow addition
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 3059 3071

Catalytic Hydroamination of Alkynes
3059 3071
of the catalytic activities of [Ind2TiMe2] and titanium dipyr-
rolylmethane catalysts is not possible at the moment, be-
cause for the latter catalysts, reaction rates were determined
for a different reaction.[11d] The linear relationship between
kobs and the concentration of [Ind2TiMe2] indicates that the
reaction is first-order in the concentration of [Ind2TiMe2].
The small deviation from linearity for high catalyst concen-
trations can be explained by the fact that the hydroamina-
tion reactions are very fast in these cases. As a result, the
hydroamination reactions already proceed significantly
while [Ind2TiMe2] is still being converted to the catalytically
active species. Therefore, the obtained kobs data are not as
high as expected for these catalyst concentrations. Since the
curve obtained for [Cp2TiMe2] can only be explained by a
reversible dimerization of the catalytically active species (a
titanium imido complex), the [Ind2TiMe2]-catalyzed hydro-
amination obviously takes place without a corresponding di-
merization of an imido complex. Given this result and other
mechanistic investigations of Zr- and Ti-catalyzed hydroami-
nations,[4b,7c,10a,17] the catalytic cycle shown in Scheme 7
centration of alkyne 20 and first-order in the concentration
of [Ind2TiMe2]. With regard to the concentration of amine
2, two possibilities exist. With the assumption kÀ2 @k3c(2)
the reaction rate is zero-order in the concentration of amine
2. Therefore, the amine concentration does not influence
the rate of the hydroamination. With the assumption kÀ2
!
k3c(2) the rate of the reaction is inverse-first-order in the
concentration of amine 2. Such a dependence has already
been observed for the Zr-catalyzed addition of 2,6-dimethy-
laniline (18) to diphenylacetylene (1).[4b] As a result, the hy-
droamination is assumed to be fast for lowamine concentra-
tions and slowfor high amine concentrations. Since the
latter case was qualitatively observed for hydroamination re-
actions with sterically less hindered n-alkyl- and benzyla-
mines, one can assume that for these amines the protonation
of the azametallacyclobutene intermediate (k3) is faster than
its cleavage into the alkyne and the catalytically active tita-
nium imido complex (kÀ2). Note that with the assumption
kÀ2 !k3c(2) the rate of a corresponding hydroamination re-
action that involves reversible dimerization of the catalyti-
cally active imido complex is also expected to increase with
decreasing amine concentration.[7c] However, in this case, a
more complex relationship between the rate and the amine
concentration is expected. Thus, the behavior observed for
n-alkyl- and benzylamines can easily be understood. To
verify the observation that hydroamination reactions of ster-
ically less demanding amines are indeed fast for lowamine
concentrations, an initial NMR experiment was performed.
An NMR tube containing a mixture of 1.30 mmol diphenyl-
acetylene (1), 0.14 mmol benzylamine (7) (ratio 9:1),
0.0013 mmol [Ind2TiMe2] (9.3 mol%), 0.5 mL [D8]toluene,
and hydroquinone dimethyl ether as internal standard was
heated to 1058C. Unfortunately, the progress of the reaction
could not be monitored exactly because the reaction went to
completion within less than 5 min. However, this finding un-
doubtedly proves that the investigated reaction is indeed
fast for lowamine concentrations. The fact that a corre-
sponding reaction is extremely slowfor high amine concen-
trations was confirmed in an additional kinetic experiment.
In this case, a Schlenk tube containing a mixture of benzyla-
mine (7, c(7)=2.42 molLÀ1), 1-phenylpropyne (20, c0(20)=
0.27 molLÀ1, ratio 9:1), [Ind2TiMe2] [c([Ind2TiMe2])=1.72î
10À2 molLÀ1 (6.4 mol%)], toluene, and hydroquinone di-
methyl ether as internal standard was heated to 1058C. As
expected, the reaction did not reach 10% conversion after
40 h.
Scheme 7. Proposed mechanism of the [Ind2TiMe2]-catalyzed hydroami-
nation of 1-phenylpropyne (20) with 4-methylaniline (2).
seems to be appropriate to describe the [Ind2TiMe2]-cata-
lyzed addition of 2 to 20. This catalytic cycle, which is essen-
tially the same as that published by Bergman et al. for the
Zr-catalyzed addition of 2,6-dimethylaniline (18) to dipheny-
lacetylene (1),[4b] includes irreversible and quantitative trans-
formation of [Ind2TiMe2] into the catalytically active imido
complex 59, reversible addition of 2 to 59, reversible [2+2]
cycloaddition between 59 and alkyne 20, irreversible proto-
nation of the formed azametallacyclobutene 61, and final a-
elimination of the product, which regenerates 59.
Conclusion
By applying a steady-state assumption to the mechanism
shown in Scheme 7 with respect to all intermediates, the
rate lawgiven in Equation (2) can be derived.
In summary, the investigation presented here undoubtedly
proves that [Ind2TiMe2] is a highly active and general cata-
lyst for the intermolecular hydroamination of alkynes. With
this catalyst, reactions of primary aryl-, tert-alkyl-, sec-alkyl-,
and n-alkylamines can be performed with internal and ter-
minal alkynes. In the case of unsymmetrically substituted 1-
phenyl-2-alkylalkynes, the reactions take place with modest
to excellent regioselectivities, and formation of the anti-Mar-
kovnikov regioisomers is favored. While the major product
[4b]
k1k2k3cð20Þcð½Ind2TiMe2ŠÞ
ð2Þ
n ¼
kÀ1½kÀ2 þ k3cð2ފ
Equation (2) is in good agreement with the experimental-
ly observed facts that the reaction is first-order in the con-
Chem. Eur. J. 2004, 10, 3059 3071
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3065

S. Doye et al.
FULL PAPER
heated to 1058C (TLC control). Then, the mixture was cooled to room
temperature and a mixture of NaBH3CN (302 mg, 4.80 mmol) and ZnCl2
(326 mg, 2.40 mmol) in methanol (10 mL) was added. After this mixture
had been stirred at 258C for 20 h, CH2Cl2 (50 mL) and saturated Na2CO3
solution (20 mL) were added. The resulting mixture was filtered and the
solid residue was washed with CH2Cl2 (50 mL). After extraction, the or-
ganic layer was separated. The aqueous layer was extracted with CH2Cl2
(6î50 mL). The combined organic layers were dried with Na2SO4. After
concentration under vacuum, the residue was purified by flash chroma-
tography (SiO2).
of hydroamination reactions of terminal arylalkynes is
always the anti-Markovnikov isomer, alkylalkynes react
with arylamines to give the Markovnikov products prefera-
bly. However, to achieve reasonable rates for the addition of
sterically less hindered n-alkyl- and benzylamines to alkynes
these amines must be added slowly to the reaction mixtures.
This behavior can be understood by the fact that the catalyt-
ic cycle proposed on the basis of an initial kinetic investiga-
tion includes the possibility that the rate of the reaction in-
creases with decreasing concentration of the employed
amine. Furthermore, the same kinetic study revealed that no
dimerization of the catalytically active imido complex is ob-
served for hydroamination reactions of alkyne 20 with 4-
methylaniline (2) in the presence of [Ind2TiMe2] as catalyst.
This finding is in contrast to results obtained for correspond-
ing [Cp2TiMe2]-catalyzed reactions. In general, a one-pot
combination of the [Ind2TiMe2]-catalyzed hydroamination of
alkynes with a subsequent reduction leads to the formation
of secondary amines with good to excellent yields. At
1058C, in the presence of 5.0 mol% [Ind2TiMe2], typical re-
action times for the hydroamination step are in the range of
1 24 h. Particularly impressive is the fact that using
[Ind2TiMe2] makes it possible for the first time to perform
reactions of n-alkyl- and benzylamines with 1-phenylpro-
pyne (20) in a highly regioselective fashion. In our opinion,
[Ind2TiMe2] is the first general catalyst with improved activi-
ty that can be used efficiently for all substrate combinations
in intermolecular hydroamination reactions. Moreover,
[Ind2TiMe2] is a stable crystalline compound that can be
conveniently handled in air. It can be synthesized in one
step from [Ind2TiCl2] and methyllithium.[15] [Ind2TiMe2] is
also commercially available.[18]
Hydroamination of diphenylacetylene (1) with n-hexylamine (50): A
Schlenk tube equipped with a Teflon stopcock and a magnetic stirring
bar was charged with diphenylacetylene (1, 428 mg, 2.40 mmol), n-hexyl-
amine (50, 36 mg, 0.36 mmol), [Ind2TiMe2] (37 mg, 0.12 mmol, 5.0 mol%),
and toluene (1.0 mL). The resulting mixture was heated to 1058C. After
30 min at 1058C another portion of 50 (24 mg, 0.24 mmol) was added to
the reaction mixture. The remaining 50 (192 mg, 1.92 mmol) was added
in eight portions (0.24 mmol every 30 min) over 4 h. Finally, the mixture
was stirred for a further 2 h at 1058C. Then, the mixture was cooled to
room temperature, and a mixture of NaBH3CN (302 mg, 4.80 mmol) and
ZnCl2 (326 mg, 2.40 mmol) in methanol (10 mL) was added. After the re-
sulting mixture had been stirred at 258C for 20 h, CH2Cl2 (50 mL) and sa-
turated Na2CO3 solution (20 mL) were added. The resulting mixture was
filtered and the solid residue was washed with CH2Cl2 (50 mL). After ex-
traction, the organic layer was separated. The aqueous layer was extract-
ed with CH2Cl2 (6î50 mL). The combined organic layers were dried with
Na2SO4. After concentration under vacuum and purification by flash
chromatography (PE/EtOAc, 5/1), 55 (487 mg, 1.73 mmol, 72%) was iso-
lated as a colorless oil. For characteristic data, see Amine 55.
Hydroamination of diphenylacetylene (1) with n-alkyl- and benzyl-
amines: general procedure B: A Schlenk tube equipped with a rubber
septum and a magnetic stirring bar was charged with diphenylacetylene
(1, 428 mg, 2.40 mmol), [Ind2TiMe2] (37 mg, 0.12 mmol, 5.0 mol%), and
toluene (1.0 mL). The resulting mixture was heated to 1058C, and a solu-
tion of the amine (2.64 mmol) in toluene (c=2.64 molLÀ1) was added by
syringe pump over 4 h. Then, the mixture was cooled to room tempera-
ture, and
a mixture of NaBH3CN (302 mg, 4.80 mmol) and ZnCl2
(326 mg, 2.40 mmol) in methanol (10 mL) was added. After the resulting
mixture had been stirred at 258C for 20 h, CH2Cl2 (50 mL) and saturated
Na2CO3 solution (20 mL) were added. The resulting mixture was filtered
and the solid residue was washed with CH2Cl2 (50 mL). After extraction,
the organic layer was separated. The aqueous layer was extracted with
CH2Cl2 (6î50 mL). The combined organic layers were dried with
Na2SO4. After concentration under vacuum, the residue was purified by
flash chromatography (SiO2).
