An Aminopyridinato Titanium Catalyst for the Intramolecular Hydroaminoalkylation of Secondary Aminoalkenes

Article abstract of DOI:10.1002/adsc.201500287

The easily accessible 2-(methylamino)pyridinato titanium complex initially synthesized by Kempe is used as catalyst for efficient intramolecular hydroaminoalkylation reactions of secondary aminoalkenes. The corresponding reactions of N-aryl-substituted 1-aminohept-6-enes and 1-aminohex-5-enes directly give access to 2-methylcyclohexyl- or 2-methylcyclopentylamines in good yields. In addition, intramolecular hydroaminoalkylations of an N-alkyl-substituted secondary aminoalkene and a geminally β-disubstituted substrate are described for the first time. While all products are formed as mixtures of two diastereoisomers, better trans/cis ratios are observed during the formation of 2-methylcylopentylamines.

Full text of DOI:10.1002/adsc.201500287

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DOI: 10.1002/adsc.201500287
Very Important Publication
An Aminopyridinato Titanium Catalyst for the Intramolecular
Hydroaminoalkylation of Secondary Aminoalkenes
Jaika Dçrfler,a Besnik Bytyqi,a Sascha Hüller,a Nicola M. Mann,a
Christian Brahms,a Marc Schmidtmann,a and Sven Doyea,*
a
Institut für Chemie, Universität Oldenburg, Carl-von-Ossietzky-Strasse 9–11, 26111 Oldenburg, Germany
Fax: (+49)-441-798-3329; e-mail: doye@uni-oldenburg.de
Received: March 23, 2015; Revised: May 11, 2015; Published online: July 14, 2015
Dedicated to Professor Stephen L. Buchwald on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500287.
Abstract: The easily accessible 2-(methylamino)pyri- substituted secondary aminoalkene and a geminally
dinato titanium complex initially synthesized by b-disubstituted substrate are described for the first
Kempe is used as catalyst for efficient intramolecular time. While all products are formed as mixtures of
hydroaminoalkylation reactions of secondary amino- two diastereoisomers, better trans/cis ratios are ob-
alkenes. The corresponding reactions of N-aryl-sub- served during the formation of 2-methylcylopentyl-
stituted 1-aminohept-6-enes and 1-aminohex-5-enes amines.
directly give access to 2-methylcyclohexyl- or 2-
methylcyclopentylamines in good yields. In addition, Keywords: alkylation; amines; C H activation; hy-
intramolecular hydroaminoalkylations of an N-alkyl- droaminoalkylation; titanium
À
Introduction
generally proceed more smoothly than the corre-
sponding reactions of secondary aminoalkenes.[4c,6b,c]
Owing to the great importance of amines in the agro- Especially the latter transformations have rarely been
chemical, fine chemical and pharmaceutical industries, described in the literature and in all these cases, only
the development of efficient synthetic methods for N-aryl-substituted aminoalkenes of type 2 (Scheme 1)
the production of amines has become a research area were used.
of general importance. Among the various synthetic
Intramolecular hydroaminoalkylation of secondary
strategies for the synthesis and transformation of ni- N-aryl-substituted aminoalkenes of type 2 which are
À
trogen-containing molecules, metal-catalyzed C H
bond activation that can be achieved selectively in the
a-position to a nitrogen atom deserves particular at-
tention. For example, the so-called hydroaminoalkyla-
tion of alkenes[1] which takes place by direct addition
3
À
of a-C(sp ) H bonds of primary or secondary amines
across C=C double bonds offers a 100% atom eco-
nomic conversion of readily available amine and
alkene feedstocks into more complex a-alkylated
amines. Although a variety of ruthenium,[2] iridium,[3]
group 5 metal,[4] zirconium,[5] and titanium com-
plexes[6] were found to catalyze hydroaminoalkylation
reactions of alkenes, a number of limitations still
exist. For example, intermolecular transformations
can only be achieved with secondary amine substrates
and best results are obtained with N-arylated alkyl-
Scheme 1. Intramolecular hydroaminoalkylation as a key
step of the retrosynthetic analysis of 2-substituted cycloal-
amines. On the other hand, intramolecular hydroami-
noalkylation reactions of primary aminoalkenes[5,6a–c,e,j] kylamines and structure of the cytomegalovirus inhibitor 4.
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Jaika Dçrfler et al.
Results and Discussion
Due to the broad scope of titanium catalysts for the
intermolecular hydroaminoalkylation of alkenes with
N-arylated alkylamines and especially the recent im-
provements achieved with aminopyridinato titanium
catalysts 11,[6g] initially synthesized by Kempe,[10] and
12,[6i] we decided to start a reinvestigation of the intra-
molecular hydroaminoalkylation of secondary amino-
alkene 8 using 11 and 12 as the catalysts (Table 1).
For that purpose, we initially performed a control cy-
clization of 8 at 1408C in n-hexane (sealed Schlenk
tube) in the presence of 10 mol% of the catalyst
Ti(NMe2)4 which gave cyclohexylamine 10 in 21%
yield with a trans/cis ratio of 75:25 (Table 1, entry 1).
This result is in good agreement with earlier findings
that have already been presented in the literature.[6b,c]
In contrast to the poor performance of Ti(NMe2)4,
we observed a distinct increase in yield with the 2-
(methylamino)pyridinato titanium catalyst 11 which is
easily accessible from Ti(NMe2)4 and 2 equivalents of
Scheme 2. Intramolecular hydroaminoalkylation of secon-
dary aminoalkenes performed with tantalum or titanium cat-
alysts.[4c,6b]
easily accessible by reductive amination of alkenals
with anilines or by palladium-catalyzed Buchwald–
Hartwig amination of aryl halides with corresponding
primary aminoalkenes 3[7] directly gives access to 2-
substituted secondary cycloalkylamines 1 which are
common subunits of biologically active compounds.
For example, the 2-substituted cyclohexylamine
moiety present in the cytomegalovirus inhibitor 4[8] is
regarded as a privileged and frequently occurring
motif in drug design.[9] So far successful intramolecu-
lar hydroaminoalkylation of secondary aminoalkenes
has only been reported with substrates 5, 7 and 8
Table 1. Brief optimization of the intramolecular hydroami-
noalkylation of secondary aminoalkene 8.
(Scheme 2)
using
Ta(NMe2)5,[4c]
Ti(NMe2)4,[6b]
[6b]
TiBn4,[6c] or Ind2TiMe2 (Ind=h5-indenyl) as the cat-
alysts. Among these catalysts, only Ta(NMe2)5 gave
a good yield of the corresponding cyclization product
6 (88%) but unfortunately, the cis- and the trans-dia-
stereoisomers of 6 were formed in a ratio close to
1:1.[4c] On the other hand, all titanium-based catalysts
showed poor activity and, as a result, only disappoint-
ing yields of the hydroaminoalkylation products 9 and
10 (ꢀ26%) could be obtained.[6b,c] Besides the harsh
reaction conditions reported for all intramolecular hy-
droaminoalkylation reactions of the secondary amino-
alkenes 5, 7 and 8, an additional problem is that the
catalyst Ind2TiMe2 was found to isomerize the double
bond of similar geminally disubstituted aminoalkenes
which results in the formation of aminoalkenes with
internal alkene moieties.[6d]
Entry
Catalyst
(mol%)
T
[8C]
t
Yield
[%][a]
Selectivity
[h]
trans/cis[b]
1
2
3
4
5
6
7
8
Ti(NMe2)4 (10)
11 (10)
12 (10)
11 (10)
11 (10)
11 (10)
11 (10)
11 (10)
11 (5)
140
140
140
140
140
120
100
50
96
96
96
24
16
96
96
96
96
24
96
21
97
11
96
97
93
27
–
75:25
55:45
62:38
56:44
55:45
56:44
55:45
–
9
10
11
140
140
120
97
97
85
54:46
54:46
52:48
11 (5)
11 (5)
Herein, we present the first example of a titanium-
based complex that catalyzes high-yielding intramo-
lecular hydroaminoalkylation reactions of various sec-
ondary aminoalkenes and its use for the synthesis of
2-methylcyclohexyl- and 2-methylcyclopentylamines.
[a]
Reaction conditions: aminoalkene 8 (2.0 mmol, 407 mg),
catalyst (5 mol% or 10 mol%), n-hexane (2 mL), T, t.
