Neutral group-IV metal catalysts for the intramolecular hydroamination of alkenes

Article abstract of DOI:10.1002/ejoc.200701146

A detailed comparison of the group-IV metal catalysts Ti(NMe ₂)₄, Ind₂TiMe₂, Ind ₂ZrMe₂ and Ind₂HfMe₂ in the intramolecular hydroamination of amino alkenes is presente

Full text of DOI:10.1002/ejoc.200701146

FULL PAPER
DOI: 10.1002/ejoc.200701146
Neutral Group-IV Metal Catalysts for the Intramolecular Hydroamination of
Alkenes
Carsten Müller,[a] Wolfgang Saak,[a] and Sven Doye*[a]
Keywords: Alkenes / Amines / Group-IV metals / Hydroamination / Homogeneous catalysis
A detailed comparison of the group-IV metal catalysts
Ti(NMe2)4, Ind2TiMe2, Ind2ZrMe2 and Ind2HfMe2 in the in-
tramolecular hydroamination of amino alkenes is presented.
Among these catalysts, the benchmark catalyst Ti(NMe2)4 is
the most active in the formation of pyrrolidines. A compari-
tunately, the formation of aminocyclopentane side-products
by C–H activation processes is a severe drawback of the Ti
catalysts. The corresponding side-products are not formed in
Ind2ZrMe2- and Ind2HfMe2-catalyzed reactions. However,
the former catalyst gives better yields of the desired piperi-
son between Ind2TiMe2, Ind2ZrMe2 and Ind2HfMe2 suggests dine products. In contrast to the results obtained for the syn-
that in the synthesis of pyrrolidines, Zr complexes show the
highest catalytic activity of the group-IV metal catalysts. Al-
though Ind2TiMe2- and the Ind2ZrMe2-catalyzed formation
of a pyrrolidine is first-order in the concentration of the sub-
strate, the corresponding Ti(NMe2)4-catalyzed cyclization is
second-order in the concentration of the substrate. The re-
sults obtained for the formation of piperidines catalyzed by
Ti(NMe2)4, Ind2TiMe2, Ind2ZrMe2 and Ind2HfMe2 suggest
that for these reactions, Ti catalysts show increased catalytic
activity compared with the corresponding Zr catalysts. Unfor-
thesis of pyrrolidines, the formation of a piperidine is zero-
order in the concentration of the substrate for the indenyl
catalysts Ind2TiMe2 and Ind2ZrMe2, and first-order for the
homoleptic catalyst Ti(NMe2)4. Interestingly, Ind2TiMe2 is
able to catalyze a slow hydroamination of an N-methylated
amino alkene, whereas the homoleptic complex Ti(NMe2)4 as
well as Ind2ZrMe2 and Ind2HfMe2 do not catalyze the same
reaction.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
[6]
Ind2TiMe2 (Ind = indenyl) as a highly efficient catalyst
Introduction
for the intermolecular hydroamination of alkynes, we found
that Ind2TiMe2 is also a suitable catalyst for the intramolec-
ular hydroamination of alkenes.[7] However, a detailed com-
parison between the benchmark catalyst Ti(NMe2)4 and
Ind2TiMe2 regarding their scope and limitations has not
been described yet. Inspired by reports of Zr- and Hf-cata-
lyzed intramolecular hydroaminations of alkenes,[5a,5c–5i] we
decided to extend our studies to the analogous indenyl com-
plexes Ind2ZrMe2 and Ind2HfMe2 (Figure 1).
The direct addition of amines or ammonia to non-acti-
vated alkenes (hydroamination) is a highly desirable chemi-
cal transformation that allows the synthesis of alkylamines
from alkenes in a single step. As the reaction is very difficult
to realize much effort has been spent on the development
of the corresponding metal-catalyzed processes.[1,2] Among
the various classes of catalysts, lanthanide[2a,2b] and late-
transition-metal[2c–2k] complexes, as well as group-III
metal[2l–2o] complexes have been used most extensively for
alkene hydroaminations. Although Ti catalysts have been
used extremely successfully in alkyne hydroaminations,[3]
the corresponding group-IV metal catalysts have only been
identified recently as being suitable for alkene hydroamina-
tions. Initially, cationic Zr and Ti catalysts were employed Figure 1. Group-IV metal catalysts used for the intramolecular hy-
droamination of alkenes.
in the intramolecular hydroamination reactions of amino
alkenes containing a secondary amino group.[4] Sub-
sequently, neutral group-IV metal complexes[5] like
[5b]
Ti(NMe2)4
were found to catalyze intramolecular hy-
Results and Discussion
droaminations of amino alkenes containing primary amino
groups. Based on some of these reports and our studies on
Initial hydroamination experiments were performed with
the 1-amino-4-pentenes 1–6[8] (Table 1) at 105 °C in the
presence of 5 mol-% of either Ti(NMe2)4, Ind2TiMe2,
Ind2ZrMe2 or Ind2HfMe2. First of all, it should be men-
tioned that our results obtained with commercially available
Ti(NMe2)4 are comparable to those reported by Schafer
[a] Institut für Reine und Angewandte Chemie, Universität Old-
enburg,
Carl-von-Ossietzky-Str. 9–11, 26111 Oldenburg, Germany
Fax: +49-441-798-3329
E-mail: doye@uni-oldenburg.de
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C. Müller, W. Saak, S. Doye
FULL PAPER
and co-workers.[5b] Although the cyclization of 1-amino- Table 1. Synthesis of pyrrolidines by intramolecular hydroamin-
ation in the presence of group-IV metal catalysts.
2,2-diphenyl-4-pentene (1) went to completion within 24 h
with all four catalysts (entries 1–4), not surprisingly, signifi-
cantly decreased rates were observed for the cyclization of
the less Thorpe–Ingold-activated substrate 1-amino-2,2-di-
methyl-4-pentene (2, entries 5–12). In this case, the volatility
of the initial hydroamination product required derivati-
zation with benzoyl chloride, giving the benzamide 8 prior
to isolation. Interestingly, Ti(NMe2)4 turned out to give the
best results. After a relatively long reaction time (96 h) for
the hydroamination reaction, the isolated yield of product
8 was 87%. Under identical conditions, the yields obtained
with Ind2TiMe2, Ind2ZrMe2 and Ind2HfMe2 were only 74,
58 and 19%, respectively.
However, with geminally disubstituted substrate 3 pos-
sessing one phenyl and one methyl substituent at the 2-posi-
tion of the 1-amino-4-pentene chain comparable results
were obtained with Ti(NMe2)4, Ind2TiMe2 and Ind2ZrMe2
(57–58% yield, entries 13–15), whereas Ind2HfMe2 gave a
higher yield of 70% (entry 16). As observed before,[5b] the
corresponding benzamide product was always obtained as a
mixture of diastereomers 9a and 9b with modest selectivity
(1.5:1–2.4:1). The importance of the Thorpe–Ingold effect
in the intramolecular hydroamination is strongly underlined
by the lack of reactivity of unsubstituted 1-amino-4-pentene
(4, entries 17–20) in the presence of all the catalysts investi-
gated. Interestingly, the phenyl-substituted internal alkene 5
(entries 21–24) underwent successful cyclization, giving the
product 11 after 96 h reaction time in modest yields. How-
ever, with 68% yield of the product 11, Ti(NMe2)4 again
turned out to be the best catalyst for this transformation.
Finally, the alkyl-substituted internal alkene 6 showed no
reactivity towards hydroamination under the reaction con-
ditions, regardless of the catalyst employed.
In summary, the results shown in Table 1 prove that for
the formation of pyrrolidines, Ind2TiMe2, Ind2ZrMe2 and
Ind2HfMe2 do not show the same catalytic performance as
the homoleptic complex Ti(NMe2)4. Among the indenyl
complexes, no big difference could be found between the Ti
and Zr complexes, whereas the behaviour of the Hf complex
is significantly different for certain substrates (2 and 3).
