A commercially available tantalum catalyst for the highly regioselective intermolecular hydroaminoalkylation of styrenes

Article abstract of DOI:10.1002/ejoc.201400082

The C-C bond-forming catalytic hydroaminoalkylation of terminal alkenes or styrenes enables a direct and 100 % atom-efficient synthesis of amines and can generally result in the formation of two regioisomers, the branched and the linear product. Herein, we report that high-yielding intermolecular hydroaminoalkylation reactions of styrenes can be achieved with excellent regioselectivities in the presence of the commercially available homoleptic catalyst pentakis(dimethylamino)tantalum. In all cases, the branched regioisomer is formed almost exclusively. Highly regioselective intermolecular hydroaminoalkylation reactions of styrenes are achieved in the presence of the commercially available homoleptic catalyst [Ta(NMe₂)₅]. The process activates the α-C-H bonds of N-methylanilines and 1,2,3,4-tetrahydroquinoline and gives access to the corresponding branched hydroaminoalkylation products in good-to-excellent yields. Copyright

Full text of DOI:10.1002/ejoc.201400082

FULL PAPER
DOI: 10.1002/ejoc.201400082
A Commercially Available Tantalum Catalyst for the Highly Regioselective
Intermolecular Hydroaminoalkylation of Styrenes
Jaika Dörfler[a] and Sven Doye*[a]
Keywords: Homogeneous catalysis / Tantalum / Amines / C–H activation / Styrenes
The C–C bond-forming catalytic hydroaminoalkylation of
terminal alkenes or styrenes enables a direct and 100%
atom-efficient synthesis of amines and can generally result
in the formation of two regioisomers, the branched and the
linear product. Herein, we report that high-yielding intermo-
lecular hydroaminoalkylation reactions of styrenes can be
achieved with excellent regioselectivities in the presence of
the commercially available homoleptic catalyst pentakis(di-
methylamino)tantalum. In all cases, the branched re-
gioisomer is formed almost exclusively.
scribe a single corresponding hydroaminoalkylation of a
styrene derivative. Although the former limitation could
easily be overcome by the use of the more-reactive chloro-
amido complex [TaCl3(NEt2)2]2,[8d] even with this im-
proved catalyst, hydroaminoalkylations of styrene or corre-
sponding vinyl arenes were not described. On the other
hand, successful hydroaminoalkylation reactions of styrenes
could be achieved with titanium catalysts. Although the ini-
tial application of tetrabenzyltitanium [TiBn4][7c] gave only
disappointing yields, in 2010, our group was able to develop
an improved process that uses [Ind2TiMe2] (Ind = η5-in-
denyl) as an efficient hydroaminomethylation catalyst.[7d]
Interestingly, the regioselectivity of the hydroaminomethyl-
ation with this catalyst was strongly influenced by the na-
ture of the unsaturated substrate. Whereas simple 1-alkenes
usually delivered the branched regioisomer exclusively, the
use of styrenes resulted in significantly reduced regioselec-
tivities. For example, the hydroaminomethylation of styrene
(4) with 1 gave the branched (5a) and the linear product
(5b) in a ratio of only 85:15 (Scheme 1). Inspired by this
result and the subsequent finding that the regioselectivity
of hydroaminoalkylation reactions of styrenes can be influ-
Introduction
Owing to the biological and industrial importance of
amines and amine derivatives, a lot of effort has been spent
on the development of efficient methods for the synthesis
and transformation of nitrogen-containing molecules.
Among the various synthetic strategies, metal-catalyzed C–
H bond activation that can be achieved selectively in the α
position to a nitrogen atom[1] has already been used for a
variety of elegant and successful functionalization reactions
of simple and readily available amines.[2] For example, the
so-called hydroaminoalkylation[3] of alkenes and styrenes
(Scheme 1) involves the direct addition of the α-C–H bond
of a primary or a secondary amine across a C–C double
bond and gives access to α-alkylated amines in a single step
and with 100% atom efficiency. Although the correspond-
ing reactions can be achieved in the presence of catalytic
amounts of ruthenium,[4] iridium,[5] zirconium,[6] tita-
nium,[7] or group 5 metal[8] complexes, the latter two classes
of catalysts offer the broadest applicability. Inspired by
early studies with homoleptic metal amide catalysts,[8a,8b]
Hartwig and Herzon reported in 2007 that commercially
available pentakis(dimethylamino)tantalum [Ta(NMe2)5] is
a competent catalyst for the hydroaminoalkylation of vari-
ous alkenes with N-alkyl-substituted arylamines.[8c] Al-
though the reactions required elevated temperatures (160–
165 °C), the hydroaminoalkylations usually occurred with
excellent regioselectivity. For example, the [Ta(NMe2)5]-cat-
alyzed α-alkylation of N-methylaniline (1) with 1-octene (2)
gave the branched regioisomer 3a exclusively (Scheme 1).