Yields refer to the total yield of isolated product (trans+
cis).
[b]
GC analysis prior to chromatography.
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An Aminopyridinato Titanium Catalyst for Intramolecular Hydroaminoalkylation
commercially available 2-(methylamino)pyridine.[10]
Encouraged by the high catalytic activity of com-
After heating a solution of aminoalkene 8 and plex 11 with aminoalkene 8, we then studied the sub-
10 mol% of 11 in n-hexane to 1408C for 96 h it was strate scope of the intramolecular hydroaminoalkyla-
possible to isolate the hydroaminoalkylation product tion using a variety of further functionalized secon-
10 in almost quantitative yield (97%, Table 1, dary 1-aminohept-6-enes (Table 2). For that purpose,
entry 2). However, it must be noted that the diaste- we initially chose the optimized conditions of Table 1,
reoselectivity of the reaction which still slightly favors entry 10 (5 mol% 11, 1408C, 24 h) but unfortunately,
formation of the trans-diastereoisomer decreased to we recognized that several reactions do not go to
a trans/cis ratio of 55:45. In contrast to this very completion within 24 h and often significantly im-
promising result, the 2,6-bis(phenylamino)pyridinato proved yields were obtained with a catalyst loading of
titanium catalyst 12 gave a disappointing yield of only 10 mol%. For example, cyclization of the simple N-
11% under identical conditions (Table 1, entry 3), phenyl-substituted aminoalkene 5 (Table 2, entries 1
a result that is even worse than that obtained with and 2) gave the corresponding 2-methylcyclohexyl-
Ti(NMe2)4. A comparison of the results of Table 1, en- amine 6 in 43% yield after 24 h while a yield of 95%
tries 1–3 clearly supports the assumption that the ami- was obtained after 96 h. Although the sterically de-
nopyridinato ligands remain bonded to the titanium manding ortho-methyl-substituted aminoalkene 13 did
center during the course of the reaction because oth- not react at all under the applied conditions (Table 2,
erwise comparable yields and diastereoselectivities entries 3 and 4), the corresponding meta-methyl-sub-
would be expected with the catalysts Ti(NMe2)4, 11 stituted substrate 14 could be converted successfully
and 12. Inspired by the promising result obtained to cyclohexylamine 22 (Table 2, entries 5 and 6). In-
with 11, we then performed a brief optimization study terestingly, in this case a catalyst loading of 10 mol%
with this catalyst (Table 1, entries 4–12). First of all, it and a reaction time of 96 h were necessary to achieve
was noticed that stirring the reaction mixture at a yield of 94%. The fact that the corresponding para-
1408C overnight (16–24 h) is sufficient for this reac- methyl-substituted analogue 8 had already turned out
tion to reach 100% conversion and correspondingly to be far more reactive than 14 (see Table 1, entry 10)
high yields of 96% and 97% were obtained in these and the observed lack of reactivity of the ortho-
cases (Table 1, entries 4 and 5). On the other hand, methyl-substituted substrate 13 suggest that catalyst
the reaction temperature was found to influence the 11 is very sensitive to steric hindrance close to the ni-
outcome of the reaction significantly. While a slightly trogen atom of the aminoalkene. This observation is
reduced temperature of 1208C only led to a slight consistent with the proposed theory that the efficien-
drop in yield (93%, Table 1, entry 6), the yield de- cies of titanium-catalyzed intermolecular hydroami-
creased dramatically to 27% at 1008C (Table 1, noalkylation reactions of alkenes are strongly influ-
entry 7) and finally, it turned out that the reaction enced by the steric bulk of the amine.[6b,d,i,k] On the
does not proceed at all at 508C (Table 1, entry 8). Ad- other hand, the diastereoselectivity of the cyclization
ditional attempts to reduce the catalyst loading reaction does not seem to be influenced significantly
(Table 1, entries 9–11) then revealed that cyclohexyla- by the presence of methyl substituents in the meta- or
mine 10 is still formed in 97% yield at 1408C with para-position of the phenyl substituent and as
a catalyst loading of only 5 mol% of 11 and even in a result, the products 6, 10 and 22 were obtained with
this case, a reaction time of only 24 h is sufficient to almost identical trans/cis ratios ranging from 52:48 to
reach 100% conversion of aminoalkene 8 (Table 1, 56:44. Additional reactions with the N-phenylami-
entries 9 and 10). On the other hand, with the same noalkenes 15–18 (Table 2, entries 7–12) then revealed
catalyst loading, the reaction did not go to completion that the nature of the substituent on the benzene ring
within 96 h at 1208C and under these conditions, of the aminoalkene seems to influence the efficiency
product 10 was only isolated in 85% yield (Table 1, of the reaction significantly. For example, aminoal-
entry 11). As can be seen from Table 1, entries 3–11, kene 15 bearing an electron-donating para-methoxy-
the diastereoselectivity of the hydroaminoalkylation substituent on the benzene ring gave the hydroami-
of 8 catalyzed by aminopyridinato complex 11 was noalkylation product 23 in 81% yield (Table 2,
not significantly influenced by the reaction time, the entry 8, 10 mol% 11) while the corresponding sub-
reaction temperature or the catalyst loading and as strate 16 with the strongly electron-withdrawing para-
a result, the trans- and the cis-isomers of 10 were trifluoromethyl substituent did not react successfully
always formed in a ratio close to 1:1 with this catalyst. (Table 2, entries 9 and 10). The latter result is in good
However, a comparison of the diastereoselectivities agreement with the established fact that N-methyl-
obtained with the catalysts Ti(NMe2)4, 11 and 12 para-trifluoromethylaniline has already been identi-
(Table 1, entries 1–3) leads to the impression that fied as a poor substrate for intermolecular titanium-
a future optimization of the diastereoselectivity of the or tantalum-catalyzed hydroaminoalkylation reac-
reaction might be possibly by varying the ligands tions.[4m,6d,h] In this context, it is worth mentioning that
bound to the titanium center.
aminoalkene 16 is not consumed under the reaction
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Table 2. Formation of 2-methylcyclohexylamines by intramolecular hydroaminoalkylation of sec-
ondary 1-aminohept-6-enes.
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An Aminopyridinato Titanium Catalyst for Intramolecular Hydroaminoalkylation
Table 2. (Continued)
[a]
Reaction conditions: aminoalkene (2.0 mmol), 11 (35 mg, 0.1 mmol, 5 mol% or 70 mg,
0.2 mmol, 10 mol%), n-hexane (2 mL), 1408C, t. Yields refer to the total yield of isolated
product (trans+cis).
[b]
[c]
[d]
GC analysis prior to chromatography.
The reaction was performed at 1808C.
Ratio of diastereoisomers determined by 1H NMR after chromatography.
conditions and as a result, no formation of any addi-
tional products could be observed. Interestingly, the
presence of the para-methoxy group in 15 also caused
a significantly improved diastereoselectivity of the re-
action in favor of the cis-diastereoisomer of 23 (trans/
cis=27:73), a behavior which was not observed with
the para-fluoro- or para-chloro-substituted aminoal-
kenes 17 and 18. In the latter two cases, the cis- and
the trans-diastereoisomers of the products 24 and 25
were again formed in ratios close to 1:1 (Table 2, en-
tries 11 and 12) and, in addition, only modest yields
Scheme 3. Intramolecular hydroaminoalkylation of a b-dis-
ubstituted secondary 1-aminohept-6-ene.
of 39% and 52%, respectively were obtained. The al- always failed in the presence of titanium catalysts.[6b,d,j]
ready observed trend that in comparison to arylalkyl- For example, with Ind2TiMe2 as the catalyst, instead
amines, dialkylamines are generally less reactive sub- of a hydroaminoalkylation reaction of 27, an isomeri-
strates for titanium- and tantalum-catalyzed intermo- zation of the C=C double bond, which is probably
À
lecular hydroaminoalkylation reactions with alk- caused by a competing C H bond activation in the
enes[1c,4,6] was then strongly underlined by the lack of sterically less hindered allylic position, occurs.[6d]
reactivity of the N-cylohexyl- and N-benzyl-substitut- However, using 10 mol% of catalyst 11, it was possi-
ed aminoalkenes 19 and 20 (Table 2, entries 13 and ble to achieve a successful hydroaminoalkylation of
14). Both substrates did not undergo any reaction substrate 27 at 1408C which delivered the correspond-
under the applied conditions. However, finally, we ing product 28 as a mixture of two diastereoisomers
were delighted to recognize that catalyst 11 is able to in a trans/cis ratio of 63:37. Although the yield of
convert the N-(2-phenylethyl)-substituted aminoal- 15% was only modest and a comparable result was
kene 21 into cyclohexylamine 26 if the reaction was obtained at 1808C, to the best of our knowledge, this
performed at 1808C. Although the obtained yield is the first example of a successful intramolecular hy-
(30%) and the diastereoselectivity (trans/cis=1:1) droaminoalkyation of a geminally disubstituted secon-
were only modest, to the best of our knowledge, this dary aminoalkene and correspondingly, this result can
reaction represents the first example of an intramo- be regarded as the starting point for further optimiza-
lecular metal-catalyzed hydroaminoalkylation of an tion studies.