Experimental Section
General: All reactions were performed under an inert atmosphere of
argon in flame-dried Duran glassware (e.g., Schlenk tubes equipped with
Teflon stopcocks). Toluene was distilled from molten sodium under
argon. Methanol was dried with molecular sieves (3 ä). [Ind2TiMe2] w as
synthesized according to ref. [15]. Diphenylacetylene (1) was dissolved in
CH2Cl2, dried with Na2SO4, and recovered by evaporation of the solvent.
All other alkynes (except 20 and 33) and amines (except 5) were distilled
and stored over molecular sieves (4 ä). All other reagents were pur-
chased from commercial sources and were used without further purifica-
tion. Unless otherwise noted, yields refer to isolated pure compounds, as
gauged by TLC and 1H and 13C NMR. All products were characterized
by 1H NMR, 13C NMR, and IR spectroscopy, and mass spectrometry
(MS). Additional characteristic data were obtained by high-resolution
MS (HRMS) and/or CHN elemental analysis. NMR spectra were record-
Hydroamination of 1-phenylpropyne (20) with n-alkyl- and benzyl-
amines: general procedure C: A Schlenk tube equipped with a rubber
septum and a magnetic stirring bar was charged with 1-phenylpropyne
(20, 279 mg, 2.40 mmol), [Ind2TiMe2] (37 mg, 0.12 mmol, 5.0 mol%), and
toluene (1.0 mL). The resulting mixture was heated to 1058C, and a solu-
tion of the amine (2.64 mmol) in toluene (c=2.64 molLÀ1) was added by
syringe pump over 2 h. Then, the mixture was cooled to room tempera-
ture, and
a mixture of NaBH3CN (302 mg, 4.80 mmol) and ZnCl2
(326 mg, 2.40 mmol) in methanol (10 mL) was added. After this mixture
had been stirred at 258C for 20 h, CH2Cl2 (50 mL) and saturated Na2CO3
solution (20 mL) were added. The resulting mixture was filtered and the
solid residue was washed with CH2Cl2 (50 mL). After extraction, the or-
ganic layer was separated. The aqueous layer was extracted with CH2Cl2
(6î50 mL). The combined organic layers were dried with Na2SO4. After
concentration under vacuum, the residue was purified by flash chroma-
tography (SiO2).
1
ed on a Bruker Avance 400 MHz spectrometer. All H NMR data are re-
ported relative to TMS as internal standard. All 13C NMR data are re-
ported relative to the central line of the triplet for CDCl3 at d=
77.0 ppm. IR spectra were recorded on a Bruker Vector 22 spectrometer
by using an attenuated total reflection (ATR) method. Mass spectra were
recorded on a Finnigan MAT 312 or a VG Autospec (EI) with an ioniza-
tion potential of 70 eV or a Micromass LCT (ESI). Elemental analyses
were carried out on an Elementar Vario EL machine. PE: light petrole-
um ether, b.p. 40 608C.
Amine 8: General procedure A was used to synthesize amine 8 from di-
phenylacetylene (1) and 4-methylaniline (2). The reaction time of the hy-
droamination step was 24 h. After purification by flash chromatography
(PE/EtOAc, 40/1), 8 (675 mg, 2.35 mmol, 98%) was isolated as a color-
less oil. 1H NMR (400 MHz, CDCl3): d=7.17 7.32 (m, 8H), 7.09 7.11
(m, 2H), 6.85 (d, J=8.0 Hz, 2H), 6.37 (d, J=8.5 Hz, 2H), 4.54 (dd, J=
5.6, 8.3 Hz, 1H), 4.02 (brs, 1H), 3.11 (dd, J=5.6, 13.9 Hz, 1H), 2.98 (dd,
J=8.3, 14.1 Hz, 1H), 2.15 ppm (s, 3H); 13C NMR (100.6 MHz, DEPT,
CDCl3): d=145.0 (C), 143.6 (C), 137.8 (C), 129.5 (CH), 129.2 (CH),
128.5 (CH), 128.5 (CH), 127.0 (CH), 126.6 (CH), 126.6 (C), 126.4 (CH),
Hydroamination of alkynes: general procedure A: A Schlenk tube equip-
ped with a Teflon stopcock and a magnetic stirring bar was charged with
the alkyne (2.40 mmol), the amine (2.64 mmol), [Ind2TiMe2] (37 mg,
0.12 mmol, 5.0 mol%), and toluene (1.0 mL). The resulting mixture was
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 3059 3071

Catalytic Hydroamination of Alkynes
3059 3071
113.8 (CH), 59.5 (CH), 45.1 (CH2), 20.3 ppm (CH3); IR (neat): n˜ =3407,
3026, 2917, 1617, 1519, 1494, 1453, 1301, 808, 757, 700 cmÀ1; MS (258C):
m/z (%): 287 (11) [M+], 196 (100) [M+ÀC7H7], 91 (29) [C7H7+]; HRMS
calcd for C21H21N: 287.1674; found: 287.1674; elemental analysis (%)
calcd for C21H21N: C 87.76, H 7.37, N 4.87; found: C 87.63, H 7.44, N
4.83.
140.5 (C), 138.8 (C), 129.2 (CH), 128.4 (CH), 128.3 (CH), 128.2 (CH),
127.9 (CH), 127.4 (CH), 127.1 (CH), 126.7 (CH), 126.3 (CH), 63.6 (CH),
51.3 (CH2), 45.3 ppm (CH2); IR (neat): n˜ =3026, 1601, 1494, 1453, 1113,
1028, 756, 694 cmÀ1; MS (1008C): m/z (%): 196 (91) [M+ÀC7H7], 91
(100) [C7H7+]; HRMS calcd for C14H14N: 196.1126; found: 196.1127; ele-
mental analysis (%) calcd for C21H21N: C 87.76, H 7.36, N 4.87; found: C
87.52, H 7.38, N 4.91.
Amine 9: General procedure A was used to synthesize amine 9 from di-
phenylacetylene (1) and tert-butylamine (3). The reaction time of the hy-
droamination step was 5 h. After purification by flash chromatography
(PE/EtOAc, 10/1), 9 (511 mg, 2.02 mmol, 84%) was isolated as a color-
less oil. 1H NMR (400 MHz, CDCl3): d=7.38 (d, J=7.4 Hz, 2H), 7.24
7.29 (m, 4H), 7.17 7.21 (m, 2H), 7.12 (d, J=7.0 Hz, 2H), 3.98 (dd, J=
5.6, 9.0 Hz, 1H), 2.92 (dd, J=5.6, 12.0 Hz, 1H), 2.72 (dd, J=9.0, 12.0 Hz,
1H), 1.20 (brs, 1H), 0.84 ppm (s, 9H); 13C NMR (100.6 MHz, DEPT,
CDCl3): d=147.6 (C), 139.3 (C), 129.3 (CH), 128.3 (CH), 128.0 (CH),
127.1 (CH), 126.4 (CH), 126.3 (CH), 59.2 (CH), 51.1 (C), 47.2 (CH2),
29.9 ppm (CH3); IR (neat): n˜ =2958, 1601, 1493, 1453, 1364, 1228, 1096,
1069, 1027, 757, 697 cmÀ1; MS (258C): m/z (%): 238 (4) [M+ÀCH3], 162
(32) [M+ÀC7H7], 106 (100) [C7H8N+], 91 (9) [C7H7+]; HRMS calcd for
C17H20N: 238.1596; found: 238.1593; elemental analysis (%) calcd for
C18H23N: C 85.32, H 9.15, N 5.53; found: C 85.11, H 8.87, N 5.78.
Amine 16: General procedure A was used to synthesize amine 16 from
3-hexyne (14) and (ꢀ)-1-phenylethylamine (15). The reaction time of the
hydroamination step was 24 h (not minimized). After purification by
flash chromatography (PE/EtOAc, 10/1), 16 (399 mg, 1.95 mmol, 81%)
was isolated as a colorless oil. The two diastereomers (ratio 1:1 (GC))
could not be separated by flash chromatography. The data refer to the
mixture of diastereomers. 1H NMR (400 MHz, CDCl3): d=7.21 7.31 (m,
5H), 3.86 (dq, J=2.5, 6.7 Hz, 1H), 2.25 2.30 (m, 1H), 1.12 1.50 (m, 7H),
1.32 (d, J=6.7 Hz, 3H), 0.78 0.91 ppm (m, 6H); 13C NMR (100.6 MHz,
DEPT, CDCl3): d=146.5 (C), 146.4 (C), 128.2 (CH), 126.6 (CH), 55.4
(CH), 55.1 (CH), 54.9 (CH), 54.7 (CH), 36.5 (CH2), 35.7 (CH2), 27.1
(CH2), 25.7 (CH2), 24.9 (CH3), 24.8 (CH3), 19.0 (CH2), 18.5 (CH2), 14.5
(CH3), 14.2 (CH3), 10.1 (CH3), 9.1 ppm (CH3); IR (neat): n˜ =2957, 2925,
2871, 1452, 1368, 1120, 760, 699 cmÀ1; MS (258C): m/z (%): 190 (24) [M+
ÀCH3], 176 (53) [M+ÀC2H5], 161 (42) [M+ÀC3H8], 105 (100) [C7H7N+],
106 (37) [M+ÀC7H7N]; elemental analysis (%) calcd for C14H23N: C
81.89, H 11.29, N 6.82; found: C 82.18, H 11.19, N 6.91.
Amine 10: General procedure A was used to synthesize amine 10 from
diphenylacetylene (1) and cyclopentylamine (4). The reaction time of the
hydroamination step was 3 h. After purification by flash chromatography
(PE/EtOAc, 5/1), 10 (579 mg, 2.18 mmol, 91%) was isolated as a color-
less oil. 1H NMR (400 MHz, CDCl3): d=7.10 7.30 (m, 10H), 3.92 (dd,
J=6.0, 8.0 Hz, 1H), 2.82 2.92 (m, 3H), 1.67 1.73 (m, 2H), 1.47 1.53 (m,
3H), 1.35 1.39 (m, 2H), 1.11 1.18 ppm (m, 2H); 13C NMR (100.6 MHz,
DEPT, CDCl3): d=144.2 (C), 139.0 (C), 129.2 (CH), 128.3 (CH), 128.2
(CH), 127.3 (CH), 126.9 (CH), 126.2 (CH), 63.2 (CH), 57.3 (CH), 45.4
(CH2), 33.7 (CH2), 32.3 (CH2), 23.5 (CH2), 23.5 ppm (CH2); IR (neat):
n˜ =2948, 1946, 1602, 1493, 1453, 756, 699 cmÀ1; MS (258C): m/z (%): 264
(2) [M+], 174 (100) [M+ÀC7H7], 106 (59) [C7H8N+], 91 (27) [C7H7+]; el-
emental analysis (%) calcd for C19H23N: C 85.99, H 8.74, N 5.28; found:
C 85.82; H 8.76; N 5.24.