However, in this context it should be noted that during all
the Ind2HfMe2-catalyzed reactions, a precipitate was per-
manently present in the reaction mixture. Our initial im-
pression that Ind2HfMe2 is not completely soluble under
the reaction conditions was confirmed by the finding that
identical cyclizations of substrate 1 performed with either 5
[a] Reaction conditions: amino alkene (2.4 mmol), catalyst
or 2.5 mol-% Ind2HfMe2 gave comparable yields (81 and (0.12 mmol, 5 mol-%), toluene (2.0 mL), 105 °C. Yields refer to the
isolated pure compounds. [b] Two diastereomers were obtained.
66%) of pyrrolidine 7 after 6 h reaction time.
In addition to the preparative results presented in
Table 1, we performed kinetic investigations to directly
The diastereomeric ratio was determined by 1H NMR spectroscopy
(comparison with ref.[5b]). [c] cis/trans = 1.5:1. [d] cis/trans = 1.6:1.
[e] cis/trans = 1.7:1. [f] cis/trans = 2.4:1.
compare the catalysts Ti(NMe2)4, Ind2TiMe2 and
Ind2ZrMe2. For this purpose, we performed cyclization re-
actions of amino alkene 1 under identical reaction condi- within one hour. Although the Ind2ZrMe2-catalyzed reac-
tions with constant catalyst concentrations (5 mol-%). tion is significantly slower it should be noted that
Monitoring of the substrate concentration by NMR spec- Ind2ZrMe2 is more than twice as active as the Ind2TiMe2
troscopy (Figure 2) revealed that the Ti(NMe2)4-catalyzed catalyst. An analogous observation has been reported for
reaction is very fast and reaches more than 90% conversion Ti- and Zr-amido and -imido catalysts before.[5c]
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Catalysts for the Intramolecular Hydroamination of Alkenes
the amine. This suggestion is strongly supported by the fact
that free indene was observed by NMR spectroscopy during
our kinetic studies. In addition, a similar process has al-
ready been reported for the Cp2TiMe2-catalyzed hydroa-
mination of allenes.[11]
Figure 2. Plot of c(1)/c0(1) vs. t for the catalysts Ti(NMe2)4 (᭹),
Ind2TiMe2 (᭡) and Ind2ZrMe2 (᭿).
Analysis of the kinetic data revealed that a striking dif-
ference exists between reactions catalyzed by the group-IV
metal-indenyl complexes and reactions performed with the
homoleptic complex Ti(NMe2)4. After relatively long induc-
tion periods, the Ind2TiMe2- and Ind2ZrMe2-catalyzed re-
actions are first-order in the concentration of substrate 1
(Figure 3). Although this behaviour is consistent with ki-
netic studies performed with Ti- and Zr-amido and -imido
catalysts,[5c] the Ti(NMe2)4-catalyzed cyclization of 1 is sec-
ond-order in the concentration of the substrate (Figure 4).
Corresponding second-order dependences on the substrate
concentration have only been reported for selected examples
of rare-earth-metal-catalyzed intramolecular hydroamin-
ation[9] and hydrophosphination reactions.[10] On the other
hand, comparable kinetic studies performed with two ansa-
Zr catalysts suggested a zero-order dependence on the sub-
strate concentration.[5h]
The significant induction period observed in the case of
the metallocene catalysts suggests that the catalytically
active species are formed slowly from Ind2TiMe2 or
Ind2ZrMe2 and the amine 1. As the cleavage of the metal–
carbon σ bonds that liberates methane and generates cata-
lytically active imido- or amidometal complexes is usually
a fast process one possible explanation is that during the
activation period one indenyl ligand is also exchanged by
Figure 4. Second-order plot {[c(1)/c0(1)]–1 vs. t} for the catalysts
Ti(NMe2)4 (᭹), Ind2TiMe2 (᭡) and Ind2ZrMe2 (᭿).
Subsequently, the initial intramolecular hydroamination
reactions were performed with the 1-amino-5-hexenes 13,
16 and 17 (see Schemes 1 and 2) at 105 °C in the presence
of 5 mol-% of one of the four catalysts. All reactions were
stopped after 24 h and the products isolated. In the case of
substrates 16 and 17 (Scheme 2), the initially formed vola-
tile products were treated with p-touenesulfonyl chloride to
give the corresponding tosylamides prior to isolation. The
initial hydroamination experiments performed with 1-
amino-2,2-diphenyl-5-hexene (13) and catalyzed by one of
the three indenyl catalysts Ind2TiMe2, Ind2ZrMe2 or
Ind2HfMe2 gave the expected piperidine 14 in very good
yields (89, 95 and 98%, Scheme 1). However, the corre-
sponding Ti(NMe2)4-catalyzed reaction gave the same
product in a surprisingly decreased yield of only 76%. An
explanation for this result was found when a careful investi-
gation of the crude reaction mixture revealed that a single
diastereomer of the aminocyclopentane derivative 15 was
formed as a side-product in 10% yield during the Ti(NMe2)4-
catalyzed reaction. Interestingly, this side-product, which is
clearly formed by a C–H activation process, could not be
detected at all (GC) in reactions catalyzed by Ind2TiMe2,
Ind2ZrMe2 or Ind2HfMe2.
Scheme 1. Hydroamination/cyclization of 1-amino-2,2-diphenyl-5-
hexene (13) in the presence of group-IV metal catalysts. [a] A single
diastereomer was obtained.
Figure 3. First-order plot {–ln[c(1)/c0(1)] vs. t} for the catalysts
Ti(NMe2)4 (᭹), Ind2TiMe2 (᭡) and Ind2ZrMe2 (᭿).
Eur. J. Org. Chem. 2008, 2731–2739
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C. Müller, W. Saak, S. Doye
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Figure 5. X-ray crystal structure of N-(2,2,5-trimethylcyclopentyl)-
p-toluenesulfonamide (23). Hydrogen atoms have been omitted for
clarity. Thermal ellipsoids are drawn at the 50% probability level.
The ellipsoid of C6 is an average description of both the cis and
trans isomers.
with Ind2ZrMe2 as the catalyst. In this context, it is worth
mentioning that the desired piperidine product 24 could not
be isolated from the Ti-catalyzed reactions of substrate 17
because in these cases inseparable mixtures of 24 and 25
were always obtained.
Scheme 2. Synthesis of piperidines by intramolecular hydroamin-
ation in the presence of group-IV metal catalysts. [a] Two dia-
stereomers were obtained. The diastereomeric ratio was determined
The results of an additional kinetic investigation of the
cyclization of 1-amino-2,2-diphenyl-5-hexene (13) catalyzed
by Ti(NMe2)4, Ind2TiMe2 and Ind2ZrMe2 are shown in
Figure 6. Surprisingly, the formation of the piperidine prod-
uct 14 is zero-order in the concentration of substrate 13 for
the indenyl catalysts Ind2TiMe2 and Ind2ZrMe2 (Figure 6)
and first-order for the homoleptic catalyst Ti(NMe2)4 (Fig-
ure 7). This is in contrast to the formation of the pyrrolidine
product 2 in which a first-order dependence was observed
for Ind2TiMe2 and Ind2ZrMe2 and a second-order depen-
dence for Ti(NMe2)4. However, in both cases, the order of
the reaction is enhanced for the homoleptic catalyst, behav-
iour that has been reported for a rare-earth-metal-catalyzed
hydroamination.[8] Another interesting fact, which is in
sharp contrast to the pyrrolidine formation described
above, is the observation that the catalytic activity of
Ind2TiMe2 is more than five times higher than the activity
of Ind2ZrMe2. Surprisingly, no induction period is observed
for the Ti catalyst.
1
by GC and H NMR to be cis/trans = 4:1. [b] Yield determined by
GC from an inseparable mixture of 24 and 25. [c] Two dia-
stereomers were obtained. The diastereomeric ratio was determined
by GC. [d] dr = 2.5:1. [e] dr = 4:1. [f] dr = 2:1. [g] dr = 1:1.