N-alkyl-substituted secondary aminoalkene.
After additional attempts to synthesize the cyclo-
Impressed by the unique reactivity of catalyst 11, pentylamine 33 from secondary 1-aminohex-5-ene 29
we also tried to convert the sterically hindered gemi- (Table 3, entry 2), which were initially performed in
nally b-disubstituted 1-aminohept-6-ene 27 into cyclo- the presence of 5 mol% of catalyst 11 and/or with a re-
hexylamine 28 (Scheme 3). In this context, it must be action time of 24 h, gave the desired product 33 only
noted that, so far, corresponding reactions have in low yields (19–22%), we decided to run all further
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Table 3. Formation of 2-methylcyclopentylamines by intramolecular hydroaminoalkylation of
secondary 1-aminohex-5-enes.
[a]
Reaction conditions: aminoalkene (2.0 mmol), 11 (70 mg, 0.2 mmol, 10 mol%), n-hexane
(2 mL), 1408C, 96 h. Yields refer to the total yield of isolated product (trans+cis).
GC analysis prior to chromatography.
Under identical conditions, no conversion of 31 was observed with 10 mol% Ti(NMe2)4.
An experiment performed with 20 mol% Ta(NMe2)5 gave a yield of 24% and a trans/cis ratio
[b]
[c]
[d]
of 71:29.
cyclization experiments with secondary 1-aminohex-5- mation of the cis-diastereoisomer has been observed
enes with a catalyst loading of 10 mol% and a reaction before during the synthesis of cyclopentylamines from
time of 96 h. The corresponding results which are pre- primary 1-aminohex-5-enes by hydroaminoalkylation
sented in Table 3 clearly prove that 11 can also be performed with a 2-pyridonate titanium catalyst.[6j] In
used for intramolecular hydroaminoalkylation reac- this context it should be noted that secondary N-
tions (73–86%) of N-arylated secondary 1-aminohex- methyl- or N-phenylaminoalkene substrates were un-
5-enes. The reaction tolerates electron-donating (CH3, reactive with this catalyst.[6j] Although structure as-
OCH3) as well as electron-withdrawing substituents signment of the cis- and trans-diastereoisomers of the
(F, Cl) on the phenyl group of the aminohexene and, cyclopentylamines could be achieved by 1H NMR
in all cases, formation of the cis-diastereoisomer was spectroscopy using NOE experiments, we additionally
clearly favored with trans/cis ratios in a range be- converted the major diastereoisomer of the para-
tween approximately 1:2 and 1:3. The preferential for- fluoro-substituted product 35 (Table 3, entry 4) into
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An Aminopyridinato Titanium Catalyst for Intramolecular Hydroaminoalkylation
dary aminoalkenes. With this catalyst, various N-aryl-
substituted 1-aminohept-6-enes and 1-aminohex-5-
enes can be directly converted to 2-methylcyclohexyl-
or 2-methylcyclopentylamines, which are common
subunits of biologically active compounds, in good
yields. In addition, it was possible for the first time, to
achieve the metal-catalyzed intramolecular hydroami-
noalkylation of an N-alkyl-substituted secondary ami-
noalkene as well as a geminally b-disubstituted sub-
strate. While all products were formed as mixtures of
a trans- and a cis-diastereoisomer, better diastereose-
lectivities with trans/cis ratios of approximately 1:3
were observed with 1-aminohex-5-enes which were
converted to 2-methylcylopentylamines.
Figure 1. Single crystal X-ray structure of cis-35·HCl,[11] el-
lipsoid representation at the 50% probability level. Selected
À
À
bond distances [Š] and angles [8]: N1 C1=1.4670(15), N1
À
À
C7A=1.558(2),
C7A C8A=1.524(3),
C7A C11A=
Experimental Section
À
À
1.530(2),
C8A C9A=1.517(3),
C9A C10A=1.523(4),
C10A C11A=1.553(4), C11A C12A=1.498(3), C7A N1
C1=111.27(11), N1 C7A C8A=112.70(15), C7A C8A
C9A=105.96(16), C7A C11A C10A=104.39(17), C8A
À
À
À
À
General Remarks
À
À
À
À
À
À
À
Unless otherwise noted, all reactions were performed under
an inert atmosphere of nitrogen in oven-dried Schlenk tubes
(Duran glassware, 100 mL, ø=30 mm) equipped with
Teflonꢁ stopcocks and magnetic stirring bars (15”4.5 mm).
n-Hexane was purified by distillation from sodium wire and
degassed. The catalyst 11[6g,10] and the aminoalkenes[7,12] were
synthesized according to literature procedures. Prior to use,
À
À
À
C9A C10A=105.97(18),
C9A C10A C11A=106.66(16),
À
À
À
À
C12A C11A C7A=117.59(17),
C12A C11A C10A=
112.2(2).
the corresponding hydrochloride (cis-35·HCl) to
obtain crystals suitable for X-ray single-crystal analy- all aminoalkenes were distilled and degassed. The catalyst,
the aminoalkenes and n-hexane were stored in a nitrogen-
filled glove box (M. Braun, Unilab). All other chemicals
were purchased from commercial sources and were used
without further purification. Unless otherwise noted, yields
refer to isolated mixtures of two diastereoisomers (trans+
cis). The ratio of the diastereoisomers formed during the re-
actions was usually determined by gas chromatography prior
to flash chromatography. For thin layer chromatography,
silica on TLC aluminium foils with fluorescent indicator
254 nm from Fluka was used. The substances were detected
sis. As can be seen from Figure 1, the solid state struc-
ture of cis-35·HCl[11] confirms the mentioned cis-1,2-
disubstitution of the major diastereoisomer formed
from 1-amino-5-hexene 31.
To verify the outstanding catalytic activity of 11, we
additionally performed hydroaminoalkylation experi-
ments with the fluoro-substituted 1-aminohex-5-ene
31 in the presence of Ta(NMe2)5 and Ti(NMe2)4.
While the latter catalyst turned out to be completely
inactive under the typical reaction conditions (1408C, with UV light and/or iodine. For flash chromatography,
silica gel from Fluka (particle size 0.037–0.063 mm) was
used. Light petroleum ether (bp 40–608C, PE), ethyl acetate
(EtOAc), hexanes, tert-butyl methyl ether (MTBE) and di-
ethyl ether (Et2O) used for flash chromatography were dis-
tilled prior to use. All products that have already been re-
ported in the literature were identified by comparison of the
obtained 1H NMR and 13C NMR spectra with those reported
in the literature. New compounds were additionally charac-
terized by infrared (IR) spectroscopy, GC-MS and high-res-
olution mass spectrometry (HR-MS). NMR spectra were re-
96 h), an experiment performed with an increased cat-
alyst loading of 20 mol% Ta(NMe2)5 led to the forma-
tion of product 35 in modest yield of 24% and with
a trans/cis ratio of 71:29. The fact that, in comparison
to catalyst 11, the diastereoselectivity of the reaction
is reversed suggests again that catalyst optimization
should be an appropriate approach to control the dia-
stereoselectivity of the intramolecular hydroaminoal-
kylation. Finally, it must be mentioned that attempts
to achieve intramolecular hydroaminoalkylation of N- corded on the following spectrometers: Bruker Avance
DRX 500 or Bruker Avance III, 500 MHz. All 1H NMR
(oct-7-en-1-yl)-4-methoxyaniline to obtain the corre-
spectra are reported in d units (ppm) relative to the signal
sponding cycloheptylamine failed with catalyst 11,
of TMS at 0.00 ppm or relative to the signal of CDCl3 at
even at temperatures of 2008C.