Amine 19: General procedure A was used to synthesize amine 19 from
4-octyne (17) and 2,6-dimethylaniline (18). The reaction time of the hy-
droamination step was 24 h (not minimized). After purification by flash
chromatography (PE/EtOAc, 40/1), compound 19 (513 mg, 2.20 mmol,
92%) was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3): d=
6.95 (d, J=7.4 Hz, 2H), 6.75 (t, J=7.4 Hz, 1H), 3.19 3.20 (m, 1H), 2.84
(brs, 1H), 2.24 (s, 6H), 1.23 1.47 (m, 10H), 0.85 0.89 ppm (m, 6H);
13C NMR (100.6 MHz, DEPT, CDCl3): d=145.3 (C), 128.9 (CH), 128.3
(C), 120.6 (CH), 55.9 (CH), 37.9 (CH2), 35.2 (CH2), 28.2 (CH2), 23.0
(CH2), 19.2 (CH2), 14.3 (CH3), 14.1 ppm (CH3); IR (neat): n˜ =2955, 2929,
2859, 1995, 1473, 1257, 1221, 1099, 760, 711 cmÀ1; MS (258C): m/z (%):
233 (28) [M+], 190 (100) [M+ÀC3H7], 176 (78) [M+ÀC4H9]; HRMS
calcd for C16H27N: 233.2144; found: 233.2140; elemental analysis (%)
calcd for C16H27N: C 82.34, H 11.66, N 6.00; found: C 82.21, H 11.38, N
6.11.
Amine 11: General procedure A was used to synthesize amine 11 from
diphenylacetylene (1) and benzhydrylamine (5). The reaction time of the
hydroamination step was 5 h. After purification by flash chromatography
(PE/EtOAc, 40/1), 11 (781 mg, 2.15 mmol, 90%) was isolated as a color-
less oil. 1H NMR (400 MHz, CDCl3): d=7.13 7.34 (m, 16H), 7.05 7.07
(m, 2H), 6.91 6.93 (m, 2H), 4.56 (s, 1H), 3.74 (dd, J=5.4, 8.7 Hz, 1H),
2.86 2.97 (m, 2H), 2.01 ppm (brs, 1H); 13C NMR (100.6 MHz, DEPT,
CDCl3): d=144.6 (C), 143.8 (C), 143.0 (C), 138.9 (C), 129.4 (CH), 128.4
(CH), 128.3 (CH), 128.2 (CH), 128.2 (CH), 127.6 (CH), 127.3 (CH),
127.3 (CH), 127.0 (CH), 126.8 (CH), 126.7 (CH), 126.3 (CH), 63.2 (CH),
61.3 (CH), 45.2 ppm (CH2); IR (neat): n˜ =3025, 1600, 1492, 1452, 1028,
744, 694 cmÀ1; MS (1408C): m/z (%): 272 (31) [M+ÀC7H7], 167 (100)
[C13H11+], 91 (8) [C7H7+]; elemental analysis (%) calcd for C20H27N: C
85.35, H 9.67, N 4.98; found: C 85.15, H 9.61, N 5.19.
Amines 23a/23b: General procedure A was used to synthesize amines
23a/23b from 1-phenylpropyne (20) and 4-methylaniline (2). The reac-
tion time of the hydroamination step was 24 h (not minimized). After pu-
rification by flash chromatography (PE/EtOAc, 40/1), 23a (522 mg,
2.33 mmol, 97%) and 23b (11 mg, 0.05 mmol, 2%) were isolated as col-
orless oils. 23a: 1H NMR (400 MHz, CDCl3): d=7.25 7.32 (m, 2H),
7.15 7.23 (m, 3H), 6.99 (d, J=8.0 Hz, 2H), 6.55 (d, J=8.4 Hz, 2H), 3.66
3.77 (m, 1H), 2.93 (dd, J=4.7, 13.4 Hz, 1H), 2.67 (dd, J=7.3, 13.3 Hz,
1H), 2.24 (s, 3H), 1.13 ppm (d, J=6.4 Hz, 3H); 13C NMR (100.6 MHz,
DEPT, CDCl3): d=145.0 (C), 138.7 (C), 129.9 (CH), 129.5 (CH), 128.3
(CH), 126.4 (C), 126.2 (CH), 113.7 (CH), 49.7 (CH), 42.4 (CH2), 20.4
(CH3), 20.2 ppm (CH3); IR (neat): n˜ =2920, 1617, 1517, 1452, 1250, 1150,
805, 743, 699 cmÀ1; MS (258C): m/z (%): 225 (34) [M+], 134 (100) [M+
ÀC7H7], 91 (34) [C7H7+]; HRMS calcd for C16H19N: 225.1518; found:
225.1514; elemental analysis (%) calcd for C16H19N: C 85.29, H 8.50, N
6.22; found: C 85.64, H 8.65, N 6.35. 23b: 1H NMR (400 MHz, CDCl3):
d=7.27 7.34 (m, 4H), 7.17 7.23 (m, 1H), 6.88 (d, J=6.5 Hz, 2H), 6.43
(d, J=6.7 Hz, 2H), 4.19 (t, J=6.6 Hz, 1H), 2.17 (s, 3H), 1.74 1.87 (m,
2H), 0.94 ppm (t, J=7.4 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3):
d=145.3 (C), 144.1 (C), 129.6 (CH), 128.4 (CH), 126.8 (CH), 126.5 (CH),
126.2 (C), 113.4 (CH), 60.0 (CH), 31.7 (CH2), 20.3 (CH3), 10.8 ppm
(CH3); IR (neat): n˜ =2963, 2921, 1618, 1518, 1452, 1301, 805, 749,
700 cmÀ1; MS (258C): m/z (%): 225 (46) [M+], 196 (100) [M+ÀC2H5], 91
(49) [C7H7+]; HRMS calcd for C16H19N: 225.1518; found: 225.1518; ele-
mental analysis (%) calcd for C16H19N: C 85.29, H 8.50, N 6.22; found: C
85.24, H 8.40, N 6.14.
Amine 12: General procedure A was used to synthesize amine 12 from
diphenylacetylene (1) and n-propylamine (6). The reaction time of the
hydroamination step was 3 h. After purification by flash chromatography
(PE/EtOAc, 3/1), compound 12 (511 mg, 2.14 mmol, 89%) was isolated
as a colorless oil. 1H NMR (400 MHz, CDCl3): d=7.10 7.35 (m, 10H),
3.83 (dd, J=5.9, 8.0 Hz, 1H), 2.93 (dd, J=5.9, 13.4 Hz, 1H), 2.88 (dd,
J=8.2, 13.4 Hz, 1H), 2.28 2.41 (m, 2H), 1.51 (brs, 1H), 1.37 (sext, J=
7.3 Hz, 2H), 0.76 ppm (t, J=7.4 Hz, 3H); 13C NMR (100.6 MHz, DEPT,
CDCl3): d=144.1 (C), 139.0 (C), 129.2 (CH), 128.3 (CH), 128.2 (CH),
127.3 (CH), 126.9 (CH), 126.3 (CH), 64.8 (CH), 49.6 (CH2), 45.3 (CH2),
23.1 (CH2), 11.6 ppm (CH3); IR (neat): n˜ =2957, 2928, 1602, 1494, 1453,
756, 696 cmÀ1; MS (258C): m/z (%): 239 (2) [M+], 148 (100) [M+ÀC7H7];
elemental analysis (%) calcd for C17H21N: C 85.31, H 8.84, N 5.85;
found: C 84.91, H 8.82, N 5.88.
Amine 13: General procedure B was used to synthesize amine 13 from
diphenylacetylene (1) and benzylamine (7). After purification by flash
chromatography (PE/EtOAc, 5/1), 13 (462 mg, 1.61 mmol, 67%) was iso-
lated as a colorless oil. 1H NMR (400 MHz, CDCl3): d=7.31 7.37 (m,
4H), 7.17 7.28 (m, 7H), 7.09 7.11 (m, 4H), 3.87 (dd, J=5.5, 8.7 Hz, 1H),
3.65 (d, J=13.6 Hz, 1H), 3.45 (d, J=13.6 Hz, 1H), 2.86 2.98 (m, 2H),
1.72 ppm (brs, 1H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=143.7 (C),
Amine 24a: General procedure A was used to synthesize amine 24a
from 1-phenylpropyne (20) and 2,6-dimethylaniline (18). The reaction
time of the hydroamination step was 24 h (not minimized). After purifi-
cation by flash chromatography (PE/EtOAc, 40/1), 24a (515 mg,
2.15 mmol, 90%) was isolated as a colorless oil. 1H NMR (400 MHz,
CDCl3): d=7.25 7.29 (m, 2H), 7.15 7.22 (m, 3H), 6.98 (d, J=7.5 Hz,
Chem. Eur. J. 2004, 10, 3059 3071
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3067

S. Doye et al.
FULL PAPER
2H), 6.79 (t, J=7.4 Hz, 1H), 3.45 3.53 (m, 1H), 2.90 2.94 (m, 2H), 2.54
(dd, J=8.5, 13.0 Hz, 1H), 2.22 (s, 6H), 1.03 ppm (d, J=6.2 Hz, 3H);
13C NMR (100.6 MHz, DEPT, CDCl3): d=144.8 (C), 139.4 (C), 129.4
(CH), 129.2 (C), 128.9 (CH), 128.2 (CH), 126.1 (CH), 121.4 (CH), 54.0
(CH), 44.4 (CH2), 20.8 (CH3), 19.0 ppm (CH3); IR (neat): n˜ =2962, 1594,
1473, 1453, 1259, 1220, 1099, 761, 737, 698; MS (258C): m/z (%): 239 (9)
[M+], 148 (100) [M+ÀC7H7]; HRMS calcd for C17H21N: 239.1674; found:
239.1667; elemental analysis (%) calcd for C17H21N: C 85.31, H 8.84, N
5.85; found: C 85.12, H 8.58, N 6.53.
805, 750, 698 cmÀ1; MS (608C): m/z (%): 251 (11) [M+], 196 (100) [M+
ÀC4H7], 119 (19) [C8H9N+], 91 (42) [C7H7+]; HRMS calcd for C18H21N:
251.1674; found: 251.1674; elemental analysis (%) calcd for C18H21N: C
86.01, H 8.42, N 5.57; found: C 85.67, H 8.20, N 6.03.