By analogy to a hydroaminoalkylation process recently
reported for a Ta catalyst,[12] the aminocyclopentane side-
product 15 is probably formed by an initial activation of the
α-C–H bond of the amino alkene and subsequent alkene
insertion into the resulting Ti–C bond. However, it should
also be noted that related side-products have been observed
in base-catalyzed intermolecular hydroaminations of sty-
renes with amine substrates possessing more or less acidi-
fied α-C–H bonds.[13]
Subsequent studies with the less Thorpe–Ingold-acti-
vated substrates 16 and 17 (Scheme 2) showed that the for-
mation of side-products caused by C–H activation seems to
be a general problem (or challenge) in Ti-catalyzed intra-
molecular hydroamination reactions of 1-amino-5-hexenes.
The reaction of 1-amino-2,2-dimethyl-5-hexene (16) with
5 mol-% of either Ti(NMe2)4 or Ind2TiMe2 and subsequent
transformation into the corresponding tosylamide gave the
aminocyclopentane side-product 23 in 26 and 28% yields,
respectively. As a direct consequence, the desired hydroa-
mination product 22 was only obtained in 72 and 71%
yields. Although in both cases 23 was obtained as a 4:1
mixture of the cis and trans diastereomers, it was possible
to obtain crystals of 23 that were suitable for X-ray crystal
structure analysis (Figure 5).
In agreement with the results presented in Scheme 1, all
the hydroamination reactions of the 1-amino-5-hexene sub-
strates 16 and 17 performed in the presence of catalytic
amounts of Ind2ZrMe2 or Ind2HfMe2 took place without
any formation of side-products. However, for both sub-
Figure 6. Plot of c(13)/c0(13) vs. t for the catalysts Ti(NMe2)4 (᭹),
strates, the best yields (22: 95%; 24: 98%) were obtained Ind2TiMe2 (᭡) and Ind2ZrMe2 (᭿).
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Catalysts for the Intramolecular Hydroamination of Alkenes
substrates with secondary amino groups. As our kinetic stud-
ies are not sufficient to rule out one of the two possible
mechanistic pathways we decided to investigate the behav-
iour of 28 (Scheme 4),[15] the N-methylated version of amino
alkene 1, in the presence of the four hydroamination cata-
lysts. In order to compare the results directly with those ob-
tained for 1 (Table 1, entries 1–4), all the reactions were per-
formed with a catalyst loading of 5 mol-% at 105 °C. As ob-
served before,[5a–5c,5e,5f] pyrrolidine 29[16] was not detected in
the presence of Ti(NMe2)4, Ind2ZrMe2 or Ind2HfMe2 after
a reaction time of 24 h. This finding is in sharp contrast to
a lanthanide-like mechanism which proceeds by insertion of
the alkene into a M–N(H)R σ bond of a metal-amido com-
plex. However, with Ind2TiMe2 as the catalyst, a significant
amount (13%) of 29 was detected by GC and 1H NMR spec-
troscopy. Although this observation supports the idea of a
lanthanide-like mechanism, one must bear in mind that the
cyclization of the secondary amino alkene 28 is much slower
than the corresponding reaction of the primary amino alkene
1 (96% yield after 24 h). A possible explanation for this may
be that primary and secondary amino alkenes do not react
by the same mechanistic pathway.
Figure 7. First-order plot {–ln[c(13)/c0(13)] vs. t} for the catalysts
Ti(NMe2)4 (᭹), Ind2TiMe2 (᭡) and Ind2ZrMe2 (᭿).
In summary, the results obtained for the formation of
piperidines from 1-amino-5-hexenes suggest that for these
reactions Ti catalysts show increased catalytic activity com-
pared with the corresponding Zr catalysts. However, the
formation of aminocyclopentane side-products by C–H ac-
tivation processes turned out to be a severe drawback of the
Ti catalysts. Fortunately, this problem can be overcome by
the use of Ind2ZrMe2 or Ind2HfMe2 as the catalyst. Al-
though neither catalyst leads to the formation of any side-
products, better yields are obtained with Ind2ZrMe2.
To further investigate the scope of the process, we finally
attempted to synthesize azepane 27 (Scheme 3) by intramo-
lecular hydroamination of 1-amino-6-heptene 26 in the
presence of Ti(NMe2)4, Ind2TiMe2, Ind2ZrMe2 or
Ind2HfMe2. Unfortunately, none of the catalysts was able to
achieve the formation of the seven-membered ring product.
Scheme 4. Cyclization of N-methylated amino alkene 28 in the
presence of group-IV metal catalysts.
Conclusions
The presented data show that significant differences exist
between the group-IV-metal-catalyzed synthesis of pyrroli-
dines and piperidines by intramolecular hydroamination.
Among the catalysts investigated, the benchmark catalyst
Ti(NMe2)4 was the most active for the formation of pyrroli-
dines. However, a comparison between three catalysts pos-
sessing the same ligands (Ind2TiMe2, Ind2ZrMe2 and
Scheme 3. Attempted synthesis of azepane 27 by intramolecular
hydroamination of 26 in the presence of group-IV metal catalysts.
At the moment, the mechanism of the hydroamination of Ind2HfMe2) suggests that for the synthesis of pyrrolidines,
amino alkenes catalyzed by neutral group-IV metal com- Zr complexes show the highest catalytic activity among the
plexes is under discussion. By analogy to the mechanism of group-IV metal catalysts. This result is in good agreement
Ti-catalyzed alkyne and allene hydroamination reac- with an analogous observation reported by Schafer and co-
tions,[11,14] it has been proposed that the cyclization of amino workers for Ti- and Zr-amido and -imido catalysts.[5c] Al-
alkenes proceeds via a imidometal complex (M=NR), under- though our finding that the Ind2TiMe2- and Ind2ZrMe2-
going a [2+2] cycloaddition with the alkene.[5a–5g,5j] Conse- catalyzed formation of pyrrolidine 7 from amino alkene 1
quently, the reaction should be limited to amino alkenes is first-order in the concentration of substrate 1 is consistent
bearing a primary amino group. However, a lanthanide-like with the results of Schafer and co-workers,[5c] it is in sharp
mechanism involving insertion of the alkene into a M–N(H) contrast to a recent report of a zero-order dependence on
R σ bond of a metal-amido complex has also been sugges- the Zr-catalyzed cyclization of 1-amino-2,2-dimethyl-4-pen-
ted.[5h] In this case the reaction should also be suitable for tene (2) by Stubbert and Marks.[5h] Furthermore, we found
Eur. J. Org. Chem. 2008, 2731–2739
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2735

C. Müller, W. Saak, S. Doye
FULL PAPER
CaH2 on molecular sieves at ambient pressure under an inert atmo-
sphere. Non-volatile amines (1, 6, 13, 17, 26 and 28) were purified
by kugelrohr distillation. 2,2,5-Triphenyl-1-amino-4-pentene (5)
was crystallized from EtOAc. All amino alkenes and catalysts were
stored in a nitrogen filled glovebox (M. Braun, Unilab). Unless
otherwise noted, yields refer to isolated yields of pure compounds
as gauged by thin-layer chromatography (TLC) and 1H and 13C
NMR spectroscopy. All products were characterized by infrared
(IR), 1H and 13C NMR spectroscopy and mass spectrometry (MS).