7.26 ppm or relative to the signal of D2O at 4.79 ppm. J
values are given in Hz. All 13C NMR spectra are reported in
d units (ppm) relative to the central line of the triplet for
Conclusions
CDCl3 at 77.0 ppm or the central line of the septet for
DMSO-d6 at 39.5 ppm. Infrared spectra were recorded on
a Bruker Vector 22 spectrometer or a Bruker Tensor 27
spectrometer (ATR). GC-MS analyses were performed on
In summary, our studies have shown that 2-aminopyri-
dinato titanium complex 11 is an efficient catalyst for
the intramolecular hydroaminoalkylation of secon- a Thermo Finnigan Focus gas chromatograph equipped with
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Jaika Dçrfler et al.
a DSQ mass detector and Agilent DB-5 column [length:
30 m, inner diameter: 0.32 mm, film thickness: 0.25 mm,
(CH), 39.2 (CH), 34.8 (CH2), 33.6 (CH2), 25.9 (CH2), 25.6
(CH2), 20.3 (CH3), 19.6 (CH3); [minor diastereoisomer (cis-
10)]: d=145.4 (C), 129.7 (CH), 125.7 (C), 113.3 (CH), 53.4
(CH), 33.1 (CH), 30.4 (CH2), 28.6 (CH2), 23.0 (CH2), 22.9
(CH2), 20.3 (CH3), 15.4 (CH3).
(94%-methyl)-(5%-phenyl)-(1%-vinyl)polysiloxan].
GC
analyses were performed on a Shimadzu GC-2010 plus or
a Thermo Electron Corporation Focus gas chromatograph.
Both were equipped with a flame ionization detector. High-
resolution mass spectra (HR-MS) were recorded on
Amine 22: The general procedure was used to synthesize
22 from N-(hept-6-en-1-yl)-3-methylaniline (14, 407 mg,
2.0 mmol). After purification by flash chromatography (PE/
EtOAc, 50:1), a mixture of two diastereoisomers of 22 was
isolated as a yellow oil; yield: 381 mg (1.88 mmol, 94%,
10 mol% 11). Prior to chromatography, the trans/cis ratio
was determined to be 56:44. 1H NMR [500 MHz, CDCl3,
TMS, mixture of two diastereoisomers; important signals of
the major diastereoisomer (trans-22)]: d=7.07–6.92 (m,
1H), 6.50–6.27 (m, 3H), 3.46 (br. s, 1H), 2.86 (td, J=10.2,
3.6 Hz, 1H), 2.26 (s, 3H), 2.17–2.10 (m, 1H), 1.00 (d, J=
6.4 Hz, 3H); [important signals of the minor diastereoiso-
mer (cis-22)]: d=7.07–6.92 (m, 1H), 6.50–6.27 (m, 3H),
3.53–3.45 (m, 1H), 3.46 (br. s, 1H), 2.26 (s, 3H), 2.05–1.93
(m, 1H), 0.91 (d, J=6.9 Hz, 3H); 13C NMR [125 MHz,
CDCl3, mixture of two diastereoisomers; major diastereoiso-
mer (trans-22)]: d=148.1 (C), 138.9 (C), 129.1 (CH), 117.4
(CH), 113.6 (CH), 109.9 (CH), 58.0 (CH), 39.1 (CH), 34.8
(CH2), 33.5 (CH2), 25.9 (CH2), 25.5 (CH2), 21.6 (CH3), 19.6
(CH3); [minor diastereoisomer (cis-22)]: d=147.7 (C), 138.9
(C), 129.1 (CH), 117.6 (CH), 113.9 (CH), 110.2 (CH), 53.1
(CH), 33.1 (CH), 30.3 (CH2), 28.7 (CH2), 23.0 (CH2), 22.8
(CH2), 21.6 (CH3), 15.6 (CH3); IR (neat, mixture of two dia-
stereoisomers): 1/l=3402, 3042, 2924, 2853, 1603, 1510,
a
Waters Q-TOF Premier spectrometer in ESI mode
(ESI+, TOF).
General Procedure for the Hydroaminoalkylation of
Secondary Aminoalkenes
An oven-dried Schlenk tube equipped with a Teflon stop-
cock and a magnetic stirring bar was transferred into a nitro-
gen-filled glovebox and charged with catalyst 11 (35 mg,
0.1 mmol, 5 mol% or 70 mg, 0.2 mmol, 10 mol%) and n-
hexane (1.0 mL). Afterwards the aminoalkene (2.0 mmol)
and n-hexane (1.0 mL) were added. After heating the mix-
ture to 1408C for 96 h, the mixture was cooled to room tem-
perature and dichloromethane (40 mL) was added. Then the
diastereoselectivity of the reaction was determined by GC
(if applicable) and finally, the crude product was purified by
flash column chromatography (SiO2).
Amine 6:[4c] The general procedure was used to synthesize
from N-(hept-6-en-1-yl)aniline (5, 379 mg, 2.0 mmol).
6
After purification by flash chromatography (PE/EtOAc,
30:1), a mixture of two diastereoisomers of 6 was isolated as
a yellow oil; yield: 358 mg (1.89 mmol, 95%, 5 mol% 11).
Prior to chromatography, the trans/cis ratio was determined
1489, 1447, 1325, 1263, 1178, 1116, 991, 842, 766, 692 cmÀ1
;
GC-MS (major diastereoisomer, trans-22): m/z=203 ([M]+
32), 146 (100), 120 (26), 91 ([C7H7]+ 23); HR-MS (ESI+,
mixture of two diastereoisomers): m/z=204.1755, calcd. for
C14H22N: 204.1752 ([M+H]+).
1
to be 54:46. H NMR [500 MHz, CDCl3, mixture of two dia-
stereoisomers; important signals of the major diastereoiso-
mer (trans-6)]: d=7.21–7.14 (m, 2H), 6.70–6.58 (m, 3H),
3.48 (br. s, 1H), 2.91 (td, J=10.3, 3.8 Hz, 1H), 2.21–2.14 (m,
1H), 1.04 (d, J=6.5 Hz, 3H); [important signals of the
minor diastereoisomer (cis-6)]: d=7.21–7.14 (m, 2H), 6.70–
6.58 (m, 3H), 3.57–3.51 (m, 1H), 3.48 (br. s, 1H), 2.08–1.99
(m, 1H), 0.94 (d, J=7.0 Hz, 3H); 13C NMR [125 MHz,
CDCl3, mixture of two diastereoisomers; major diastereoiso-
mer (trans-6)]: d=148.2 (C), 129.2 (CH), 116.4 (CH), 112.8
(CH), 58.0 (CH), 39.2 (CH), 34.8 (CH2), 33.5 (CH2), 25.9
(CH2), 25.5 (CH2), 19.6 (CH3); [minor diastereoisomer (cis-
6)]: d=147.7 (C), 129.2 (CH), 116.5 (CH), 113.1 (CH), 53.1
(CH), 33.1 (CH), 30.3 (CH2), 28.7 (CH2), 23.0 (CH2), 22.8
(CH2), 15.5 (CH3).
Amine 23:[9] The general procedure was used to synthe-
size 23 from N-(hept-6-en-1-yl)-4-methoxyaniline (15,
439 mg, 2.0 mmol). After purification by flash chromatogra-
phy (PE/Et2O, 30:1), a mixture of two diastereoisomers of
23 was isolated as a yellow oil; yield: 355 mg (1.62 mmol,
81%, 10 mol% 11). Prior to chromatography, the trans/cis
ratio was determined to be 27:73. 1H NMR [500 MHz,
CDCl3, TMS, mixture of two diastereoisomers; important
signals of the major diastereoisomer (cis-23)]: d=6.78–6.72
(m, 2H), 6.57 (d, J=8.9 Hz, 2H), 3.73 (s, 3H), 3.42–3.37 (m,
1H), 2.04–1.96 (m, 1H), 0.91 (d, J=7.0 Hz, 3H); [important
signals of the minor diastereoisomer (trans-23)]: d=6.78–
6.72 (m, 2H), 6.54 (d, J=8.9 Hz, 2H), 3.73 (s, 3H), 2.76 (td,
J=10.2, 3.8 Hz, 1H), 2.18–2.09 (m, 1H), 1.01 (d, J=6.5 Hz,
3H); 13C NMR [125 MHz, CDCl3, mixture of two diastereo-
isomers; major diastereoisomer (cis-23)]: d=151.6 (C), 142.0
(C), 114.9 (CH), 114.6 (CH), 55.8 (CH3), 54.3 (CH), 33.0
(CH), 30.5 (CH2), 28.6 (CH2), 23.0 (CH2), 22.9 (CH2), 15.2
(CH3); [minor diastereoisomer (trans-23)]: d=151.5 (C),
142.5 (C), 114.9 (CH), 114.3 (CH), 59.3 (CH), 55.9 (CH3),
39.2 (CH), 34.8 (CH2), 33.6 (CH2), 25.9 (CH2), 25.6 (CH2),
19.7 (CH3).