Amines 28a/28b: General procedure A was used to synthesize amines
28a/28b from alkyne 21 and tert-butylamine (3). The reaction time of the
hydroamination step was 24 h (not minimized). After purification by
flash chromatography (PE/EtOAc, 5/1), 28a (338 mg, 1.56 mmol, 65%)
was isolated as a colorless oil. 28b (56 mg, 0.26 mmol, 11%) could not be
obtained in pure form. 28a: 1H NMR (400 MHz, CDCl3): d=7.19 7.31
(m, 5H), 2.88 (dd, J=5.8, 13.3 Hz, 1H), 2.80 (dd, J=7.2, 13.3 Hz, 1H),
2.18 2.23 (m, 1H), 1.38 (brs, 1H), 1.09 (s, 9H), 0.71 0.80 (m, 1H), 0.38
0.47 (m, 2H), 0.13 0.18 (m, 1H), (À0.03) 0.02 ppm (m, 1H); 13C NMR
(100.6 MHz, DEPT, CDCl3): d=139.9 (C), 129.6 (CH), 128.0 (CH), 125.9
(CH), 58.1 (CH), 50.4 (C), 44.9 (CH2), 30.2 (CH3), 18.1 (CH), 4.7 (CH2),
4.1 ppm (CH2); IR (neat): n˜ =2959, 1494, 1454, 1361, 1227, 1017, 743,
Amine 25a: General procedure A was used to synthesize amine 25a
from 1-phenylpropyne (20) and tert-butylamine (3). The reaction time of
the hydroamination step was 24 h (not minimized). After purification by
flash chromatography (PE/EtOAc, 10/1), 25a (368 mg, 1.92 mmol, 80%)
was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3): d=7.26 7.30
(m, 2H), 7.17 7.21 (m, 3H), 2.97 (sext, J=6.6 Hz, 1H), 2.68 (dd, J=6.7,
13.2 Hz, 1H), 2.57 (dd, J=7.3, 13.2 Hz, 1H), 1.17 (brs, 1H), 1.06 (d, J=
6.3 Hz, 3H), 1.01 ppm (s, 9H); 13C NMR (100.6 MHz, DEPT, CDCl3):
d=140.1 (C), 129.2 (CH), 128.2 (CH), 126.0 (CH), 50.9 (C), 49.1 (CH),
46.3 (CH2), 29.8 (CH3), 23.8 ppm (CH3); IR (neat): n˜ =2959, 1494, 1453,
1362, 1228, 743, 698; MS (258C): m/z (%): 191 (22) [M+], 176 (48) [M+
ÀCH3], 105 (71) [C8H9+], 100 (80) [M+ÀC7H7], 91 (100) [C7H7+]; due to
the lowboiling point of 25a, no elemental analysis and no HRMS could
be obtained.
698 cmÀ1
;
MS (258C): m/z (%): 202 (5) [M+ÀCH3], 126 (82) [M+
ÀC7H7], 91 (32) [C7H7+]; HRMS calcd for C14H20N: 202.1596; found:
202.1596; elemental analysis (%) calcd for C15H23N: C 82.89, H 10.67, N
6.44, found: C 82.28, H 10.78, N 6.33.
Amines 29a/29b: General procedure A was used to synthesize amines
29a/29b from alkyne 21 and cyclopentylamine (4). The reaction time of
the hydroamination step was 24 h (not minimized). After purification by
flash chromatography (PE/EtOAc, 5/1!1/1), 29a (467 mg, 2.04 mmol,
85%) and 29b (41 mg, 0.18 mmol, 7%) were isolated as colorless oils.
29a: 1H NMR (400 MHz, CDCl3): d=7.26 7.29 (m, 2H), 7.18 7.21 (m,
3H), 3.33 (quint, J=7.0 Hz, 1H), 2.89 (dd, J=5.5, 13.4 Hz, 1H), 2.78 (dd,
J=7.5, 13.4 Hz, 1H), 1.99 2.05 (m, 1H), 1.40 1.91 (m, 7H), 1.15 1.25 (m,
1H), 1.03 1.11 (m, 1H), 0.67 0.76 (m, 1H), 0.50 0.57 (m, 1H), 0.36 0.43
(m, 1H), 0.18 0.24 (m, 1H), (À0.07) (À0.01) ppm (m, 1H); 13C NMR
(100.6 MHz, DEPT, CDCl3): d=139.5 (C), 129.3 (CH), 128.2 (CH), 126.0
(CH), 62.9 (CH), 56.9 (CH), 42.1 (CH2), 33.7 (CH2), 32.9 (CH2), 23.8
(CH2), 23.7 (CH2), 16.4 (CH), 4.6 (CH2), 2.4 ppm (CH2); IR (neat): n˜ =
2949, 2865, 1603, 1494, 1454, 1017, 742, 697 cmÀ1; MS (258C): m/z (%):
228 (3) [M+ÀH], 138 (100) [M+ÀC7H7], 106 (66) [C7H8N+], 91 (68)
[C7H7+]; HRMS calcd for C16H22N: 228.1752; found: 228.1747. 29b:
1H NMR (400 MHz, CDCl3): d=7.29 7.32 (m, 4H), 7.21 7.26 (m, 1H),
3.75 (t, J=7.0 Hz, 1H), 2.87 (quint, J=7.1 Hz, 1H), 1.57 1.86 (m, 6H),
1.17 1.51 (m, 5H), 0.48 0.58 (m, 1H), 0.38 0.43 (m, 1H), 0.29 0.35 (m,
1H), 0.05 0.10 (m, 1H), (À0.08) (À0.02) ppm (m, 1H); 13C NMR
(100.6 MHz, DEPT, CDCl3): d=144.9 (C), 128.1 (CH), 127.3 (CH), 126.7
(CH), 62.4 (CH), 57.2 (CH), 43.6 (CH2), 33.9 (CH2), 32.7 (CH2), 23.8
(CH2), 23.8 (CH2), 8.3 (CH), 4.6 (CH2), 4.1 ppm (CH2); IR (neat): n˜ =
2950, 2858, 1453, 1015, 753, 699 cmÀ1; MS (258C): m/z (%): 228 (2) [M+
ÀH], 174 (100) [M+ÀC4H7], 106 (85) [C7H8N+], 91 (30) [C7H7+]; HRMS
calcd for C16H22N: 228.1752; found: 228.1744.
Amines 26a/26b: General procedure A was used to synthesize amines
26a/26b from 1-phenylpropyne (20) and cyclopentylamine (4). The reac-
tion time of the hydroamination step was 24 h (not minimized). After pu-
rification by flash chromatography (PE/EtOAc, 5/1!1/1), 26a (408 mg,
2.01 mmol, 84%) and 26b (23 mg, 0.11 mmol, 5%) were isolated as col-
orless oils. 26a: 1H NMR (400 MHz, CDCl3): d=7.26 7.30 (m, 2H),
7.18 7.22 (m, 3H), 3.18 (quint, J=7.1 Hz, 1H), 2.96 (sext, J=6.5 Hz,
1H), 2.74 (dd, J=6.8, 13.2 Hz, 1H), 2.58 (dd, J=6.8, 13.3 Hz, 1H), 1.76
1.93 (m, 2H), 1.44 1.65 (m, 4H), 1.09 1.28 (m, 3H), 1.05 ppm (d, J=
6.3 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=139.6 (C), 129.2
(CH), 128.3 (CH), 126.0 (CH), 56.9 (CH), 52.8 (CH), 43.9 (CH2), 33.8
(CH2), 33.0 (CH2), 23.7 (CH2), 23.6 (CH2), 20.6 ppm (CH3); IR (neat):
n˜ =2953, 2865, 1452, 1372, 1140, 752, 698 cmÀ1; MS (258C): m/z (%): 188
(6) [M+ÀCH3], 112 (100) [M+ÀC7H7], 91 (19) [C7H7+]; HRMS calcd for
C13H18N: 188.1439; found: 188.1439; elemental analysis (%) calcd for
C14H21N: C 82.70, H 10.41, N 6.89; found: C 82.43, H 10.47, N 7.04. 26b:
1H NMR (400 MHz, CDCl3): d=7.14 7.26 (m, 5H), 3.45 (dd, J=5.8,
8.0 Hz, 1H), 2.77 (quint, J=7.0 Hz, 1H), 1.08 1.76 (m, 11H), 0.71 ppm
(t, J=7.4 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=144.6 (C),
128.1 (CH), 127.3 (CH), 126.7 (CH), 63.5 (CH), 57.1 (CH), 33.9 (CH2),
32.7 (CH2), 31.2 (CH2), 23.8 (CH2), 23.8 (CH2), 10.9 ppm (CH3); IR
(neat): n˜ =2950, 2865, 1453, 1015, 753, 699 cmÀ1; MS (258C): m/z (%):
+
203 (2) [M+], 174 (100) [M+ÀC2H5], 106 (76) [C7H8N+], 91 (70) [C7H7
]; HRMS calcd for C14H20N: 202.1596; found: 202.1598.
Amines 30a/30b: General procedure A was used to synthesize amines
30a/30b from alkyne 21 and n-propylamine (6). The reaction time of the
hydroamination step was 24 h (not minimized). After purification by
flash chromatography (PE/EtOAc, 5/1!1/1), 30a (290 mg, 1.43 mmol,
60%) and 30b (95 mg, 0.47 mmol, 20%) were isolated as colorless oils.