Additional characterization data were obtained by CHN elemental
that the Ti(NMe2)4-catalyzed cyclization of 1 is second-or-
der in the concentration of substrate. As far as we know,
a similar result has not been reported for group-IV-metal-
catalyzed cyclization reactions of amino alkenes. However,
second-order dependences on the substrate concentration
have been described for selected examples of rare-earth-
metal-catalyzed intramolecular hydroamination[9] and hy-
drophosphination reactions.[10]
Although the results obtained for the formation of piper-
idines catalyzed by Ti(NMe2)4, Ind2TiMe2, Ind2ZrMe2 and analysis or high-resolution mass spectrometry (HRMS). NMR
spectra were recorded with the following spectrometers: Bruker Av-
ance DPX 300 and Bruker Avance DRX 500. All H NMR data
Ind2HfMe2 suggest that for these reactions Ti catalysts
show increased catalytic activity compared with the corre-
sponding Zr catalysts, the formation of aminocyclopentane
side-products by C–H activation processes was found to be
a severe drawback of the Ti catalysts. Fortunately, these
side-products are not formed in Ind2ZrMe2- and
Ind2HfMe2-catalyzed reactions. However, the former cata-
lyst gives better yields of the desired piperidine products. In
contrast to the synthesis of pyrrolidine 7, the formation of
1
are reported in δ [ppm] relative to the signal of CDCl3 at δ =
7.26 ppm. All 13C NMR data are reported in δ [ppm] relative to
the central line of the triplet for CDCl3 at δ = 77.0 ppm. The NMR
spectroscopic data recorded for kinetic studies are reported in δ
[ppm] relative to the signal of ferrocene (internal standard) at δ =
4.15 ppm. Infrared spectra were recorded with a Bruker Vector 22
(liquids) or Tensor 27 (solids) spectrometer using an attenuated to-
tal reflection (ATR) method. Mass spectra were recorded with a
the piperidine product 14 is zero-order in the concentration JEOL JMS-700, a Finnigan TSQ 700 or a Finnigan MAT 95 spec-
trometer (EI) with an ionization potential of 70 eV. Elemental
analyses were carried out with an Elementar Vario EL machine.
PE refers to light petroleum ether, boiling range 40–60 °C.
of substrate 13 for the indenyl catalysts Ind2TiMe2 and
Ind2ZrMe2 and first-order for the homoleptic catalyst
Ti(NMe2)4. Interestingly, in both cases, in the formation of
pyrrolidine 7 and of piperidine 14, the order of the reaction
is enhanced for the homoleptic catalyst, behaviour that has
only been reported for a rare-earth-metal-catalyzed hydroa-
mination.[8]
Interestingly, Ind2TiMe2 is able to catalyze a slow hy-
droamination of the N-methylated amino alkene 28,
whereas the homoleptic complex Ti(NMe2)4 as well as
Ind2ZrMe2 and Ind2HfMe2 do not catalyze the same reac-
tion. This observation and the results of the kinetic studies
make it impossible at this moment to suggest a general
mechanism.
X-ray Diffraction: Single-crystal experiments were performed with
a Stoe IPDS diffractometer with graphite-monochromated Mo-Kα
radiation (λ = 0.71073 Å). Table 2 summarizes the crystal data, in-
tensity collection and refinement parameters. Intensity measure-
ments were recorded at 153(2) K. The structure was solved by di-
rect-phase determination (SHELXL-97)[17] and refined on F2
(SHELXL-97)[17] with anisotropic thermal parameters for all non-
hydrogen atoms.
CCDC-669328 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
In summary, it should be noted that the mechanistic de-
tails of the group-IV-metal-catalyzed intramolecular hy-
droamination reactions of alkenes seem to be far more com-
plicated than expected. Our studies strongly suggest that
variation of the metal, the ligands present at the metal
centres involved, as well as the ring size of the product
formed can result in significant mechanistic changes. There-
fore, more detailed kinetic and mechanistic studies are in
progress.
Hydroamination of Volatile Amino Alkenes and Subsequent Forma-
tion of Benzamides. General Procedure A: An oven-dried Schlenk
tube equipped with a Teflon stopcock and a magnetic stirring bar
was transferred to a nitrogen-filled glovebox and charged with the
amino alkene (2.40 mmol), the catalyst (0.12 mmol, 5 mol-%) and
toluene (2.0 mL). Then the tube was sealed and the resulting mix-
ture was heated to 105 °C for the appropriate time. After the mix-
ture had been cooled to room temperature, NEt3 (1.0 mL,
7.2 mmol), benzoyl chloride (0.3 mL, 2.64 mmol) and CH2Cl2
(5.0 mL) were added. The resulting mixture was stirred at 25 °C for
12 h. Then the solution was diluted with Et2O (30 mL) and washed
with a saturated aqueous NH4Cl solution. The aqueous layer was
extracted with Et2O (3ϫ50 mL) and the combined organic layers
were dried with MgSO4. After concentration under vacuum in the
presence of Celite®, the product was isolated by flash chromatog-
raphy.
Experimental Section
General Remarks: All reactions were performed under an inert at-
mosphere of nitrogen in oven-dried Schlenk tubes (Duran glass-
ware, 100 mL, Ø 30 mm) equipped with Teflon stopcocks and
magnetic stirring bars (15ϫ4.5 mm). Ind2TiMe2 was synthesized
according to a literature procedure.[6c] All other catalysts were pur-
chased from Acros Organics [Ti(NMe2)4], Strem Chemicals
(Ind2ZrMe2) or Sigma–Aldrich (Ind2HfMe2) and were used with-
out further purification. [D8]Toluene was distilled from molten so-
dium; regular toluene was purchased (toluene extra dry with molec-
ular sieves) from Acros Organics. The amino alkenes 1–6, 13, 16,
17, 26 and 28 were synthesized according to literature pro-
cedures.[8,15] Prior to use, the volatile amines (2–4 and 16) were
purified and dried by distillation (20 cm vigreux column) from
Hydroamination of Volatile Amino Alkenes and Subsequent Forma-
tion of Tosylamides. General Procedure B: An oven-dried Schlenk
tube equipped with a Teflon stopcock and a magnetic stirring bar
was transferred into a nitrogen-filled glovebox and charged with
the amino alkene (2.40 mmol), the catalyst (0.12 mmol, 5 mol-%),
and toluene (2.0 mL). Then the tube was sealed and the resulting
mixture was heated to 105 °C for the appropriate time. After the
mixture had been cooled to 0 °C, p-toluenesulfonyl chloride
(915 mg, 4.80 mmol) and pyridine (15 mL) were added. The re-
2736
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2731–2739

Catalysts for the Intramolecular Hydroamination of Alkenes
[M + H]+, 237 (73) [M]+, 222 (8) [M – CH3]+, 193 (12), 178 (23),
165 (20), 115 (16), 91 (10), 77 (4), 57 (100). C17H19N (237.3): calcd.
C 86.03, H 8.07, N 5.90; found C 85.78, H 8.14, N 5.93.
Table 2. X-ray crystal structure data for 23.
Empirical formula
Formula mass
Diffractometer
Crystal dimensions [mm]
Colour
C15H23NO2S
281.40
Stoe IPDS
0.70ϫ0.14ϫ0.08
colourless
N-Benzoyl-2,4,4-trimethylpyrrolidine (8): General procedure A was
used to synthesize 8 from 1-amino-2,2-dimethyl-4-pentene (2,
272 mg, 2.40 mmol). After chromatography (SiO2, PE/EtOAc,
10:1), 8 [452 mg, 2.08 mmol, 87%, catalyst: Ti(NMe2)4, reaction
¯
P1
Space group
Crystal system
a [Å]
b [Å]
c [Å]
α [°]
β [°]
γ [°]
V [Å]
triclinic
8.2188(9)
9.7698(14)
10.9826(18)
69.157(18)
71.241(16)
87.053(16)
779.4(2)
2
1
time: 96 h] was obtained as a colourless oil. H NMR (500 MHz,
CDCl3): δ = 0.90 (s, 3 H), 1.04 (s, 3 H), 1.31–1.47 (m, 4 H), 1.93
(dd, J = 7.4, 12.0 Hz, 1 H), 3.10 (d, J = 10.4 Hz, 1 H), 3.29 (d, J
= 10.7 Hz, 1 H), 4.30–4.42 (m, 1 H), 7.34–7.42 (m, 3 H), 7.52 (d,
J = 6.0 Hz, 2 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3): δ =
20.1 (CH3), 25.3 (CH3), 25.6 (CH3), 38.1 (C), 47.4 (CH2), 52.7
(CH), 62.5 (CH2), 127.4 (CH), 128.0 (CH), 129.8 (CH), 137.2 (C),
Z
170.0 (C) ppm. IR (neat): ν = 3059, 3029, 2958, 2928, 2868, 1629,
˜
Dcalcd. [Mgm–3]
1.201
0.206
1603, 1578, 1496, 1465, 1447, 1409, 1372, 1352, 1321, 1290, 1213,
1137, 794, 719, 699, 662 cm–1. MS (25 °C): m/z (%) = 218 (1) [M
+ H]+, 217 (4) [M]+, 202 (4), 160 (4), 105 (77), 77 (100), 56 (26),
55 (19), 51 (37), 41 (30), 39 (17), 29 (11), 27 (13). C14H19NO
(217.1): calcd. C 77.38, H 8.81, N 6.45, O 7.36; found C 77.07, H
8.67, N 6.49.