Amine 10:[6b] The general procedure was used to synthe-
size 10 from N-(hept-6-en-1-yl)-4-methylaniline (8, 407 mg,
2.0 mmol). After purification by flash chromatography (PE/
EtOAc, 40:1), a mixture of two diastereoisomers of 10 was
isolated as a yellow oil; yield: 395 mg (1.94 mmol, 97%,
5 mol% 11). Prior to chromatography, the trans/cis ratio was
1
determined to be 54:46. H NMR [500 MHz, CDCl3, TMS,
mixture of two diastereoisomers; important signals of the
major diastereoisomer (trans-10)]: d=6.99–6.92 (m, 2H),
6.49 (d, J=8.3 Hz, 2H), 3.34 (br. s, 1H), 2.82 (td, J=10.2,
3.6 Hz, 1H), 2.22 (s, 3H), 2.17–2.10 (m, 1H), 1.00 (d, J=
6.5 Hz, 3H); [important signals of the minor diastereoiso-
mer (cis-10)]: d=6.99–6.92 (m, 2H), 6.53 (d, J=8.3 Hz,
2H), 3.48–3.43 (m, 1H), 3.34 (br. s, 1H), 2.04–1.95 (m, 1H),
0.91 (d, J=7.0 Hz, 3H); 13C NMR [125 MHz, CDCl3, mix-
ture of two diastereoisomers; major diastereoisomer (trans-
10)]: d=146.0 (C), 129.7 (CH), 125.6 (C), 113.0 (CH), 58.4
Amine 24: The general procedure was used to synthesize
24 from 4-fluoro-N-(hept-6-en-1-yl)-aniline (17, 415 mg,
2.0 mmol). After purification by flash chromatography (PE/
MTBE/Et3N, 800:10:1), a mixture of two diastereoisomers
of 24 was isolated as a yellow oil; yield: 160 mg (0.77 mmol,
39%, 10 mol% 11). Prior to chromatography, the trans/cis
2272
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An Aminopyridinato Titanium Catalyst for Intramolecular Hydroaminoalkylation
ratio was determined to be 53:47. 1H NMR [500 MHz,
CDCl3, mixture of two diastereoisomers; important signals
of the major diastereoisomer (trans-24)]: d=6.89–6.83 (m,
2H), 6.54–6.48 (m, 2H), 3.31 (br. s, 1H), 2.81 (td, J=10.2,
3.8 Hz, 1H), 2.18–2.10 (m, 1H), 1.03 (d, J=6.5 Hz, 3H);
[important signals of the minor diastereoisomer (cis-24)]:
d=6.93–6.87 (m, 2H), 6.58–6.52 (m, 2H), 3.47–3.40 (m,
1H), 3.31 (br. s, 1H), 2.07–1.98 (m, 1H), 0.94 (d, J=7.0 Hz,
3H); 13C NMR [125 MHz, CDCl3, mixture of two diastereo-
isomers; important signals of the major diastereoisomer
(trans-24)]: d=59.0 (CH), 39.2 (CH), 34.8 (CH2), 33.5
(CH2), 25.8 (CH2), 25.5 (CH2), 19.6 (CH3); [important sig-
nals of the minor diastereoisomer (cis-24)]: d=54.0 (CH),
33.0 (CH), 30.4 (CH2), 28.6 (CH2), 22.9 (CH2), 15.3 (CH3);
[additional signals]: d=155.3 (d, 1JC,F =234.2 Hz, C), 155.3
(m, 1H), 2.63–2.28 (m, 7H), 1.90–1.79 (m, 2H), 1.67–1.05
(m, 14H), 1.01–0.85 (m, 2H); 13C NMR [125 MHz, CDCl3,
mixture of two diastereoisomers; important signals of trans-
26]: d=62.9 (CH), 37.6 (CH), 34.5 (CH2), 32.0 (CH2), 25.9
(CH2), 25.4 (CH2), 19.0 (CH3); [important signals of cis-26]:
d=58.4 (CH), 32.4 (CH), 31.0 (CH2), 28.0 (CH2), 23.8
(CH2), 21.8 (CH2), 13.3 (CH3); [additional signals]: d=140.2
(C), 140.0 (C), 128.6 (CH), 128.3 (CH), 128.3 (CH), 126.0
(CH), 126.0 (CH), 48.4 (CH2), 48.0 (CH2), 36.5 (CH2), 36.5
(CH2); IR (neat, mixture of two diastereoisomers): 1/l=
3027, 2925, 2853, 2360, 2341, 1671, 1633, 1602, 1495, 1454,
1376, 1126, 1082, 1030, 748 cmÀ1; GC-MS (mixture of two
diastereoisomers): m/z=217 ([M]+ 1), 126 (100), 97 (25);
HR-MS (ESI+, mixture of two diastereoisomers): m/z=
218.1908, calcd. for C15H24N: 218.1909 ([M+H]+).
1
2
(d, JC,F =233.9 Hz, C), 144.6 (C), 144.1 (C), 115.6 (d, JC,F
=
=
Amine 28: The general procedure was used to synthesize
28 from N-(2,2-dimethylhept-6-en-1-yl)-4-methylaniline (27,
463 mg, 2.0 mmol). After purification by flash chromatogra-
phy (PE/EtOAc, 100:1), three fractions of the diastereoiso-
mers of 28 were isolated as pale yellow oils; yield: 70 mg
(0.30 mmol, 15%, 10 mol% 11). Fraction 1 contained the
pure cis-diastereoisomer (cis-28); yield: 6 mg (0.03 mmol,
1%), fraction 2 contained a mixture of both diastereoiso-
mers (trans/cis=61:39); yield: 52 mg (0.22 mmol, 11%) and
fraction 3 contained the pure trans-diastereoisomer (trans-
28); yield: 12 mg (0.05 mmol, 3%). After chromatography,
the trans/cis ratio of the combined fractions was determined
2
3
22.2 Hz, CH), 115.6 (d, JC,F =22.2 Hz, CH), 114.0 (d, JC,F
3
7.2 Hz, CH), 113.6 (d, JC,F =7.2 Hz, CH); IR (neat, mixture
of two diastereoisomers): 1/l=3424, 2926, 2855, 1612, 1509,
1448, 1404, 1311, 1257, 1220, 1155, 1117, 1092, 818, 763 cmÀ1
;
GC-MS (major diastereoisomer, trans-24): m/z=207 ([M]+
25), 150 (100), 124 (28), 95 (10); HR-MS (ESI+, mixture of
two diastereoisomers): m/z=208.1496, calcd. for C13H19FN:
208.1502 ([M+H]+).