30a: 1H NMR (400 MHz, CDCl3): d=7.28 7.32 (m, 2H), 7.21 7.23 (m,
3H), 2.92 (dd, J=5.1, 13.4 Hz, 1H), 2.74 2.81 (m, 2H), 2.48 2.55 (m,
1H), 1.92 1.98 (m, 1H), 1.28 1.53 (m, 3H), 0.85 (t, J=7.4 Hz, 3H), 0.69
0.78 (m, 1H), 0.53 0.60 (m, 1H), 0.39 0.45 (m, 1H), 0.21 0.27 (m, 1H),
(À0.04) 0.02 ppm (m, 1H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=
139.5 (C), 129.3 (CH), 128.2 (CH), 126.0 (CH), 64.8 (CH), 49.8 (CH2),
42.0 (CH2), 23.3 (CH2), 16.1 (CH), 11.7 (CH3), 4.7 (CH2), 2.0 ppm (CH2);
IR (neat): n˜ =2957, 2924, 1494, 1454, 1126, 1018, 741, 697 cmÀ1; MS
(258C): m/z (%): 162 (30) [M+ÀC3H5], 112 (100) [M+ÀC7H7]; elemental
analysis (%) calcd for C14H21N: C 82.70, H 10.41, N 6.89; found: C 82.41,
H 10.50, N 6.87. 30b: 1H NMR (400 MHz, CDCl3): d=7.22 7.32 (m,
5H), 3.68 (t, J=7.0 Hz, 1H), 2.35 2.46 (m, 2H), 1.65 1.72 (m, 2H), 1.41
1.52 (m, 3H), 0.87 (t, J=7.3 Hz, 3H), 0.51 0.59 (m, 1H), 0.39 0.46 (m,
1H), 0.30 0.37 (m, 1H), 0.06 0.11 (m, 1H), (À0.07) (À0.01) ppm (m,
1H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=144.7 (C), 128.2 (CH),
127.2 (CH), 126.7 (CH), 64.0 (CH), 49.7 (CH2), 43.4 (CH2), 23.3 (CH2),
11.8 (CH3), 8.3 (CH), 4.6 (CH2), 4.1 (CH2); IR (neat): n˜ =2958, 2921,
Amines 27a/27b: General procedure A was used to synthesize amines
27a/27b from alkyne 21 and 4-methylaniline (2). The reaction time of
the hydroamination step was 24 h (not minimized). After purification by
flash chromatography (PE/EtOAc, 40/1), 27a (465 mg, 1.85 mmol, 77%)
and 27b (42 mg, 0.17 mmol, 7%) were isolated as colorless oils. 27a:
1H NMR (400 MHz, CDCl3): d=7.19 7.28 (m, 5H), 6.98 (d, J=8.0 Hz,
2H), 6.52 (d, J=8.4 Hz, 2H), 3.52 (brs, 1H), 2.98 3.02 (m, 1H), 2.92 (d,
J=5.4 Hz, 2H), 2.23 (s, 3H), 0.72 0.80 (m, 1H), 0.39 0.50 (m, 2H), 0.23
0.29 (m, 1H), 0.11 0.17 ppm (m, 1H); 13C NMR (100.6 MHz, DEPT,
CDCl3): d=145.4 (C), 138.5 (C), 129.8 (CH), 129.7 (CH), 128.1 (CH),
126.3 (C), 126.1 (CH), 113.5 (CH), 58.3 (CH), 40.6 (CH2), 20.3 (CH3),
15.7 (CH), 3.7 (CH2), 3.0 ppm (CH2); IR (neat): n˜ =3001, 2918, 1616,
1516, 1494, 1453, 1317, 1300, 1248, 805, 699 cmÀ1; MS (258C): m/z (%):
251 (13) [M+], 210 (5) [M+ÀC3H5], 160 (100) [M+ÀC7H7], 91 (23)
[C7H7+]; HRMS calcd for C18H21N: 251.1674; found: 251.1673; elemental
analysis (%) calcd for C18H21N: C 86.01, H 8.42, N 5.57; found: C 85.98,
H 8.21, N 5.89. 27b: 1H NMR (400 MHz, CDCl3): d=7.36 (d, J=7.3 Hz,
2H), 7.29 (t, J=7.5 Hz, 2H), 7.20 (t, J=7.2 Hz, 1H), 6.89 (d, J=8.3 Hz,
2H), 6.44 (d, J=8.4 Hz, 2H), 4.38 (t, J=6.7, 1H), 4.16 (brs, 1H), 2.17 (s,
3H), 1.61 1.75 (m, 2H), 0.64 0.74 (m, 1H), 0.40 0.53 (m, 2H), 0.03
0.15 ppm (m, 2H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=145.3 (C),
144.4 (C), 129.5 (CH), 128.4 (CH), 126.7 (CH), 126.4 (CH), 126.3 (C),
113.4 (CH), 59.2 (CH), 43.9 (CH2), 20.3 (CH3), 8.1 (CH), 4.7 (CH2),
4.4 ppm (CH2); IR (neat): n˜ =2999, 2917, 1617, 1517, 1453, 1300, 1017,
1454, 1126, 1016, 752, 699 cmÀ1
.
Amines 31a/31b: General procedure A was used to synthesize amines
31a/31b from alkyne 22 and tert-butylamine (3). The reaction time of the
3068
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 3059 3071

Catalytic Hydroamination of Alkynes
3059 3071
hydroamination step was 24 h (not minimized). After purification by
flash chromatography (PE/EtOAc, 10/1), a mixture of 31a and 31b
(538 mg, 2.10 mmol, 87%, 31a/31b 3/1) was isolated as a colorless oil.
Only the minor product 31b (105 mg, 0.45 mmol, 19%) could be ob-
tained in pure form after a second chromatographic purification step.
31b: 1H NMR (400 MHz, CDCl3): d=7.32 (d, J=7.2 Hz, 2H), 7.19 (t,
J=7.5 Hz, 2H), 7.08 7.11 (m, 1H), 5.42 (s, 1H), 3.77 (dd, J=4.2,
10.0 Hz, 1H), 1.80 2.07 (m, 6H), 1.44 1.57 (m, 4H), 1.21 (brs, 1H),
0.87 ppm (s, 9H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=148.7 (C),
135.1 (C), 127.9 (CH), 126.9 (CH), 126.1 (CH), 125.2 (CH), 54.6 (CH),
50.8 (C), 49.9 (CH2), 30.1 (CH3), 28.0 (CH2), 25.3 (CH2), 22.9 (CH2),
22.4 ppm (CH2); IR (neat): n˜ =2923, 2855, 1494, 1454, 1361, 1227, 754,
Amine 39a: General procedure A was used to synthesize amine 39a
from 1-dodecyne (33) and tert-butylamine (3). The reaction time of the
hydroamination step was 2 h. After purification by flash chromatography
(MeOH/EtOAc, 1/2), compound 39a (437 mg, 1.81 mmol, 75%) was iso-
lated as a colorless oil. 1H NMR (400 MHz, CDCl3): d=2.53 (t, J=
7.3 Hz, 2H), 1.41 1.48 (m, 2H), 1.26 1.33 (m, 18H), 1.10 (s, 9H),
0.88 ppm (t, J=6.8 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=
50.2 (C), 42.6 (CH2), 31.9 (CH2), 31.1 (CH2), 29.6 (CH2), 29.6 (CH2), 29.6
(CH2), 29.6 (CH2), 29.6 (CH2), 29.3 (CH2), 29.0 (CH3), 27.6 (CH2), 22.7
(CH2), 14.1 ppm (CH3); IR (neat): n˜ =2922, 2853, 1464, 1359, 1231,
692 cmÀ1; MS (258C): m/z (%): 241 (7) [M+], 226 (100) [M+ÀCH3];
HRMS calcd for C15H32N: 226.2535; found: 226.2535.
798 cmÀ1
;
MS (258C): m/z (%): 242 (4) [M+ÀCH3], 162 (79) [M+
Amines 40a/40b: General procedure A was used to synthesize amines
40a/40b from 1-dodecyne (33) and cyclopentylamine (4). The reaction
time of the hydroamination step was 24 h (not minimized). After purifi-
cation by flash chromatography (MeOH/EtOAc, 1/2), 40a (297 mg,
1.17 mmol, 49%) and 40b (198 mg, 0.78 mmol, 32%) were isolated as
colorless oils. 40a: 1H NMR (400 MHz, CDCl3): d=3.06 (quint, J=
6.9 Hz, 1H), 2.58 (t, J=7.4 Hz, 2H), 2.05 (brs, 1H), 1.82 1.90 (m, 2H),
1.64 1.72 (m, 2H), 1.48 1.56 (m, 2H), 1.26 1.38 (m, 20H), 0.88 ppm (t,
J=6.8 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=59.9 (CH),
48.7 (CH2), 33.0 (CH2), 31.9 (CH2), 30.2 (CH2), 29.8 (CH2), 29.7 (CH2),
29.6 (CH2), 29.6 (CH2), 29.6 (CH2), 29.6 (CH2), 29.3 (CH2), 27.5 (CH2),
24.1 (CH2), 24.1 (CH2), 22.7 (CH2), 14.1 ppm (CH3); IR (neat): n˜ =2921,
2852, 1456, 1375, 721 cmÀ1; MS (258C): m/z (%): 253 (13) [M+], 113 (58)
[C8H17+]; HRMS calcd for C17H35N: 253.2770; found: 253.2765. 40b:
1H NMR (400 MHz, CDCl3): d=3.23 (quint, J=7.2 Hz, 1H), 2.71 2.77
(m, 1H), 1.89 1.92 (m, 2H), 1.70 1.73 (m, 2H), 1.52 1.56 (m, 4H), 1.26
1.45 (m, 19H), 1.11 (d, J=6.3 Hz, 3H), 0.88 ppm (t, J=6.8 Hz, 3H);
13C NMR (100.6 MHz, DEPT, CDCl3): d=56.8 (CH), 51.9 (CH), 36.6
(CH2), 31.9 (CH2), 29.8 (CH2), 29.7 (CH2), 29.6 (CH2), 29.3 (CH2), 29.3
(CH2), 27.4 (CH2), 26.1 (CH2), 24.0 (CH2), 23.8 (CH2), 23.8 (CH2), 22.7
(CH2), 19.8 (CH3), 14.1 ppm (CH3); IR (neat): n˜ =2920, 2852, 1456, 1376,
1056, 721 cmÀ1; MS (258C): m/z (%): 253 (3) [M+], 238 (7) [M+ÀCH3],
113 (100) [C8H17+]; HRMS calcd for C17H35N: 253.2770; found: 253.2766.
ÀC7H11], 106 (100) [C7H8N+], 91 (13) [C7H7+]; elemental analysis (%)
calcd for C18H27N: C 83.99, H 10.57, N 5.44; found: C 83.71, H 10.50, N
5.30.
Amines 37a/37b: General procedure A was used to synthesize amines
37a/37b from 1-octyne (32) and 4-methylaniline (2). The reaction time of
the hydroamination step was 1 h. After purification by flash chromatog-
raphy (PE/EtOAc, 40/1), 37a (100 mg, 0.46 mmol, 19%) and 37b
(399 mg, 1.82 mmol, 76%) were isolated as colorless oils. 37a: 1H NMR
(400 MHz, CDCl3): d=6.97 (d, J=8.2 Hz, 2H), 6.52 (d, J=8.4 Hz, 2H),
3.42 (brs, 1H), 3.06 (t, J=7.1 Hz, 2H), 2.23 (s, 3H), 1.59 (quint, J=
7.2 Hz, 2H), 1.28 1.39 (m, 10H), 0.88 ppm (t, J=6.8 Hz, 3H); 13C NMR
(100.6 MHz, DEPT, CDCl3): d=146.3 (C), 129.7 (CH), 126.2 (C), 112.9
(CH), 44.4 (CH2), 31.8 (CH2), 29.6 (CH2), 29.4 (CH2), 29.2 (CH2), 27.2
(CH2), 22.6 (CH2), 20.3 (CH3), 14.1 ppm (CH3); IR (neat): n˜ =2920, 2851,
1620, 1522, 1468, 1306, 1246, 1182, 807 cmÀ1; MS (258C): m/z (%): 219
+
(48) [M+], 134 (29) [M+ÀC6H13], 120 (100) [M+ÀC7H15], 91 (28) [C7H7
]; HRMS calcd for C15H25N: 219.1987; found: 219.1986; elemental analy-
sis (%) calcd for C15H25N: C 82.13, H 11.49, N 6.39; found: C 82.20, H
11.65, N 6.34. 37b: 1H NMR (400 MHz, CDCl3): d=6.99 (d, J=8.2 Hz,
2H), 6.53 (d, J=8.4 Hz, 2H), 3.43 (sext, J=6.1 Hz, 1H), 3.29 (brs, 1H),
2.25 (s, 3H), 1.55 1.61 (m, 1H), 1.30 1.40 (m, 9H), 1.18 (d, J=6.3 Hz,
3H), 0.91 ppm (t, J=6.8 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3):
d=145.5 (C), 129.7 (CH), 125.9 (C), 113.3 (CH), 48.8 (CH), 37.3 (CH2),
31.8 (CH2), 29.4 (CH2), 26.1 (CH2), 22.6 (CH2), 20.8 (CH3), 20.3 (CH3),
14.0 ppm (CH3); IR (neat): n˜ =2924, 2855, 1618, 1518, 1455, 1316, 1300,
1249, 804 cmÀ1; MS (258C): m/z (%): 219 (36) [M+], 204 (29) [M+
ÀCH3], 134 (100) [M+ÀC6H13], 91 (19) [C7H7+]; HRMS calcd for
C15H25N: 219.1987; found: 219.1987; elemental analysis (%) calcd for
C15H25N: C 82.13, H 11.49, N 6.39; found: C 82.07, H 11.71, N 6.69.