ν [mm–1]
F(000)
304
0.71073
153(2)
2.46–26.21
9711
1503
λ (Mo-Kα, graphite) [Å]
Temperature [K]
θ range for collection [°]
Number of reflections collected
Number of obsd. reflections
[IϾ2σ(I)]
N-Benzoyl-2,4-dimethyl-4-phenylpyrrolidine (9): General procedure
A was used to synthesize 9 from 1-amino-2-methyl-2-phenyl-4-pen-
tene (3, 421 mg, 2.40 mmol). After chromatography (SiO2, PE/
EtOAc, 5:1), 9 (472 mg, 1.69 mmol, 70%, catalyst: Ind2HfMe2, re-
action time: 24 h) was obtained as a colourless oil. The dia-
Number of independent reflections
Absorption correction method
Max., min. transmission
No. data/restraints/parameters
R indices (all data)
2899
none
0.9837, 0.8690
2899/7/204
R1 = 0.0891, wR2 =
0.0845
1
stereomeric ratio was determined by GC and H NMR (compari-
son with ref.[5b]). 1H NMR (500 MHz, CDCl3, mixture of two dia-
stereomers): major diastereomer: δ = 1.22 (s, 3 H), 1.46 (d, J =
6.1 Hz, 3 H), 1.90–1.97 (m, 1 H), 2.43 (ddd, J = 1.7, 7.2, 12.3 Hz,
1 H), 3.61 (d, J = 10.4 Hz, 1 H), 3.73 (d, J = 10.4 Hz, 1 H), 7.03–
7.68 (m, 10 H) ppm; minor diastereomer: δ = 1.37 (s, 3 H), 1.40–
1.51 (m, 2 H), 1.75–1.88 (m, 1 H), 1.75 (dd, J = 9.8, 12.8 Hz, 1 H),
2.60–2.73 (m, 1 H), 3.53 (d, J = 11.1 Hz, 1 H), 3.88 (d, J = 11.1 Hz,
1 H), 4.02–4.17 (m, 1 H), 7.03–7.68 (m, 10 H) ppm. 13C NMR
(125 MHz, DEPT, CDCl3, mixture of two diastereomers): major
diastereomer: δ = 20.2 (CH3), 27.3 (CH3), 45.4 (CH2), 45.7 (C),
52.5 (C), 60.9 (CH2), 125.6 (CH), 126.5 (CH), 127.6 (CH), 128.3
(CH), 128.5 (CH), 130.1 (CH), 137.0 (C), 146.6 (C), 170.3 (C) ppm;
additional signals of the minor diastereomer: δ = 20.0 (CH3), 27.2
(CH3), 52.4 (C), 169.8 (C) ppm. IR (neat, mixture of two dia-
Final R indices [IϾ2σ(I)]
R1 = 0.0384, wR2 =
0.0760
0.761
GoF on F2
Largest diff. peak, hole [eÅ–3]
0.196, –0.214
sulting mixture was stirred for 12 h while warming to room tem-
perature. Then the solution was diluted with EtOAc (50 mL) and
washed with 2  aqueous HCl (2ϫ50 mL) to remove excess pyr-
idine. The combined aqueous layers were extracted with EtOAc
(3ϫ50 mL) and the combined organic layers were subsequently
dried with MgSO4. After concentration under vacuum in the pres-
ence of Celite®, the product was isolated by flash chromatography.
Hydroamination of Non-Volatile Amino Alkenes. General Procedure
C: An oven-dried Schlenk tube equipped with a Teflon stopcock
and a magnetic stirring bar was transferred into a nitrogen-filled
glovebox and charged with the amine (2.40 mmol), the catalyst
(0.12 mmol, 5 mol-%) and toluene (2.0 mL). Then the tube was se-
aled and the resulting mixture was heated to 105 °C for the appro-
priate time. After the mixture had been cooled to room tempera-
ture, the product was directly isolated by flash chromatography.
stereomers): ν = 3084, 3058, 3028, 2962, 2927, 2870, 2340, 1958,
˜
1894, 1816, 1629, 1577, 1496, 1408, 1351, 1322, 1228, 1131, 1076,
1029, 793 cm–1. MS (25 °C, mixture of two diastereomers): m/z (%)
= 280 (15) [M + H]+, 279 (82) [M]+, 264 (14), 161 (15), 160 (14),
131 (9), 105 (100), 77 (16), 56 (18). C19H21NO (279.2): calcd. C
81.68, H 7.58, N 5.01, O 5.73; found C 81.12, H 7.62, N 4.94.
2-Benzyl-4,4-diphenylpyrrolidine (11): General procedure C was
used to synthesize 11 from 1-amino-2,2,5-triphenyl-4-pentene (5,
752 mg, 2.40 mmol). After chromatography [SiO2, PE/EtOAc (2:1)
+ 1% 7  NH3 in methanol], 11 [514 mg, 1.64 mmol, 68%, catalyst:
Ti(NMe2)4, reaction time: 96 h] was obtained as a bright-yellow
2-Methyl-4,4-diphenylpyrrolidine (7): General procedure C was used
to synthesize 7 from 1-amino-2,2-diphenyl-4-pentene (1, 570 mg,
2.40 mmol). After chromatography [SiO2, PE/EtOAc (1:2) + 1%
7  NH3 in methanol], 7 (556 mg, 2.34 mmol, 98%, catalyst:
Ind2HfMe2, reaction time: 24 h) was obtained as a colourless oil.
1H NMR (500 MHz, CDCl3): δ = 1.18 (d, J = 6.4 Hz, 3 H), 1.98–
2.04 (m, 2 H), 2.70 (dd, J = 6.4, 12.4 Hz, 1 H), 3.30–3.38 (m, 1 H),
1
oil. H NMR (500 MHz, CDCl3): δ = 1.88 (s, 1 H), 2.10 (dd, J =
9.0, 12.8 Hz, 1 H), 2.59–2.70 (m, 2 H), 2.79 (dd, J = 7.1, 13.4 Hz,
1 H), 3.39–3.51 (m, 2 H), 3.63 (dd, J = 1.3, 11.3 Hz, 1 H), 6.84–
3.45 (d, J = 11.4 Hz, 1 H), 3.64 (d, J = 11.4 Hz, 1 H), 7.10–7.14 7.29 (m, 15 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3): δ =
(m, 2 H), 7.19–7.29 (m, 8 H) ppm. 13C NMR (125 MHz, DEPT, 43.5 (CH2), 44.9 (CH2), 55.6 (C), 57.6 (CH2), 59.1 (CH), 126.0
CDCl3): δ = 22.2 (CH3), 46.9 (CH2), 52.9 (CH), 57.1 (C), 57.7 (CH), 126.1 (CH), 126.9 (CH), 127.0 (CH), 128.2 (CH), 128.3
(CH2), 125.7 (CH), 125.8 (CH), 126.8 (CH), 126.8 (CH), 128.1 (CH), 128.4 (CH), 128.4 (CH), 128.4 (CH), 129.1 (CH), 139.8 (C),
(CH), 128.1 (CH), 146.9 (C), 147.6 (C) ppm. IR (neat): ν = 3084,
146.7 (C), 147.6 (C) ppm. IR (neat): ν = 3359, 3287, 3083, 3057,
˜
˜
3057, 3025, 2958, 2920, 2968, 1598, 1493, 1446, 1372, 1129, 1098,
3025, 2999, 2918, 2864, 1948, 1875, 1806, 1746, 1599, 1581, 1493,
1032, 906, 869, 773, 756, 700 cm–1. MS (25 °C): m/z (%) = 238 (27) 1446, 1096, 1029, 969, 910, 751, 700, 656 cm–1. MS (25 °C): m/z
Eur. J. Org. Chem. 2008, 2731–2739
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2737

C. Müller, W. Saak, S. Doye
(%) = 313 (1) [M]+, 223 (16), 222 (100) [M – PhCH2]+, 205 (8), 179 stereomer (cis): δ = 0.74 (d, J = 7.2 Hz, 3 H), 0.82 (s, 3 H), 0.87 (s,
FULL PAPER
(4), 178 (5), 132 (4), 115 (3), 91 (9). C23H23N (313.2): calcd. C
88.13, H 7.40, N 4.47; found C 87.14, H 7.48, N 4.17.