Interestingly, dialkylamines failed to react in the presence
of [Ta(NMe2)5] and, in addition, the authors did not de-
[a] Institut für Chemie, Universität Oldenburg,
Carl-von-Ossietzky-Str. 9–11, 26111 Oldenburg, Germany
E-mail: doye@uni-oldenburg.de
http://www.chemie.uni-oldenburg.de/oc/doye
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400082.
Scheme 1. Metal-catalyzed hydroaminoalkylation of alkenes and
styrenes.[7d,7g,8c]
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Catalyst for Intermolecular Hydroaminoalkylation
enced strongly by the structure of the titanium catalyst, we Table 1. Optimization of the [Ta(NMe2)5]-catalyzed hydroamino-
recently presented (aminopyridinato)titanium catalysts[7g]
alkylation of styrene (4) with N-methylaniline (1).
that delivered the linear hydroaminoalkylation products as
the major products of the reactions. For example, with the
catalyst [(2-MeN-Py)2Ti(NMe2)2] (Py = pyridyl), selectivi-
ties between approximately 2:1 and 10:1 in favor of the lin-
ear products could be achieved (Scheme 1).
The first successful hydroaminoalkylation reactions of
styrenes catalyzed by group 5 metal catalysts have only been Entry [Ta(NMe2)5]
t
[h]
T
[°C]
Yield 5a
Selectivity
[mol-%]
[%][a]
5a/5b[b]
realized very recently with binaphtholate[8i] or phos-
phoramidate[8j] complexes as well as with [TaMe3Cl2].[8k] In
all of these cases, the branched product was always formed
as the major regioisomer, and selected reactions could even
be performed at room temperature.[8j] However, despite the
efficiency achieved with the mentioned catalysts, it is still
of considerable interest to identify more simple and readily
available catalysts that convert styrenes selectively either to
the branched or the linear hydroaminoalkylation products.
In this context, it should be noted that both classes of prod-
ucts possess pharmaceutically extremely promising struc-
tural motifs (2-phenylethylamine or 3-phenylpropylamine
moieties), which have already attracted significant attention
for medicinal applications.[9] Herein, we report the first suc-
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
8
96
96
96
72
24
16
96
96
96
140
120
100
140
140
140
140
140
140
93
73
18
89
71
52
92
80
53
98:2
99:1
98:2
98:2
99:1
98:2
98:2
99:1
98:2
5
2
[a] Reaction conditions:
1 (214 mg, 2.0 mmol), 4 (313 mg,
3.0 mmol), [Ta(NMe2)5] (2–10 mol-%), hexanes (1.0 mL), yields re-
fer to the yield of the isolated branched product 5a. [b] Determined
by GC analysis prior to chromatography.
cessful use of commercially available pentakis(dimethyl- at lower reaction temperatures of 120 or 100 °C (Table 1,
amino)tantalum [Ta(NMe2)5] as a catalyst for the hydro- Entries 2 and 3) or with shorter reaction times (16–72 h;
aminoalkylation of styrenes and describe its excellent ability Table 1, Entries 4–6). On the other hand, it was possible to
to selectively produce the corresponding branched products. reduce the catalyst loading to 8 mol-% without any signifi-
cant negative effects (Table 1, Entry 7). In this context, it
is also worth mentioning that even with only 2 mol-% of
[Ta(NMe2)5] a reasonable yield of 53% could be obtained
Results and Discussion
at 140 °C after a reaction time of 96 h (Table 1, Entry 9).
Inspired by the promising yields and regioselectivities of Most impressively, the regioselectivity of the [Ta(NMe2)5]-
hydroaminoalkylation reactions of styrenes achieved with catalyzed reaction does not seem to be influenced at all by
(aminopyridinato)titanium catalysts[7g] and the well-estab- the reaction conditions. In all cases, the branched hydroa-
lished ability of tantalum catalysts to deliver the branched minoalkylation product 5a was formed with excellent re-
hydroaminoalkylation products, our initial idea was to use gioselectivity (Ն98:2) and could always be isolated in pure
the corresponding (aminopyridinato)tantalum catalysts for form from the crude reaction mixture. In this context, it
hydroaminoalkylation reactions of styrenes. For that pur- should be noted that styrene polymerization was not ob-
pose, it was planned to generate the tantalum catalysts in served as a significant side reaction. Correspondingly, it was
situ from the commercially available precursor [Ta(NMe2)5] always possible to detect monomeric styrene (4) in the
and various 2-aminopyridines. However, at an early stage crude reaction mixture by GC analysis prior to chromato-
of our study, in an initial control experiment performed in graphic purification. With these combined results in hand,
the absence of any 2-aminopyridine, we surprisingly found we then decided to use the conditions of Table 1, Entry 7
that [Ta(NMe2)5] itself can successfully be used as a catalyst {8 mol-% [Ta(NMe2)5], hexanes, 140 °C, 96 h, sealed tube}
for the high-yielding hydroaminoalkylation of styrene (4) for a subsequent investigation of the scope and limitations
with N-methylaniline (1, Table 1).