Amines 41a/41b: General procedure A was used to synthesize amines
41a/41b from phenylacetylene (34) and 4-methylaniline (2). The reaction
time of the hydroamination step was 6 h. The temperature was 758C.
After purification by flash chromatography (PE/EtOAc, 40/1), com-
pounds 41a (319 mg, 1.51 mmol, 63%) and 41b (72 mg, 0.34 mmol, 14%)
were isolated as colorless oils. 41a: 1H NMR (400 MHz, CDCl3): d=
7.29 7.32 (m, 2H), 7.20 7.24 (m, 3H), 6.98 (d, J=8.0 Hz, 2H), 6.53 (d,
J=8.4 Hz, 2H), 3.52 (brs, 1H), 3.36 (t, J=7.0 Hz, 2H), 2.89 (t, J=
7.0 Hz, 2H), 2.23 ppm (s, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3):
d=145.7 (C), 139.4 (C), 129.7 (CH), 128.8 (CH), 128.5 (CH), 126.6 (C),
126.3 (CH), 113.2 (CH), 45.4 (CH2), 35.5 (CH2), 20.3 ppm (CH3); IR
(neat): n˜ =3404, 3024, 2917, 1615, 1518, 1257, 806, 747, 698 cmÀ1; MS
(258C): m/z (%): 211 (65) [M+], 120 (100) [M+ÀC7H7], 91 (66) [C7H7+];
HRMS calcd for C15H17N: 211.1361; found: 211.1362; elemental analysis
(%) calcd for C15H17N: C 85.26, H 8.11, N 6.63; found: C 85.08, H 7.96,
Amines 38a/38b: General procedure A was used to synthesize amines
38a/38b from 1-dodecyne (33) and 4-methylaniline (2). The reaction
time of the hydroamination step was 8 h. The temperature was 758C.
After purification by flash chromatography (PE/EtOAc, 40/1), 38a
(137 mg, 0.50 mmol, 21%) and 38b (515 mg, 1.87 mmol, 78%) were iso-
lated as colorless oils. 38a: 1H NMR (400 MHz, CDCl3): d=6.98 (d, J=
8.2 Hz, 2H), 6.53 (d, J=8.4 Hz, 2H), 3.42 (brs, 1H), 3.07 (t, J=7.2 Hz,
2H), 2.23 (s, 3H), 1.60 (quint, J=7.2 Hz, 2H), 1.26 1.40 (m, 18H),
0.88 ppm (t, J=6.8 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=
146.3 (C), 129.7 (CH), 126.3 (C), 112.9 (CH), 44.4 (CH2), 31.9 (CH2),
29.7 (CH2), 29.6 (CH2), 29.6 (CH2), 29.6 (CH2), 29.6 (CH2), 29.5 (CH2),
29.3 (CH2), 27.2 (CH2), 22.7 (CH2), 20.3 (CH3), 14.1 ppm (CH3); IR
(neat): n˜ =2921, 2852, 1619, 1519, 1300, 805, 720 cmÀ1; MS (708C): m/z
(%): 275 (51) [M+], 260 (3) [M+ÀCH3], 232 (2) [M+ÀC3H7], 120 (100)
[M+ÀC8H10N], 91 (4) [C7H7+]; HRMS calcd for C19H33N: 275.2613;
found: 275.2612; elemental analysis (%) calcd for C19H33N: C 82.84, H
12.07, N 5.08; found: C 82.76, H 12.23, N 5.04. 38b: 1H NMR (400 MHz,
CDCl3): d=6.96 (d, J=8.2 Hz, 2H), 6.49 (d, J=8.4 Hz, 2H), 3.40 (sext,
J=6.1 Hz, 1H), 3.26 (brs, 1H), 2.22 (s, 3H), 1.52 1.59 (m, 1H), 1.26 1.43
(m, 17H), 1.14 (d, J=6.3 Hz, 3H), 0.88 ppm (t, J=6.8 Hz, 3H);
13C NMR (100.6 MHz, DEPT, CDCl3): d=145.5 (C), 129.7 (CH), 125.9
(C), 113.3 (CH), 48.8 (CH), 37.2 (CH2), 31.9 (CH2), 29.7 (CH2), 29.6
(CH2), 29.6 (CH2), 29.6 (CH2), 29.3 (CH2), 26.1 (CH2), 22.7 (CH2), 20.8
(CH3), 20.3 (CH3), 14.1 ppm (CH3); IR (neat): n˜ =2923, 2853, 1620, 1520,
1465, 1317, 1301, 806 cmÀ1; MS (258C): m/z (%): 275 (12) [M+], 134
(100) [C9H12N+]; HRMS calcd for C19H33N: 275.2613; found: 275.2613;
elemental analysis (%) calcd for C19H33N: C 82.84, H 12.07, N 5.08;
found: C 82.73, H 12.02, N 5.24.
1
N 6.53. 41b: H NMR (400 MHz, CDCl3): d=7.19 7.34 (m, 5H), 6.89 (d,
J=8.0 Hz, 2H), 6.42 (d, J=8.4 Hz, 2H), 4.44 (q, J=6.7 Hz, 1H), 3.89
(brs, 1H), 2.18 (s, 3H), 1.49 ppm (d, J=6.8 Hz, 3H); 13C NMR
(100.6 MHz, DEPT, CDCl3): d=145.4 (C), 145.0 (C), 129.6 (CH), 128.6
(CH), 126.8 (CH), 126.3 (C), 125.8 (CH), 113.4 (CH), 53.7 (CH), 25.0
(CH3), 20.3 ppm (CH3); IR (neat): n˜ =3408, 2955, 2916, 1616, 1519, 1299,
1256, 808, 755, 700 cmÀ1; MS (258C): m/z (%): 211 (82) [M+], 196 (77)
[M+ÀCH3], 120 (100) [M+ÀC7H7], 107 (87) [C7H8N+], 91 (62) [C7H7+];
HRMS calcd for C15H17N: 211.1361; found: 211.1360; elemental analysis
(%) calcd for C15H17N: C 85.26, H 8.11, N 6.63; found: C 85.30, H 7.76,
N 6.55.
Amine 42a: General procedure A was used to synthesize amine 42a
from 4-methoxyphenylacetylene (35) and tert-butylamine (3). The reac-
tion time of the hydroamination step was 8 h. The temperature was 758C.
After purification by flash chromatography (MeOH/EtOAc, 1/2), 42a
(380 mg, 1.84 mmol, 77%) was isolated as a colorless oil. 1H NMR
(400 MHz, CDCl3): d=7.14 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.5 Hz, 2H),
3.79 (s, 3H), 2.77 2.81 (m, 2H), 2.70 2.74 (m, 2H), 1.07 ppm (s, 9H);
13C NMR (100.6 MHz, DEPT, CDCl3): d=158.0 (C), 132.2 (C), 129.5
(CH), 113.8 (CH), 55.2 (CH3), 50.2 (C), 44.2 (CH2), 36.2 (CH2), 28.9 ppm
(CH3); IR (neat): n˜ =2956, 1612, 1243, 1176, 1109, 1035, 821, 700 cmÀ1
;
Chem. Eur. J. 2004, 10, 3059 3071
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3069

S. Doye et al.
FULL PAPER
MS (258C): m/z (%): 207 (2) [M+], 192 (25) [M+ÀCH3], 135 (88)
[C9H11O+], 121 (37) [C8H9O+]; HRMS calcd for C12H18NO: 192.1388;
found: 192.1388; elemental analysis (%) calcd for C13H21NO: C 68.07, H
8.57, N 6.62; found: C 67.78, H 8.67, N 6.54.
2.88 (dd, J=8.5, 13.6 Hz, 1H), 1.84 ppm (brs, 1H); 13C NMR
(100.6 MHz, DEPT, CDCl3): d=158.5 (C), 143.7 (C), 138.8 (C), 132.5
(C), 129.2 (CH), 129.1 (CH), 128.3 (CH), 128.3 (CH), 127.4 (CH), 127.0
(CH), 126.3 (CH), 113.6 (CH), 63.5 (CH), 55.2 (CH3), 50.7 (CH2),
45.2 ppm (CH2); IR (neat): n˜ =2833, 1610, 1510, 1494, 1453, 1243, 1173,
1104, 1033, 821, 754, 697 cmÀ1; MS (708C): m/z (%): 316 (1) [M+ÀH],
226 (64) [M+ÀC7H7], 121 (100) [C8H9O+].
Amine 43a: General procedure A was used to synthesize amine 43a
from 4-chlorophenylacetylene (36) and tert-butylamine (3). The reaction
time of the hydroamination step was 8 h. The temperature was 758C.
After purification by flash chromatography (MeOH/EtOAc, 1/2), com-
pound 43a (359 mg, 1.70 mmol, 71%) was isolated as a colorless oil.
1H NMR (400 MHz, CDCl3): d=7.26 (d, J=8.4 Hz, 2H), 7.15 (d, J=
8.4 Hz, 2H), 2.73 2.83 (m, 4H), 1.32 (brs, 1H), 1.08 ppm (s, 9H);
13C NMR (100.6 MHz, DEPT, CDCl3): d=138.6 (C), 131.9 (C), 130.0
(CH), 128.5 (CH), 50.4 (C), 43.8 (CH2), 36.5 (CH2), 28.9 ppm (CH3); IR
(neat): n˜ =2961, 2863, 1492, 1360, 1229, 1091, 1015, 809, 706 cmÀ1; MS
(258C): m/z (%): 198 (19) [M+(37Cl)ÀCH3], 141 (27) [M+
(37Cl)ÀC4H10N], 139 (37) [M+(35Cl)ÀC4H10N], 106 (76) [C7H8N+], 91
(70) [C7H7+], 86 (100) [M+ÀC5H12N]; HRMS calcd for C11H15NCl:
196.0893; found: 196.0890; elemental analysis (%) calcd for C12H18NCl:
C 68.07, H 8.57, N 6.62; found: C 67.78, H 8.67, N 6.54.