3 H), 1.16–1.26 (m, 1 H), 1.27–1.36 (m, 1 H), 1.39–1.47 (m, 1 H),
1.73–1.83 (m, 1 H), 2.08–2.19 (m, 1 H), 2.41 (s, 3 H), 3.24 (dd, J
= 8.2, 10.3 Hz, 1 H), 4.56 (d, J = 10.3 Hz, 1 H), 7.27 (d, J = 7.3 Hz,
2 H), 7.77 (d, J = 8.3 Hz, 2 H) ppm; important signals of the minor
diastereomer (trans): δ = 0.73 (d, J = 6.5 Hz, 3 H), 0.80 (s, 3 H),
0.82 (s, 3 H), 2.77 (t, J = 9.6 Hz, 1 H) ppm. 13C NMR (125 MHz,
DEPT, CDCl3, mixture of two diastereomers): major diastereomer
(cis): δ = 16.6 (CH3), 21.5 (CH3), 23.7 (CH3), 28.7 (CH3), 30.4
(CH2), 35.0 (CH), 37.9 (CH2), 41.7 (C), 65.4 (C), 127.0 (CH), 127.1
(CH), 129.4 (CH), 129.5 (CH), 138.6 (C), 143.0 (C) ppm; important
signals of the minor diastereomer (trans): δ = 18.2 (CH3), 23.0
(CH3), 27.8 (CH3), 39.6 (CH), 40.6 (C), 70.0 (CH) ppm. IR (neat,
2-Methyl-5,5-diphenylpiperidine (14): The general procedure C was
used to synthesize 14 from 1-amino-2,2-diphenyl-5-hexene (13,
603 mg, 2.40 mmol). After chromatography [SiO2, PE/EtOAc (1:1)
+ 1% 7  NH3 in methanol], 14 (590 mg, 2.35 mmol, 98%, catalyst:
Ind2HfMe2, reaction time: 24 h) was obtained as a colourless oil.
When Ti(NMe2)4 was used as the catalyst, the side-product 15
(59 mg, 0.24 mmol, 10%, reaction time: 96 h) was isolated as a
1
colourless solid. Piperidine 14: H NMR (500 MHz, CDCl3): δ =
1.00 (d, J = 6.4 Hz, 3 H), 1.10–1.20 (m, 1 H), 1.29 (br. s, 1 H),
1.60–1.65 (m, 1 H), 2.21 (td, J = 13.4, 3.7 Hz, 1 H), 2.67–2.81 (m,
2 H), 3.10 (d, J = 13.7 Hz, 1 H), 3.91 (dd, J = 3.0, 13.7 Hz, 1 H),
7.08–7.43 (m, 10 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3): δ
= 22.5 (CH3), 31.4 (CH2), 35.4 (CH2), 45.2 (C), 52.3 (CH), 55.8
(CH2), 125.7 (CH), 125.7 (CH), 126.4 (CH), 128.1 (CH), 128.2
mixture of two diastereomers): ν = 3282, 2955, 2872, 1598, 1455,
˜
1436, 1318, 1290, 1154, 1125, 1094, 1054, 1025, 1014, 927, 909,
897, 815, 707, 667 cm–1. MS (25 °C, mixture of two diastereomers):
m/z (%) = 282 (12) [M + H]+, 281 (80) [M]+, 225 (13), 224 (100),
155 (54), 126 (44), 110 (43), 92 (11), 91 (63), 70 (22), 69 (16), 65
(12), 57 (11), 41 (18). C15H23NO2S (281.4): calcd. C 64.02, H 8.24,
N 4.98, O 11.37, S 11.39; found C 64.06, H 8.19, N 5.01, S 11.42.
(CH), 128.6 (CH), 144.8 (C), 148.8 (C) ppm. IR (neat): ν = 3086,
˜
3057, 3027, 2931, 2864, 2797, 1599, 1494, 1462, 1445, 1376, 1156,
1130, 1107, 925, 844, 751, 699 cm–1. MS (25 °C): m/z (%) = 252 (5)
[M + H]+, 251 (10) [M]+, 236 (5) [M – CH3]+, 193 (3), 179 (32), N-(2,5-Dimethyl-5-phenylpiperidyl)-p-toluenesulfonamide (24): Ge-
165 (40), 115 (7), 91 (9), 71 (7), 58 (100). C18H21N (251.4): calcd. neral procedure B was used to synthesize 24 from 1-amino-2-
C 86.01, H 8.42, N 5.57; found C 85.78, H 8.44, N 5.84. Cyclopen-
methyl-2-phenyl-5-hexene (17, 454 mg, 2.40 mmol). After
tane 15: H NMR (500 MHz, CDCl3): δ = 0.93 (d, J = 7.0 Hz, 3 chromatography (SiO2, PE/EtOAc, 10:1), 24 (811 mg, 2.36 mmol,
1
H), 0.99 (br. s, 2 H), 1.36–1.46 (m, 1 H), 1.83 (ddd, J = 8.7, 13.3,
18.6 Hz, 1 H), 2.11–2.23 (m, 1 H), 2.46–2.59 (m, 2 H), 3.93 (d, J
= 4.8 Hz, 1 H), 6.98–7.08 (m, 2 H), 7.03 (dd, J = 7.4, 16.9 Hz, 2
98%, catalyst: Ind2ZrMe2, reaction time: 24 h) was obtained as a
colourless oil. When Ind2TiMe2 or Ti(NMe2)4 were used as cata-
lysts, an inseparable mixture of 24 and the side-product 25 was
H), 7.12–7.21 (m, 4 H), 7.24 (d, J = 7.24 Hz, 2 H), 7.32 (d, J = obtained. In these cases, the yields presented in Scheme 2 are calcu-
7.6 Hz, 2 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3): δ = 15.6 lated from GC analysis of the mixture. Pure 24 was obtained as a
1
(CH3), 29.0 (CH2), 32.7 (CH2), 34.8 (CH), 61.2 (C), 61.6 (CH),
mixture of diastereomers from Ind2ZrMe2-catalyzed reactions. H
125.6 (CH), 125.6 (CH), 126.5 (CH), 127.9 (CH), 128.2 (CH), 128.4 NMR (500 MHz, CDCl3, mixture of two diastereomers): charac-
(CH), 146.7 (C), 147.2 (C) ppm. IR (neat): ν = 3350, 3289, 3082, teristic signals of the major diastereomer: δ = 1.07 (d, J = 6.8 Hz,
˜
3051, 3025, 2955, 2933, 2888, 2869, 2362, 1947, 1877, 1804, 1491,
1444, 1363, 1332, 1305, 1262, 1197, 1155, 1095, 1073, 1032, 1005,
984, 970, 942, 895, 860, 816, 772, 749, 695, 649, 612 cm–1. MS
(25 °C): m/z (%) = 252 (18) [M + H]+, (18), 251 (82) [M]+, 234 (21),
219 (11), 206 (19), 205 (100), 193 (13), 180 (20), 179 (27), 178 (31),
167 (11), 165 (45), 115 (25), 91 (18), 84 (20), 71 (12), 70 (99), 57
(17), 56 (41). HRMS: calcd. (C18H21N) 251.1674; found 251.1675.