Amine 25: The general procedure was used to synthesize
25 from 4-chloro-N-(hept-6-en-1-yl)-aniline (18, 446 mg,
2.0 mmol). After purification by flash chromatography (PE/
MTBE/Et3N, 800:10:1), a mixture of two diastereoisomers
of 25 was isolated as a yellow oil; yield: 230 mg (1.03 mmol,
52%, 10 mol% 11). Prior to chromatography, the trans/cis
ratio was determined to be 51:49. 1H NMR [500 MHz,
CDCl3, mixture of two diastereoisomers; important signals
of trans-25]: d=3.54 (br. s, 1H), 2.87 (td, J=10.3, 3.8 Hz,
1H), 2.19–2.11 (m, 1H), 1.05 (d, J=6.5 Hz, 3H); [important
signals of cis-25]: d=3.54 (br. s, 1H), 3.52–3.45 (m, 1H),
2.09–2.01 (m, 1H), 0.96 (d, J=7.0 Hz, 3H); 13C NMR
[125 MHz, CDCl3, mixture of two diastereoisomers; impor-
tant signals of trans-25]: d=58.2 (CH), 39.1 (CH), 34.6
(CH2), 33.3 (CH2), 25.7 (CH2), 25.4 (CH2), 19.5 (CH3); [im-
portant signals of cis-25]: d=53.3 (CH), 33.0 (CH), 30.2
(CH2), 28.5 (CH2), 22.9 (CH2), 22.7 (CH2), 15.4 (CH3); [ad-
ditional signals]: d=146.8 (C), 146.3 (C), 128.9 (CH), 128.8
(CH), 120.8 (C), 120.6 (C), 114.1 (CH), 113.7 (CH); IR
(neat, mixture of two diastereoisomers): 1/l=3417, 2926,
1
by H NMR to be approximately 63:37. Major diastereoiso-
1
mer (trans-28): H NMR (500 MHz, CDCl3) d=6.94 (d, J=
8.2 Hz, 2H), 6.52 (d, J=8.3 Hz, 2H), 3.20 (br. s, 1H), 2.67
(d, J=10.6 Hz, 1H), 2.22 (s, 3H), 1.80–1.73 (m, 1H), 1.56–
1.38 (m, 4H), 1.35–1.25 (m, 1H), 1.10–1.00 (m, 1H), 0.93 (s,
3H), 0.89 (s, 3H), 0.89 (d, J=6.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=148.2 (C), 129.7 (CH), 124.8 (C),
112.3 (CH), 66.3 (CH), 40.9 (CH2), 36.6 (C), 36.2 (CH), 35.6
(CH2), 30.5 (CH3), 21.6 (CH2), 20.3 (CH3), 20.2 (CH3), 19.5
(CH3); IR (neat): 1/l=3413, 3015, 2945, 2921, 2866, 1617,
1518, 1456, 1316, 1281, 1250, 1181, 1097, 953, 803 cmÀ1; GC-
MS: m/z=231 ([M]+ 82), 160 (100), 120 ([C8H9N]+ 41), 91
([C7H7]+ 7); HR-MS (ESI+): m/z=232.2071, calcd. for
C16H26N: 232.2065 ([M+H]+). Minor diastereoisomer (cis-
28): 1H NMR (500 MHz, CDCl3): d=6.93 (d, J=8.2 Hz,
2H), 6.53 (d, J=8.3 Hz, 2H), 3.57 (br. s, 1H), 3.03 (d, J=
2.8 Hz, 1H), 2.21 (s, 3H), 2.09–2.00 (m, 1H), 1.56–1.50 (m,
2H), 1.47–1.40 (m, 1H), 1.37–1.28 (m, 1H), 1.23–1.16 (m,
1H), 1.13–1.01 (m, 1H), 1.05 (s, 3H), 0.89 (s, 3H), 0.85 (d,
J=6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=148.1 (C),
129.7 (CH), 124.9 (C), 112.6 (CH), 62.2 (CH), 36.2 (C), 33.7
(CH2), 31.5 (CH), 29.1 (CH3), 28.7 (CH2), 25.8 (CH3), 21.6
(CH2), 20.3 (CH3), 19.3 (CH3); IR (neat): 1/l=3426, 3014,
2952, 2922, 2865, 1618, 1518, 1459, 1312, 1249, 1182, 1155,
1028, 802 cmÀ1; GC-MS: m/z=231 ([M]+ 68), 160 (100), 120
([C8H9N]+ 43), 91 ([C7H7]+ 8); HR-MS (ESI+): m/z=
232.2059, calcd. for C16H26N: 232.2065 ([M+H]+).
2854, 1599, 1499, 1447, 1317, 1258, 1176, 1091, 813 cmÀ1
;
GC-MS (major diastereoisomer, trans-25): m/z=223 ([M]+
20), 166 (100), 130 (34), 75 ([C6H5]+ 18); HR-MS (ESI+,
mixture of two diastereoisomers): m/z=224.1213, calcd. for
C13H19ClN: 224.1206 ([M+H]+).
Amine 26: The general procedure was used to synthesize
26 from N-(2-phenethyl)hept-6-enylamine (21, 435 mg,
2.0 mmol). The reaction was performed at 1808C. After pu-
rification by flash chromatography (PE/MTBE/Et3N,
50:10:1), a mixture of two diastereoisomers of 26 was isolat-
ed as a yellow oil; yield: 140 mg (0.6 mmol, 30%, 10 mol%
11). After chromatography, the trans/cis ratio was deter-
mined by 1H NMR to be approximately 1:1. 1H NMR
[500 MHz, CDCl3, TMS, mixture of two diastereoisomers;
important signals of trans-26]: d=1.94 (td, J=10.1, 3.7 Hz,
1H), 0.76 (d, J=6.5 Hz, 3H); [important signals of cis-26]:
d=2.55–2.48 (m, 1H), 0.75 (d, J=7.1 Hz, 3H); [additional
signals]: d=7.24–7.16 (m, 4H), 7.15–7.08 (m, 6H), 2.95–2.82
Amine 9:[6b] The general procedure was used to synthesize
9
from N-(hex-5-en-1-yl)-4-methylaniline (7, 379 mg,
2.0 mmol). After purification by flash chromatography (PE/
MTBE, 10:1), a mixture of two diastereoisomers of 9 was
isolated as a pale yellow oil; yield: 318 mg (1.68 mmol, 84%,
10 mol% 11). Prior to chromatography, the trans/cis ratio
was determined to be 34:66. 1H NMR [500 MHz, CDCl3,
mixture of two diastereoisomers; important signals of the
Adv. Synth. Catal. 2015, 357, 2265 – 2276
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Jaika Dçrfler et al.
major diastereoisomer (cis-9)]: d=6.99 (d, J=8.2 Hz, 2H),
6.59–6.52 (m, 2H), 3.73 (q, J=6.7 Hz, 1H), 2.33–2.27 (m,
1H), 2.25 (s, 3H), 0.90 (d, J=7.2 Hz, 3H); [important sig-
nals of the minor diastereoisomer (trans-9)]: d=6.99 (d, J=
8.2 Hz, 2H), 6.59–6.52 (m, 2H), 3.27 (q, J=6.7 Hz, 1H),
2.25 (s, 3H), 2.20–2.10 (m, 1H), 1.09 (d, J=6.7 Hz, 3H);
13C NMR [125 MHz, CDCl3, mixture of two diastereoiso-
mers; major diastereoisomer (cis-9)]: d=145.9 (C), 129.6
(CH), 125.8 (C), 113.1 (CH), 57.5 (CH), 35.7 (CH), 31.9
(CH2), 31.4 (CH2), 21.1 (CH2), 20.3 (CH3), 14.3 (CH3);
[minor diastereoisomer (trans-9)]: d=145.9 (C), 129.6 (CH),
126.1 (C), 113.4 (CH), 62.0 (CH), 41.6 (CH), 32.8 (CH2),
32.6 (CH2), 22.5 (CH2), 20.3 (CH3), 18.9 (CH3).
Amine 35: The general procedure was used to synthesize
35 from 4-fluoro-N-(hex-5-en-1-yl)aniline (31, 387 mg,
2.0 mmol). The amount of added dichloromethane during
the work-up procedure was 20 mL. After purification by
flash chromatography (PE/MTBE, 30:1), two fractions of
the diastereoisomers of 35 were isolated as colorless to pale
yellow oils; yield: 329 mg (1.70 mmol, 85%, 10 mol% 11).