Amine 52: 1H NMR (400 MHz, CDCl3): d=7.17 7.30 (m, 8H), 7.12 7.14
(m, 2H), 3.80 (dd, J=5.7, 8.4 Hz, 1H), 2.85 (dd, J=8.4, 13.4 Hz, 1H),
2.93 (dd, J=5.7, 13.6 Hz, 1H), 2.16 2.24 (m, 2H), 1.47 1.61 (m, 6H),
1.26 1.37 (m, 1H), 1.01 1.22 (m, 3H), 0.68 0.80 ppm (m, 2H); 13C NMR
(100.6 MHz, DEPT, CDCl3): d=144.2 (C), 139.0 (C), 129.2 (CH), 128.3
(CH), 128.2 (CH), 127.2 (CH), 126.9 (CH), 126.2 (CH), 64.8 (CH), 54.5
(CH2), 45.4 (CH2), 37.9 (CH), 31.3 (CH2), 31.2 (CH2), 26.7 (CH2), 26.0
(CH2), 26.0 ppm (CH2); IR (neat): n˜ =2919, 2849, 1602, 1494, 1451, 1121,
756, 697 cmÀ1; MS (608C): m/z (%): 292 (2) [M+], 202 (100) [M+ÀC7H7].
Amine 53: 1H NMR (400 MHz, CDCl3): d=7.17 7.30 (m, 8H), 7.11 7.13
(m, 2H), 3.83 (dd, J=5.9, 8.2 Hz, 1H), 2.85 2.96 (m, 2H), 2.31 2.43 (m,
2H), 1.13 1.39 (m, 5H), 0.80 ppm (t, J=7.3 Hz, 3H); 13C NMR
(100.6 MHz, DEPT, CDCl3): d=144.1 (C), 139.0 (C), 129.2 (CH), 128.3
(CH), 128.2 (CH), 127.2 (CH), 126.9 (CH), 126.2 (CH), 64.9 (CH), 47.5
(CH2), 45.3 (CH2), 32.2 (CH2), 20.3 (CH2), 13.9 ppm (CH3); IR (neat):
n˜ =2925, 2858, 1494, 1453, 756, 697 cmÀ1; MS (508C): m/z (%): 252 (1)
[M+ÀH], 162 (100) [M+ÀC7H7].
Amines 44a/44b: General procedure A was used to synthesize amines
44a/44b from 4-methoxyphenylacetylene (35) and cyclopentylamine (4).
The reaction time of the hydroamination step was 12 h. The temperature
was 758C. After purification by flash chromatography (MeOH/EtOAc, 1/
3!1/1), 44a (290 mg, 1.32 mmol, 55%) and 44b (107 mg, 0.49 mmol,
20%) were isolated as colorless oils. 44a: 1H NMR (400 MHz, CDCl3):
d=7.13 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 3.79 (s, 3H), 3.09
(quint, J=7.0 Hz, 1H), 2.76 2.87 (m, 5H), 1.81 1.89 (m, 2H), 1.63 1.71
(m, 2H), 1.50 1.57 (m, 2H), 1.30 1.38 ppm (m, 2H); 13C NMR
(100.6 MHz, DEPT, CDCl3): d=158.0 (C), 131.8 (C), 129.6 (CH), 113.9
(CH), 59.6 (CH), 55.2 (CH3), 49.9 (CH2), 35.1 (CH2), 32.7 (CH2), 32.7
(CH2), 24.0 (CH2), 24.0 ppm (CH2); IR (neat): n˜ =2949, 1612, 1511, 1454,
1243, 1176, 1034, 821 cmÀ1; MS (258C): m/z (%): 204 (12) [M+ÀCH3], 98
(100) [M+ÀC8H9O], 121 (14) [C8H9O+]; elemental analysis (%) calcd for
C14H21NO: C 76.67, H 9.65, N 6.39; found: C 75.93, H 9.43, N 6.22. 44b:
1H NMR (400 MHz, CDCl3): d=7.23 (d, J=8.5 Hz, 2H), 6.87 (d, J=
8.7 Hz, 2H), 3.80 (s, 3H), 2.87 (q, J=7.2 Hz, 1H), 1.58 1.87 (m, 5H),
1.37 1.51 (m, 2H), 1.33 (d, J=6.5 Hz, 3H), 1.19 1.30 ppm (m, 2H);
13C NMR (100.6 MHz, DEPT, CDCl3): d=158.4 (C), 137.9 (C), 127.6
(CH), 113.7 (CH), 57.1 (CH), 55.9 (CH), 55.2 (CH3), 33.6 (CH2), 32.7
(CH2), 24.5 (CH3), 23.9 (CH2), 23.8 ppm (CH2); IR (neat): n˜ =2952, 1610,
1510, 1462, 1240, 1174, 1036, 829, 809 cmÀ1; MS (258C): m/z (%): 204
(32) [M+ÀCH3], 135 (44) [M+ÀC5H10ON], 112 (100) [M+ÀC7H7O], 91
(28) [C7H7+]; elemental analysis (%) calcd for C14H21NO: C 76.67, H
9.65, N 6.39; found: C 76.47, H 9.66, N 6.18.
Amine 54: 1H NMR (400 MHz, CDCl3): d=7.27 7.30 (m, 8H), 7.13 (m,
2H), 3.83 (dd, J=5.9, 8.2 Hz, 1H), 2.85 2.96 (m, 2H), 2.30 2.42 (m, 2H),
1.08 1.41 (m, 7H), 0.81 ppm (t, J=7.2 Hz, 3H); 13C NMR (100.6 MHz,
DEPT, CDCl3): d?=144.1 (C), 139.0 (C), 129.2 (CH), 128.3 (CH), 128.2
(CH), 127.2 (CH), 126.9 (CH), 126.3 (CH), 64.8 (CH), 47.7 (CH2), 45.3
(CH2), 29.6 (CH2), 29.3 (CH2), 22.5 (CH2), 14.0 ppm (CH3); IR (neat):
n˜ =2924, 1946, 1602, 1494, 1453, 756, 697 cmÀ1; MS (508C): m/z (%): 266
(1) [M+ÀH], 176 (100) [M+ÀC7H7].
Amine 55: General procedure B was used to synthesize amine 55 from
diphenylacetylene (1) and n-hexylamine (50). After purification by flash
chromatography (PE/EtOAc, 5/1), 55 (451 mg, 1.61 mmol, 67%) was iso-
lated as a colorless oil. 1H NMR (400 MHz, CDCl3): d=7.16 7.33 (m,
8H), 7.12 (d, J=6.9 Hz, 2H), 3.83 (dd, J=5.9, 8.2 Hz, 1H), 2.93 (dd, J=
5.9, 13.4 Hz, 1H), 2.88 (dd, J=8.3, 13.5 Hz, 1H), 2.30 2.43 (m, 2H), 1.45
(brs, 1H), 1.30 1.38 (m, 2H), 1.12 1.27 (m, 6H), 0.82 ppm (t, J=7.2 Hz,
3H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=144.0 (C), 139.0 (C),
129.2 (CH), 128.3 (CH), 128.2 (CH), 127.3 (CH), 126.9 (CH), 126.3
(CH), 64.8 (CH), 47.7 (CH2), 45.3 (CH2), 31.6 (CH2), 29.9 (CH2), 26.8
(CH2), 22.5 (CH2), 14.0 ppm (CH3); IR (neat): n˜ =2923, 2853, 1602, 1494,
1453, 756, 697 cmÀ1; MS (258C): m/z (%): 281 (1) [M+], 190 (100) [M+
ÀC7H7]; elemental analysis (%) calcd for C20H27N: C 85.35, H 9.67, N
4.98; found: C 85.15, H 9.61, N 5.19.
Amines 45a/45b: General procedure A was used to synthesize amines
45a/45b from 4-chlorophenylacetylene (36) and cyclopentylamine (4).
The reaction time of the hydroamination step was 12 h. The temperature
was 758C. After purification by flash chromatography (MeOH/EtOAc, 1/
3!1/1), 45a (286 mg, 1.28 mmol, 53%) and 45b (110 mg, 0.49 mmol,
20%) were isolated as colorless oils. 45a: 1H NMR (400 MHz, CDCl3):
d=7.26 (d, J=9.0 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 3.06 (quint, J=
6.8 Hz, 1H), 2.75 2.86 (m, 4H), 1.79 1.87 (m, 2H), 1.61 1.71 (m, 2H),
1.46 1.57 (m, 2H), 1.23 1.32 ppm (m, 3H); 13C NMR (100.6 MHz,
DEPT, CDCl3): d=138.7 (C), 131.8 (C), 130.0 (CH), 128.5 (CH), 59.8
(CH), 49.8 (CH2), 36.0 (CH2), 33.1 (CH2), 33.1 (CH2), 24.0 (CH2),
24.0 ppm (CH2); IR (neat): n˜ =2948, 2862, 1893, 1492, 1453, 1090, 1015,
808 cmÀ1; MS (258C): m/z (%): 223 (2) [M+], 139 (18) [C8H8Cl+], 125
(9) [C7H6Cl+], 98 (100) [M+ÀC7H6Cl]; elemental analysis (%) calcd for
C13H18NCl: C 69.79, H 8.11, N 6.26; found: C 69.36, H 7.85, N 6.46. 45b:
1H NMR (400 MHz, CDCl3): d=7.23 7.30 (m, 4H), 3.81 (q, J=6.6 Hz,
1H), 2.85 (quint, J=7.1 Hz, 1H), 2.74 (brs, 1H), 1.19 1.83 (m, 8H),
1.32 ppm (d, J=6.5 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=
144.5 (C), 132.3 (C), 128.5 (CH), 128.0 (CH), 57.3 (CH), 56.1 (CH), 33.7
(CH2), 32.8 (CH2), 24.6 (CH3), 23.9 (CH2), 23.8 ppm (CH2); IR (neat):
n˜ =2954, 2865, 1897, 1489, 1090, 1013, 8278 cmÀ1; MS (258C): m/z (%):
208 (72) [M+ÀCH3], 139 (100) [C8H8Cl+]; elemental analysis (%) calcd
for C13H18NCl: C 69.79, H 8.11, N 6.26; found: C 69.72, H 8.01, N 5.95.