3 H), 1.17 (s, 3 H), 2.39 (s, 3 H), 2.98 (d, J = 13.2 Hz, 1 H), 3.89–
3.96 (m, 1 H), 4.21 (dd, J = 2.09, 13.2 Hz, 1 H) ppm; characteristic
signals of the minor diastereomer: δ = 0.94 (d, J = 6.9 Hz, 3 H),
1.32 (s, 3 H), 2.40 (s, 3 H), 3.07 (d, J = 12.6 Hz, 1 H), 3.71 (dd, J
= 1.6, 12.6 Hz, 1 H), 4.26–4.35 (m, 1 H) ppm; additional signals: δ
= 1.44–1.51 (m), 1.65–1.72 (m), 1.98 (td, J = 13.7, 4.1 Hz), 2.07–
2.18 (m), 7.13–7.41 (m), 7.50 (d, J = 8.3 Hz), 8.70 (d, J =
8.3 Hz) ppm. 13C NMR (125 MHz, DEPT, CDCl3, mixture of two
diastereomers): δ = 14.0 (CH3), 14.3 (CH3), 21.5 (CH3), 23.4 (CH3),
27.2 (CH2), 27.8 (CH2), 29.8 (CH2), 30.7 (CH2), 31.3 (CH3), 37.3
(C), 38.6 (C), 47.8 (CH), 48.3 (CH), 125.2 (CH), 125.8 (CH) ppm.
N-(2,5,5-Trimethylpiperidyl)-p-toluenesulfonamide (22): General
procedure B was used to synthesize 22 from 1-amino-2,2-dimethyl-
5-hexene (16, 305 mg, 2.40 mmol). After chromatography (SiO2,
PE/EtOAc, 10:1), 22 (644 mg, 2.29 mmol, 95%, catalyst:
Ind2ZrMe2, reaction time: 24 h) was obtained as a colourless oil.
When Ind2TiMe2 or Ti(NMe2)4 were used as catalysts, the side-
product 23 (188 mg, 0.67 mmol, 28%, catalyst: Ind2TiMe2, reaction
time: 24 h) was obtained as a colourless solid. Crystallization from
cyclohexane gave 23 as colourless crystals. Piperidine 22: 1H NMR
(500 MHz, CDCl3): δ = 0.86–0.93 (m, 9 H), 1.17–1.24 (m, 1 H),
1.25–1.33 (m, 1 H), 1.40 (td, J = 13.7, 4.0 Hz, 1 H), 1.90 (tt, J =
4.8, 13.7 Hz, 1 H), 2.39 (s, 3 H), 2.67 (d, J = 12.6 Hz, 1 H), 3.22
(dd, J = 1.5, 12.6 Hz, 1 H), 4.14–4.24 (m, 1 H), 7.25 (d, J = 7.8 Hz,
IR (neat, mixture of two diastereomers): ν = 3088, 3058, 3028,
˜
2942, 2866, 1736, 1599, 1497, 1446, 1383, 1337, 1152, 1126, 1092,
1028, 1010, 985, 902, 816, 766, 701, 664, 607, 591, 550 cm–1. MS
(25 °C, mixture of two diastereomers): m/z (%) = 343 (5) [M]+, 329
(21), 328 (94), 213 (12), 212 (100), 188 (43), 159 (14), 155 (17), 118
(28), 117 (35), 105 (17), 91 (46). HRMS: calcd. for C20H25NO2S
343.1606; found 343.1606. C20H25NO2S (343.5): calcd. C 69.93, H
7.34, N 4.08, S 9.34; found C 69.91, H 7.53, N 4.06, S 9.06.
Kinetic Studies of Slow Intramolecular Hydroamination Reactions:
2 H), 7.66 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (125 MHz, DEPT, In a typical experiment, in a nitrogen-filled glovebox, an oven-dried
CDCl3): δ = 14.0 (CH3), 21.4 (CH3), 23.3 (CH3), 27.2 (CH2), 28.9 Schlenk tube (Duran glassware, 80 mL, Ø 26 mm) equipped with a
(CH3), 30.6 (C), 31.7 (CH2), 47.8 (CH), 50.5 (CH2), 127.0 (CH),
Teflon stopcock and a magnetic stirring bar was charged with the
129.4 (CH), 138.3 (C), 142.6 (C) ppm. IR (neat): ν = 3631, 3554, catalyst (0.24 mmol), the amine (4.80 mmol), the internal standard
˜
3029, 2947, 2862, 1919, 1808, 1726, 1655, 1598, 1470, 1382, 1367,
1336, 1228, 1183, 1161, 1098, 1018, 1003, 990, 896, 815, 757, 664,
ferrocene (80 mg, 0.43 mmol) and toluene (4.0 mL). A sample
(0.2 mL) of the solution was transferred into an NMR tube by
607, 549 cm–1. MS (25 °C): m/z (%) = 281 (3) [M]+, 268 (5), 267 syringe and diluted with C6D6 to determine the starting amine/
(14), 266 (100) [M – CH3]+, 155 (13), 91 (16), 55 (6). C15H23NO2S
(281.1): calcd. C 64.02, H 8.24, N 4.98, O 11.37, S 11.39; found C
64.09, H 8.27, N 4.94, S 11.59. Cyclopentane 23: 1H NMR
(500 MHz, CDCl3, mixture of two diastereomers): major dia-
standard ratio. Then the Schlenk tube was transferred into a pre-
equilibrated heating unit at 105 °C (Ϯ 0.2 °C). Every 60 min, the
relative concentration of the amine was determined by NMR spec-
troscopy. For this purpose, a sample (0.2 mL) of the reaction solu-
2738
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2731–2739

Catalysts for the Intramolecular Hydroamination of Alkenes
5266; l) F. Lauterwasser, P. G. Hayes, S. Bräse, W. E. Piers,
L. L. Schafer, Organometallics 2004, 23, 2234–2237; m) J. Y.
Kim, T. Livinghouse, Org. Lett. 2005, 7, 1737–1739; n) J. Y.
Kim, T. Livinghouse, Org. Lett. 2005, 7, 4391–4393; o) D. V.
Vitanova, F. Hampel, K. C. Hultzsch, J. Organomet. Chem.
2007, 692, 4690–4701; p) S. Datta, P. W. Roesky, S. Blechert,
Organometallics 2007, 26, 4392–4394; q) H. Wei, G. Qian, Y.
Xia, K. Li, Y. Li, W. Li, Eur. J. Org. Chem. 2007, 4471–4474.
For reviews, see: a) F. Pohlki, S. Doye, Chem. Soc. Rev. 2003,
32, 104–114; b) I. Bytschkov, S. Doye, Eur. J. Org. Chem. 2003,
935–946; c) S. Doye, Synlett 2004, 1653–1672; d) F. Alonso, I.
Beletskaya, M. Yus, Chem. Rev. 2004, 104, 3079–3160; e) A.
Odom, Dalton Trans. 2005, 225–233; f) R. Severin, S. Doye,
Chem. Soc. Rev. 2007, 36, 1407–1420.
tion was transferred into an NMR tube and diluted with C6D6
using standard Schlenk line techniques. The following NMR sig-
nals were monitored until at least 85% conversion of the amino
alkene: 1H NMR (300 MHz, C6D6): δ = 4.00–4.25 (ferrocene, 10
H), 4.80–5.30 (amino alkene H2C=CH-, 2 H) ppm. All data were
fitted by least-squares analysis.