Fraction 1 contained the pure cis-diastereoisomer (cis-35)
and fraction 2 contained a mixture of both diastereoisomers
(trans/cis=83:17). Prior to chromatography, the trans/cis
ratio was determined to be 34:66. Isolation of pure trans-35
could be achieved by column chromatography of fraction 2
using a Büchi Sepacoreꢁ Flash System X10 (Büchi Plasti-
glasꢁ column, 36”460 mm; solvent: PE/MTBE; program:
3 min 0% MTBE, 30 min +1% MTBE/min; flow rate:
90 mLminÀ1; 0–30 atm). Major diastereoisomer (cis-35):
1H NMR (500 MHz, CDCl3): d=6.90–6.83 (m, 2H), 6.57–
6.51 (m, 2H), 3.68 (q, J=6.7 Hz, 1H), 3.52 (br. s, 1H), 2.27
(sept, J=6.8 Hz, 1H), 2.04–1.94 (m, 1H), 1.92–1.82 (m, 1H),
1.79–1.67 (m, 1H), 1.64–1.47 (m, 2H), 1.45–1.36 (m, 1H),
Amine 33:[13] The general procedure was used to synthe-
size 33 from N-(hex-5-en-1-yl)aniline (29, 351 mg,
2.0 mmol). After purification by flash chromatography (PE/
MTBE, 40:1), a mixture of two diastereoisomers of 33 was
isolated as a yellow oil; yield: 256 mg (1.46 mmol, 73%,
10 mol% 11). Prior to chromatography, the trans/cis ratio
was determined to be 37:63. 1H NMR [500 MHz, CDCl3,
mixture of two diastereoisomers; important signals of the
major diastereoisomer (cis-33)]: d=7.22–7.15 (m, 2H), 6.72–
6.66 (m, 1H), 6.66–6.59 (m, 2H), 3.76 (q, J=6.6 Hz, 1H),
3.60 (br. s, 1H), 2.31 (sept, J=6.6 Hz, 1H), 0.92 (d, J=
7.0 Hz, 3H); [important signals of the minor diastereoiso-
mer (trans-33)]: d=7.22–7.15 (m, 2H), 6.72–6.66 (m, 1H),
6.66–6.59 (m, 2H), 3.60 (br. s, 1H), 3.30 (q, J=6.7 Hz, 1H),
2.23–2.13 (m, 1H), 1.10 (d, J=6.7 Hz, 3H); 13C NMR
[125 MHz, CDCl3, mixture of two diastereoisomers; major
diastereoisomer (cis-33)]: d=148.1 (C), 129.1 (CH), 116.6
(CH), 112.9 (CH), 57.2 (CH), 35.7 (CH), 31.9 (CH2), 31.5
(CH2), 21.2 (CH2), 14.3 (CH3); [minor diastereoisomer
(trans-33)]: d=148.3 (C), 129.1 (CH), 116.7 (CH), 113.0
(CH), 61.6 (CH), 41.7 (CH), 32.8 (CH2), 32.6 (CH2), 22.5
(CH2), 18.9 (CH3).
0.89 (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=
2
155.4 (d, 1JC,F =234.2 Hz, C), 144.6 (C), 115.5 (d, JC,F
=
3
22.3 Hz, CH), 113.6 (d, JC,F =7.4 Hz, CH), 57.9 (CH), 35.7
(CH), 32.0 (CH2), 31.5 (CH2), 21.2 (CH2), 14.3 (CH3); IR
(neat): 1/l=3425, 3058, 3036, 2958, 2871, 1613, 1509, 1456,
1312, 1220, 1155, 1101, 818, 773 cmÀ1; GC-MS: m/z=193
([M]+ 30), 150 (100), 111 (20); HR-MS (ESI+): m/z=
194.1342, calcd. for C12H17FN: 194.1345 ([M+H]+). Minor
1
diastereoisomer (trans-35): H NMR (500 MHz, CDCl3): d=
6.90–6.83 (m, 2H), 6.57–6.51 (m, 2H), 3.48 (br. s, 1H), 3.21
(q, J=6.6 Hz, 1H), 2.18–2.10 (m, 1H), 1.97–1.87 (m, 1H),
1.82–1.65 (m, 3H), 1.45–1.35 (m, 1H), 1.27 (dq, J=12.7,
8.3 Hz, 1H), 1.09 (d, J=6.7 Hz, 3H); 13C NMR (125 MHz,
1
CDCl3): d=155.5 (d, JC,F =234.4 Hz, C), 144.7 (C), 115.5 (d,
3
2JC,F =22.3 Hz, CH), 113.8 (d, JC,F =7.4 Hz, CH), 62.2 (CH),
Amine 34: The general procedure was used to synthesize
34 from N-(hex-5-en-1-yl)-4-methoxyaniline (30, 411 mg,
2.0 mmol). After purification by flash chromatography (PE/
MTBE, 10:1), a mixture of two diastereoisomers of 34 was
isolated as a yellow oil; yield: 354 mg (1.72 mmol, 86%,
10 mol% 11). Prior to chromatography, the trans/cis ratio
was determined to be 32:68. 1H NMR [500 MHz, CDCl3,
mixture of two diastereoisomers; important signals of the
major diastereoisomer (cis-34)]: d=6.81–6.74 (m, 2H), 6.62–
6.55 (m, 2H), 3.75 (s, 3H), 3.68 (q, J=6.8 Hz, 1H), 2.27
(sept, J=6.8 Hz, 1H), 0.89 (d, J=7.1 Hz, 3H); [important
signals of the minor diastereoisomer (trans-34)]: d=6.81–
6.74 (m, 2H), 6.62–6.55 (m, 2H), 3.75 (s, 3H), 3.23–3.18 (m,
1H), 2.16–2.07 (m, 1H), 1.08 (d, J=6.6 Hz, 3H); 13C NMR
[125 MHz, CDCl3, mixture of two diastereoisomers; major
diastereoisomer (cis-34)]: d=151.6 (C), 142.4 (C), 114.8
(CH), 114.2 (CH), 58.0 (CH), 55.8 (CH3), 35.6 (CH), 31.9
(CH2), 31.4 (CH2), 21.1 (CH2), 14.2 (CH3); [minor diastereo-
isomer (trans-34)]: d=151.8 (C), 142.6 (C), 114.8 (CH),
114.4 (CH), 62.6 (CH), 55.8 (CH3), 41.6 (CH), 32.9 (CH2),
32.6 (CH2), 22.5 (CH2), 19.0 (CH3); IR (neat, mixture of two
diastereoisomers): 1/l=3398, 2954, 2869, 1731, 1618, 1512,
1462, 1408, 1377, 1235, 1179, 1111, 1040, 818, 757 cmÀ1; GC-
MS (major diastereoisomer, cis-34): m/z=205 ([M]+ 60), 162
(100), 108 (37), 77 ([C6H5]+ 16); HR-MS (ESI+, mixture of
two diastereoisomers): m/z=206.1550, calcd. for C13H20NO:
206.1536 ([M+H]+).
41.6 (CH), 32.7 (CH2), 32.6 (CH2), 22.5 (CH2), 18.9 (CH3);
IR (neat): 1/l=3405, 3073, 3056, 3039, 2953, 2900, 2868,
1846, 1609, 1504, 1451, 1405, 1375, 1317, 1294, 1201, 1155,
1115, 1103, 991, 920, 851, 815, 801, 765 cmÀ1; GC-MS: m/z=
193 ([M]+ 31), 164 (12), 150 (100), 137 (16), 124 (11), 111
(10), 95 (8); HR-MS (ESI+): m/z=194.1347, calcd. for
C12H17FN: 194.1345 ([M+H]+).
Amine hydrochloride (cis-35·HCl): Under an atmosphere
of argon, an oven-dried Schlenk tube equipped with a mag-
netic stirring bar was charged with dry diethyl ether (2 mL)
and cis-35 (238 mg, 1.23 mmol). The resulting solution was
cooled to À108C while a solution of hydrogen chloride in di-
ethyl ether (0.6 mL, 2M, 1.23 mmol) was added dropwise.
After the resulting suspension had been stirred for addition-
al ten minutes at À108C, the suspension was filtered and the
solid material was washed with dry diethyl ether (3”2 mL).