Amines 56a/56b: General procedure C was used to synthesize amines
56a/56b from 1-phenylpropyne (20) and benzylamine (7). After purifica-
tion by flash chromatography (PE/EtOAc, 5/1!1/1), compounds 56a
(394 mg, 1.75 mmol, 73%) and 56b (14 mg, 0.06 mmol, 3%) were isolat-
ed as colorless oils. 56a: 1H NMR (400 MHz, CDCl3): d=7.10 7.30 (m,
10H), 3.84 (d, J=13.3 Hz, 1H), 3.73 (d, J=13.3 Hz, 1H), 2.93 (sext, J=
6.4 Hz, 1H), 2.76 (dd, J=7.0, 13.4 Hz, 1H), 2.64 (dd, J=6.4, 13.3 Hz,
1H), 1.54 (brs, 1H), 1.09 ppm (d, J=6.3 Hz, 3H); 13C NMR (100.6 MHz,
DEPT, CDCl3): d=140.5 (C), 139.4 (C), 129.2 (CH), 128.3 (CH), 128.3
(CH), 127.9 (CH), 126.7 (CH), 126.1 (CH), 53.7 (CH), 51.2 (CH2), 43.6
(CH2), 20.2 ppm (CH3); IR (neat): n˜ =2957, 2927, 1454, 1100, 747,
697 cmÀ1; MS (258C): m/z (%): 225 (2) [M+], 134 (100) [M+ÀC7H7], 91
(100) [C7H7+]; elemental analysis (%) calcd for C16H19N: C 85.29, H
8.50, N 6.22; found: C 85.05, H 8.65, N 6.49. 56b: 1H NMR (400 MHz,
CDCl3): d=7.13 7.35 (m, 10H), 3.65 (d, J=13.2 Hz, 1H), 3.48 3.56 (m,
2H), 1.59 1.80 (m, 3H), 0.80 (t, J=7.4 Hz, 3H) ppm; 13C NMR
(100.6 MHz, DEPT, CDCl3): d=144.1 (C), 140.8 (C), 128.3 (CH), 128.3
(CH), 128.1 (CH), 127.4 (CH), 126.9 (CH), 126.8 (CH), 64.2 (CH), 51.5
(CH2), 31.1 (CH2), 10.7 ppm (CH3); IR (neat): n˜ =2961, 2926, 1492, 1452,
1117, 1027, 741, 696 cmÀ1; MS (258C): m/z (%): 225 (3) [M+], 196 (99)
[M+ÀC2H5], 91 (100) [C7H7+].
Amine 51: 1H NMR (400 MHz, CDCl3): d=7.29 7.37 (m, 4H), 7.15 7.28
(m, 4H), 7.08 (d, J=6.7 Hz, 2H), 7.01 (d, J=8.5 Hz, 2H), 6.78 (d, J=
8.7 Hz, 2H), 3.86 (dd, J=5.7, 8.4 Hz, 1H), 3.76 (s, 3H), 3.58 (d, J=
13.2 Hz, 1H), 3.39 (d, J=13.3 Hz, 1H), 2.94 (dd, J=5.7, 13.6 Hz, 1H),
Amines 57a/57b: General procedure C was used to synthesize amines
57a/57b from 1-phenylpropyne (20) and n-hexylamine (50). After purifi-
cation by flash chromatography (PE/EtOAc, 3/1!1/1), 57a (411 mg,
3070
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3059 3071

Catalytic Hydroamination of Alkynes
3059 3071
1.88 mmol, 78%) and 57b (25 mg, 0.11 mmol, 5%) were isolated as col-
orless oils. 57a: 1H NMR (400 MHz, CDCl3): d=7.26 7.32 (m, 2H),
7.16 7.23 (m, 3H), 2.88 (sext, J=6.5 Hz, 1H), 2.47 2.76 (m, 4H), 1.36
1.48 (m, 2H), 1.18 1.32 (m, 7H), 1.05 (d, J=6.3 Hz, 3H), 0.86 ppm (t,
J=6.8 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=139.6 (C),
129.2 (CH), 128.3 (CH), 126.0 (CH), 54.6 (CH), 47.4 (CH2), 43.7 (CH2),
31.7 (CH2), 30.1 (CH2), 27.0 (CH2), 22.5 (CH2), 20.2 (CH3), 14.0 ppm
wein, M. Beller, J. Org. Chem. 2001, 66, 6339 6343; j) V. Neff, T. E.
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ushima, T. Hayashi, M. Tanaka, Org. Lett. 2003, 5, 3349 3352.
[3] For a reviewon Group 4 metal complexes as hydroamination cata-
lysts, see: I. Bytschkov, S. Doye, Eur. J. Org. Chem. 2003, 935 946.
[4] For early studies on Group 4 metal complexes as hydroamination
catalysts, see: a) J. E. Hill, R. D. Profilet, P. E. Fanwick, I. P. Roth-
well, Angew. Chem. 1990, 102, 713 715; Angew. Chem. Int. Ed.
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2763; d) P. L. McGrane, M. Jensen, T. Livinghouse, J. Am. Chem.
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Chem. 1992, 57, 1323 1324; f) P. L. McGrane, T. Livinghouse, J.
Am. Chem. Soc. 1993, 115, 11485 11489.
[5] a) N. A. Petasis in Encyclopedia of Reagents for Organic Synthesis,
Vol. 1 (Ed.: L. A. Paquette), Wiley, NewYork, 1995, pp. 470 473;
b) H. Siebeneicher, S. Doye, J. Prakt. Chem. 2000, 342, 102 106.
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266588]; b) E. Haak, I. Bytschkov, S. Doye, Angew. Chem. 1999,
111, 3584 3586; Angew. Chem. Int. Ed. 1999, 38, 3389 3391.
[7] a) E. Haak, H. Siebeneicher, S. Doye, Org. Lett. 2000, 2, 1935 1937;
b) I. Bytschkov, S. Doye, Eur. J. Org. Chem. 2001, 4411 4418; c) F.
Pohlki, S. Doye, Angew. Chem. 2001, 113, 2361 2364; Angew.
Chem. Int. Ed. 2001, 40, 2305 2308; d) E. Haak, I. Bytschkov, S.
Doye, Eur. J. Org. Chem. 2002, 457 463; e) H. Siebeneicher, S.
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er, S. Doye, Eur. J. Org. Chem. 2003, 2888 2902.
(CH3); IR (neat): n˜ =2926, 2854, 1603, 1469, 1453, 1127, 742, 698 cmÀ1
;
MS (258C): m/z (%) 219 (2) [M+], 204 (5) [M+ÀCH3], 190 (96) [M+
ÀC2H5], 128 (100) [M+ÀC7H7] 91 (55) [C7H7+]; elemental analysis (%)
calcd for C15H25N: C 82.13, H 11.49, N 6.38; found: C 81.84, H 11.87, N
6.34. 57b: 1H NMR (400 MHz, CDCl3): d=7.18 7.34 (m, 5H), 3.46 (dd,
J=5.8, 7.9 Hz, 1H), 2.33 2.49 (m, 2H), 1.70 1.82 (m, 1H), 1.56 1.69 (m,
1H), 1.36 1.50 (m, 2H), 1.18 1.33 (m, 7H), 0.86 (t, J=6.7 Hz, 3H),
0.80 ppm (t, J=7.4 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3): d=
144.4 (C), 128.2 (CH), 127.3 (CH), 126.7 (CH), 65.2 (CH), 47.8 (CH2),
31.7 (CH2), 31.0 (CH2), 30.3 (CH2), 27.0 (CH2), 22.6 (CH2), 14.0 (CH3),
10.8 ppm (CH3); IR (neat): n˜ =2958, 2926, 2854, 1453, 1125, 751,
699 cmÀ1; MS (258C): m/z (%): 219 (2) [M+], 190 (100) [M+ÀC2H5], 91
(46) [C7H7+]; HRMS calcd for C15H24N: 218.1909; found: 218.1909.
Kinetic investigations: The kinetic investigation of the [Ind2TiMe2]-cata-
lyzed reaction between 2 and 20 (Figure 1) was performed as described
in ref. [7c] The obtained data for kobs are: 7.66î10À5 sÀ1 (c([Ind2-
TiMe2])=8.36î10À3 molLÀ1 (3.0 mol%), c(2)=2.57 molLÀ1
, c0(20)=
0.28 molLÀ1);
(4.1 mol%), c(2)=2.59 molLÀ1
(c([Ind2TiMe2])=1.85î10À2 molLÀ1
9.85î10À5 sÀ1
(c([Ind2TiMe2])=1.11î10À2 molLÀ1
c0(20)=0.27 molLÀ1); 1.69î10À4 sÀ1
,
(6.8 mol%),
c(2)=2.63 molLÀ1
,
c0(20)=0.27 molLÀ1); 2.71î10À4 sÀ1 (c([Ind2TiMe2])=3.35î10À2 molLÀ1
(12.3 mol%), c(2)=2.57 molLÀ1
,
c0(20)=0.27 molLÀ1); 3.67î10À4 sÀ1
(c([Ind2TiMe2])=4.67î10À2 molLÀ1 (17.4 mol%), c(2)=2.51 molLÀ1
c0(20)=0.27 molLÀ1).
,
[8] A. Heutling, S. Doye, J. Org. Chem. 2002, 67, 1961 1964.
[9] F. Pohlki, A. Heutling, I. Bytschkov, T. Hotopp, S. Doye, Synlett
2002, 799 801.
[10] a) J. S. Johnson, R. G. Bergman, J. Am. Chem. Soc. 2001, 123, 2923
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Soc. 2003, 125, 11956 11963.
[11] a) Y. Shi, J. T. Ciszewski, A. L. Odom, Organometallics 2001, 20,
3967 3969; b) C. Cao, J. T. Ciszewski, A. L. Odom, Organometallics
2001, 20, 5011 5013; c) C. Cao, Y. Shi, A. L. Odom, Org. Lett. 2002,
4, 2853 2856; d) Y. Shi, C. Hall, J. T. Ciszewski, C. Cao, A. L.
Odom, Chem. Commun. 2003, 586 587; e) C. Cao, Y. Shi, A. L.
Odom, J. Am. Chem. Soc. 2003, 125, 2880 2881.
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Chem. 2002, 114, 2646 2648; Angew. Chem. Int. Ed. 2002, 41,
2541 2543; b) I. Garcia Castro, A. Tillack, C. G. Hartung, M.
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Tillack, M. Beller, Org. Lett. 2003, 5, 4767 4770.
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2839 2841; b) T.-G. Ong, G. P. A. Yap, D. S. Richeson, J. Am.
Chem. Soc. 2003, 125, 8100 8101.
Acknowledgement
Generous support by Professor E. Winterfeldt is most gratefully acknowl-
edged. We further thank the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie, and the Dr. Otto Rˆhm Ged‰chtnisstif-
tung, Darmstadt for financial support of our research.
[1] For general reviews on hydroamination, see a) I. A. Chekulaeva,
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tions with [Cp2TiMe2] as catalyst, amine 8 was obtained in 88%
yield (recovered 1: 11%) after subsequent reduction. In this experi-
ment, the reaction time of the hydroamination step was 29 h and the
catalyst loading was 6.0 mol%.
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[18] [Ind2TiMe2] is commercially available from MCAT (www.mcat.de).
Received: December 2, 2003
Published online: April 29, 2004
Chem. Eur. J. 2004, 10, 3059 3071
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3071