Kinetic Studies of Fast Intramolecular Hydroamination Reactions:
In a typical experiment, in a nitrogen-filled glovebox, an oven-dried
Schlenk tube equipped with a Teflon stopcock and a magnetic stir-
ring bar was charged with the catalyst (0.12 mmol), the amine
(2.4 mmol), the internal standard ferrocene (40 mg, 0.22 mmol) and
[D8]toluene (2.0 mL). A sample (0.6 mL) of the solution was trans-
ferred into a J. Young NMR tube equipped with a Teflon valve
and the NMR tube was transferred into a pre-equilibrated, pre-
shimmed thermostatted probe of a Bruker Avance 300 spectrome-
ter at 105 °C (Ϯ 0.5 °C). NMR spectra were recorded at appropri-
ate time intervals (5 min for the formation of pyrrolidines, 10 min
for the formation of piperidines) using the multizg script from the
Bruker XWinNMR software package. The following NMR signals
were monitored until at least 85% conversion of the amine: 1H
NMR (300 MHz, C6D6): δ = 4.00–4.25 (ferrocene, 10 H), 4.80–5.30
[3]
[4]
[5]
a) P. D. Knight, I. Munslow, P. N. O’Shaughnessy, P. Scott,
Chem. Commun. 2004, 894–895; b) D. V. Gribkov, K. C.
Hultzsch, Angew. Chem. 2004, 116, 5659–5663; Angew. Chem.
Int. Ed. 2004, 43, 5542–5546.
a) H. Kim, P. H. Lee, T. Livinghouse, Chem. Commun. 2005,
5205–5207; b) J. A. Bexrud, J. D. Beard, D. C. Leitch, L. L.
Schafer, Org. Lett. 2005, 7, 1959–1962; c) R. K. Thomson, J. D.
Bexrud, L. L. Schafer, Organometallics 2006, 25, 4069–4071; d)
A. V. Lee, L. L. Schafer, Organometallics 2006, 25, 5249–5254;
e) M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak, L. L.
Schafer, Angew. Chem. 2007, 119, 358–362; Angew. Chem. Int.
Ed. 2007, 46, 354–358; f) H. Kim, Y. K. Kim, J. H. Shim, M.
Kim, M. Han, T. Livinghouse, P. H. Lee, Adv. Synth. Catal.
2006, 348, 2609–2618; g) D. A. Watson, M. Chiu, R. G.
Bergman, Organometallics 2006, 25, 4731–4733; h) B. D. Stub-
bert, T. J. Marks, J. Am. Chem. Soc. 2007, 129, 6149–6167; i)
K. Marcseková, S. Doye, Synlett 2007, 2564–2568; j) J. A.
Bexrud, C. Li, L. L. Schafer, Organometallics 2007, 26, 6366–
6372.
(amino alkene H2C=CH-,
2 H), 5.40–5.80 (amino alkene
H2C=CH-, 1 H) ppm. All data were fitted by least-squares analysis.
Acknowledgments
We thank the Deutsche Forschungsgemeinschaft (DFG) and the
Fonds der Chemischen Industrie for financial support of our re-
search.
[6]
a) F. Pohlki, A. Heutling, I. Bytschkov, T. Hotopp, S. Doye,
Synlett 2002, 799–801; b) A. Heutling, F. Pohlki, S. Doye,
Chem. Eur. J. 2004, 10, 3059–3071; c) A. Heutling, R. Severin,
S. Doye, Synthesis 2005, 1200–1204.
[1] For reviews, see: a) T. E. Müller, M. Beller, Chem. Rev. 1998,
98, 675–703; b) J. J. Brunet, D. Neibecker in Catalytic Hetero-
functionalization (Eds.: A. Togni, H. Grützmacher), Wiley-
VCH, Weinheim, 2001, pp. 91–141; c) P. W. Roesky, T. E.
Müller, Angew. Chem. 2003, 115, 2812–2815; Angew. Chem. Int.
Ed. 2003, 42, 2708–2710; d) K. C. Hultzsch, Adv. Synth. Catal.
2005, 347, 367–391; e) K. C. Hultzsch, Org. Biomol. Chem.
2005, 3, 1819–1824; f) J.-J. Brunet, N.-C. Chu, M. Rodriguez-
Zubiri, Eur. J. Inorg. Chem. 2007, 4711–4722; g) I. Aillaud, J.
Collin, J. Hannedouche, E. Schulz, Dalton Trans. 2007, 5105–
5118; h) A. V. Lee, L. L. Schafer, Eur. J. Inorg. Chem. 2007,
2243–2255.
[2] For recent examples of alkene hydroamination, see: a) S. B.
Amin, T. J. Marks, J. Am. Chem. Soc. 2007, 129, 10102–10103;
b) S. Tobisch, Chem. Eur. J. 2007, 13, 9127–9136; c) C. F.
Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2005, 127,
1070–1071; d) J. Takaya, J. F. Hartwig, J. Am. Chem. Soc. 2005,
127, 5756–5757; e) D. Karshtedt, A. T. Bell, T. D. Tilley, J. Am.
Chem. Soc. 2005, 127, 12640–12646; f) J.-J. Brunet, N. C. Chu,
O. Diallo, Organometallics 2005, 24, 3104–3110; g) M. Dochn-
ahl, J.-W. Pissarek, S. Blechert, K. Löhnwitz, P. W. Roesky,
Chem. Commun. 2006, 3405–3407; h) M. Dochnahl, K.
Löhnwitz, J.-W. Pissarek, M. Biyikal, S. R. Schulz, S. Schön,
N. Meyer, P. W. Roesky, S. Blechert, Chem. Eur. J. 2007, 13,
6654–6666; i) Z. Zhang, C. F. Bender, R. A. Widenhoefer, J.
Am. Chem. Soc. 2007, 129, 14148–14149; j) A. M. Johns, Z.
Liu, J. F. Hartwig, Angew. Chem. 2007, 119, 7397–7399; Angew.
Chem. Int. Ed. 2007, 46, 7259–7261; k) C. Baudequin, J.-J. Bru-
net, M. Rodriguez-Zubiri, Organometallics 2007, 26, 5264–
[7]
C. Müller, C. Loos, N. Schulenberg, S. Doye, Eur. J. Org. Chem.
2006, 2499–2503.
S. Hong, S. Tian, M. V. Metz, T. J. Marks, J. Am. Chem. Soc.
2003, 125, 14768–14783.
D. V. Gribkov, K. C. Hultzsch, F. Hampel, Chem. Eur. J. 2003,
9, 4796–4810.
A. M. Kawaoka, M. R. Douglass, T. J. Marks, Organometallics
2003, 22, 4630–4632.
J. S. Johnson, R. G. Bergman, J. Am. Chem. Soc. 2001, 123,
2923–2924.
S. B. Herzon, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 6690–
6691.
P. Horrillo-Martinez, K. C. Hultzsch, A. Gil, V. Branchadell,
Eur. J. Org. Chem. 2007, 3311–3325.
a) P. J. Walsh, R. G. Bergman, J. Am. Chem. Soc. 1992, 114,
1708–1719; b) F. Pohlki, S. Doye, Angew. Chem. 2001, 113,
2361–2364; Angew. Chem. Int. Ed. 2001, 40, 2305–2308.
B. D. Stubbert, T. J. Marks, J. Am. Chem. Soc. 2007, 129, 4253–
4271.
E. Ciganek, J. M. Read Jr., J. C. Calabrese, J. Org. Chem. 1995,
60, 5795–5802.
G. M. Sheldrick, SHELXL-97, A Program for Refining Crystal
Structures, University of Göttingen, 1997.
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
Received: December 4, 2007
Published Online: April 15, 2008
Eur. J. Org. Chem. 2008, 2731–2739
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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