After evaporation of the solvent, hydrochloride cis-35·HCl
was obtained as a colorless solid; yield: 220 mg (0.96 mmol,
78%). 1H NMR (500 MHz, D2O): d=7.53–7.47 (m, 2H),
7.33–7.26 (m, 2H), 3.91 (q, J=7.0 Hz, 1H), 2.40 (sept, J=
7.0 Hz, 1H), 1.94–1.77 (m, 3H), 1.76–1.67 (m, 1H), 1.65–
1.54 (m, 1H), 1.52–1.45 (m, 1H), 1.11 (d, J=7.2 Hz, 3H);
1
13C NMR (125 MHz, D2O, DMSO-d6): d=164.0 (d, JC,F
=
=
3
247.5 Hz, C), 132.0 (d, 4JC,F =2.9 Hz, C), 126.7 (d, JC,F
2
9.2 Hz, CH), 118.7 (d, JC,F =23.6 Hz, CH), 68.7 (CH), 36.6
(CH), 32.5 (CH2), 28.1 (CH2), 22.0 (CH2), 15.0 (CH3); IR
(neat): 1/l=2965, 2879, 2658, 2576, 2513, 2447, 1609, 1508,
2274
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FULL PAPERS
An Aminopyridinato Titanium Catalyst for Intramolecular Hydroaminoalkylation
1454, 1427, 1236, 1196, 1160, 1099, 1017, 840, 760 cmÀ1
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Chem. Soc. 2008, 130, 14940–14941; e) P. Eisenberger,
R. O. Ayinla, J. M. P. Lauzon, L. L. Schafer, Angew.
Chem. 2009, 121, 8511–8515; Angew. Chem. Int. Ed.
2009, 48, 8361–8365; f) P. Eisenberger, L. L. Schafer,
Pure Appl. Chem. 2010, 82, 1503–1515; g) G. Zi, F.
Zhang, H. Song, Chem. Commun. 2010, 46, 6296–6298;
h) A. L. Reznichenko, T. J. Emge, S. Audçrsch, E. G.
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2011, 30, 921–924; i) A. L. Reznichenko, K. C.
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10898–10901.
HRMS (ESI+): m/z=194.1341, calcd. for C12H17NF (ammo-
nium ion): 194.1345 ([M]+). Colorless crystals suitable for X-
ray single-crystal analysis[11] were obtained by storing a test
tube filled with a saturated solution of cis-35·HCl in toluene
for three days at room temperature in a closed 500 mL Er-
lenmeyer flask which was charged with light petroleum
ether (20 mL).
Amine 36: The general procedure was used to synthesize
36 from 4-chloro-N-(hex-5-en-1-yl)aniline (32, 419 mg,
2.0 mmol). After purification by flash chromatography (PE/
MTBE, 10:1), a mixture of two diastereoisomers of 36 was
isolated as a yellow oil; yield: 344 mg (1.64 mmol, 82%,
10 mol% 11). Prior to chromatography, the trans/cis ratio
was determined to be 26:74. 1H NMR [500 MHz, CDCl3,
mixture of two diastereoisomers; important signals of the
major diastereoisomer (cis-36)]: d=7.12–7.07 (m, 2H), 6.56–
6.48 (m, 2H), 3.69 (q, J=6.7 Hz, 1H), 3.66 (br. s, 1H), 2.27
(sept, J=6.9 Hz, 1H), 0.88 (d, J=7.1 Hz, 3H); [important
signals of the minor diastereoisomer (trans-36)]: d=7.12–
7.07 (m, 2H), 6.56–6.48 (m, 2H), 3.23 (q, J=6.9 Hz, 1H),
2.18–2.09 (m, 1H), 1.07 (d, J=6.8 Hz, 3H); 13C NMR
[125 MHz, CDCl3, mixture of two diastereoisomers; major
diastereoisomer (cis-36)]: d=146.8 (C), 129.0 (CH), 121.2
(C), 114.0 (CH), 57.4 (CH), 35.7 (CH), 32.0 (CH2), 31.5
(CH2), 21.2 (CH2), 14.3 (CH3); [minor diastereoisomer
(trans-36)]: d=146.9 (C), 129.0 (CH), 121.2 (C), 114.2 (CH),
61.9 (CH), 41.7 (CH), 32.7 (CH2), 32.6 (CH2), 22.5 (CH2),
18.9 (CH3); IR (neat, mixture of two diastereoisomers): 1/
l=3420, 2957, 2870, 1600, 1499, 1456, 1318, 1249, 1176,
1089, 814 cmÀ1; GC-MS (major isomer cis-36): m/z=209
([M]+ 37), 166 (100), 154 (30), 140 (62), 111 (21); HR-MS
(ESI+, mixture of two diastereoisomers): m/z=210.1042,
calcd. for C12H17ClN: 210.1050 ([M+H]+).
[5] Zirconium catalysts: J. A. Bexrud, P. Eisenberger, D. C.
Leitch, P. R. Payne, L. L. Schafer, J. Am. Chem. Soc.
2009, 131, 2116–2118.
[6] Titanium catalysts: a) C. Müller, W. Saak, S. Doye, Eur.
J. Org. Chem. 2008, 2731–2739; b) R. Kubiak, I. Proch-
now, S. Doye, Angew. Chem. 2009, 121, 1173–1176;
Angew. Chem. Int. Ed. 2009, 48, 1153–1156; c) I. Proch-
now, R. Kubiak, O. N. Frey, R. Beckhaus, S. Doye,
ChemCatChem 2009, 1, 162–172; d) R. Kubiak, I.
Prochnow, S. Doye, Angew. Chem. 2010, 122, 2683–
2686; Angew. Chem. Int. Ed. 2010, 49, 2626–2629; e) I.
Prochnow, P. Zark, T. Müller, S. Doye, Angew. Chem.
2011, 123, 6525–6529; Angew. Chem. Int. Ed. 2011, 50,
6401–6405; f) D. Jaspers, W. Saak, S. Doye, Synlett
2012, 23, 2098–2102; g) J. Dçrfler, S. Doye, Angew.
Chem. 2013, 125, 1851–1854; Angew. Chem. Int. Ed.
2013, 52, 1806–1809; h) T. Preuß, W. Saak, S. Doye,
Chem. Eur. J. 2013, 19, 3833–3837; i) J. Dçrfler, T.
Preuß, A. Schischko, M. Schmidtmann, S. Doye,
Angew. Chem. 2014, 126, 8052–8056; Angew. Chem.
Int. Ed. 2014, 53, 7918–7922; j) E. Chong, L. L. Schafer,
Org. Lett. 2013, 15, 6002–6005; k) J. Dçrfler, T. Preuß,
C. Brahms, D. Scheuer, S. Doye, Dalton Trans. 2015,
44, DOI: 10.1039/c4dt03916e; l) M. Manßen, N. Lauter-
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft for financial
support of our research as well as Jessica Reimer and Leoni
Fritsche for experimental assistance.
References
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tal, dimensions 0.24”0.14”0.08 mm3) were measured
on a Bruker AXS Apex II diffractometer (Mo-Ka radi-
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Adv. Synth. Catal. 2015, 357, 2265 – 2276
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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FULL PAPERS
Jaika Dçrfler et al.
ation, l=0.71073 Š, Kappa
4
circle goniometer,
229.71, orthorhombic space group Pccn, a=
17.2353(5) Š, b=18.8292(5) Š, c=7.3825(2) Š, V=
Bruker Apex II detector). An absorption correction
based on symmetry-related measurements (multi-scan)
was performed with the program SADABS (G. M.
Sheldrick, University of Gçttingen, Germany, 2014);
the structure was solved with the program SHELXS
and refined with SHELXL-2014/7 (G. M. Sheldrick,
Acta Crystallogr. Sect. C 2015, 71, 3–8). The 2-methyl-
cyclopentane unit is disordered over 3 sites with refined
occupancies of 73%, 18%, and 9%. Non H atoms of
the major site were refined anisotropically, atoms be-
longing to the minor sites were refined isotropically,
and their geometries restrained to that of the major
site (using the SAME instruction within the SHELXL
program); amine H atoms were refined freely, other H
atoms were fixed to geometric positions using the
riding model. Crystal data: formula C12H17ClFN, M=
2395.82(11) Š3,
Z=8,
1=1.274 mgcmÀ3,
m=
0.300 mmÀ1, qmax =30.0348, T=100(2) K, 51502 reflec-
tions measured, 3514 unique [Rint =0.0398], 2965 ob-
served [I>2s(I)], 186 parameters refined using 40 re-
straints, R1 =0.0375, wR2 =0.0920 for the observed re-
flections, and R1 =0.0469, wR2 =0.0976 for all data,
largest difference peaks 0.567 and À0.293 eŠÀ3. CCDC
1042824 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.
[12] For experimental details, see the Supporting Informa-
tion.
[13] J. Barluenga, R. Sanz, F. J. FaÇanµs, J. Org. Chem.
1997, 62, 5953–5958.
2276
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Adv. Synth. Catal. 2015, 357, 2265 – 2276