of the new [Ta(NMe2)5]-catalyzed process. For that purpose,
As can be seen from Table 1, the initial experiment per- we initially performed a series of corresponding [Ta-
formed under standard conditions {10 mol-% [Ta(NMe2)5], (NMe2)5]-catalyzed hydroaminoalkylation reactions of vari-
hexanes, 140 °C, 96 h, sealed tube; Table 1, Entry 1}[7g] al- ous styrenes with N-methylaniline (1). The results from this
ready gave access to the pure branched hydroaminoalkyl- study are presented in Table 2 and clearly prove that the
ation product 5a in 93% isolated yield. Interestingly and in efficiency of the hydroaminoalkylation is strongly influ-
good agreement with the results obtained with group 5 enced by the steric bulk of the phenyl substituent of the
metal catalysts with more complex ancillary ligands,[8i–8k] styrene. Consequently, the para-methyl-substituted styrene
the regioselectivity of the hydroaminoalkylation reaction 6 gave a much better yield (88%) than the ortho-methyl-
was 98:2 in favor of the branched isomer 5a, as determined substituted analogue 7 (70% yield), which was significantly
by GC analysis of the crude reaction mixture prior to chro- more reactive than the sterically more-demanding
matographic purification. A short optimization study then ortho,ortho-dimethyl-substituted derivative 8 (51% yield;
revealed that significantly lower yields of 5a are obtained Table 2, Entries 1–3). Not surprisingly and in good agree-
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FULL PAPER
ment with these results, 4-tert-butylstyrene (9) also gave a Table 2. [Ta(NMe2)5]-catalyzed hydroaminoalkylation of various
styrenes with N-methylaniline (1).
very good yield of 83% (Table 2, Entry 4). However, ad-
ditional electronic substitution effects also seem to influ-
ence the reaction outcome. For example, the yields drop
from 92% with styrene (5; Table 1, Entry 7) to 88 and 83%
with 4-methylstyrene (6) and 4-tert-butylstyrene (9; Table 2,
Entries 1 and 4), respectively. This conclusion is further
supported by the fact that even worse yields of only 61 and
57% were obtained with styrenes 10 and 11, which possess
more-electron-donating phenyl or methoxy substituents at
the para position of the styrene system (Table 2, Entries 5
and 6). On the other hand, it is remarkable that both the
presence of ortho substituents and the presence of electron-
donating substituents on the benzene ring of the styrene do
not significantly alter the regioselectivity of the hydro-
aminoalkylation process. In all of these cases (Table 2, En-
tries 1–6), the branched regioisomer (17a–22a) was ob-
tained as the exclusive product, and in most cases the linear
isomer could not even be detected by GC analysis of the
crude reaction mixture. On the other hand, detectable
amounts of linear products were formed during hydro-
aminoalkylation reactions of the acceptor-substituted styr-
enes 4-trifluoromethylstyrene (12) and 4-chlorostyrene (13;
Table 2, Entries 7 and 8). However, even in these cases, the
branched isomers 23a and 24a were formed as the major
products with excellent regioselectivities (Ն96:4), and it was
always possible to isolate these products in pure form. In
comparison with the yield of 57% observed during the reac-
tion of the para-methoxy-substituted substrate 11 (Table 2,
Entry 6), the electron-deficient styrenes 12 and 13 gave the
corresponding branched products 23a and 24a in signifi-
cantly improved yields of 83 and 71%, respectively. In con-
trast to these promising results, a poor yield of only 26%
was obtained with 2-vinylnaphthalene (14; Table 2, En-
try 9). Finally, the α-substituted styrene 15 gave the
branched hydroaminoalkylation product 26a in very good
yield (82%; Table 2, Entry 10), whereas the corresponding
[a] Reaction conditions: 1 (214 mg, 2.0 mmol), styrene (3.0 mmol),
β-substituted styrene 1-phenylpropene (16) failed to react
(Table 2, Entry 11). However, the latter finding is in good
agreement with the observation made by Hartwig that 1,2-
disubstituted alkenes do not undergo successful hydro-
[Ta(NMe2)5] (64 mg, 0.16 mmol, 8 mol-%), hexanes (1.0 mL),
140 °C, 96 h, yields refer to the yield of the isolated branched prod-
uct. [b] Determined by GC analysis prior to chromatography.
aminoalkylation reactions in the presence of the catalyst under the reaction conditions. Although the general lack of
[Ta(NMe2)5].[8c]
reactivity of N-alkylanilines bearing alkyl groups larger
In a subsequent series of experiments, which were again than a methyl group was additionally confirmed by unsuc-
performed under the conditions of Table 1, Entry 7 with cessful reactions of 4 with N-propylaniline and N-benzyl-
8 mol-% of [Ta(NMe2)5] at 140 °C for 96 h, the scope of aniline, the conformationally less flexible substrate 1,2,3,4-
the amines that reacts with styrene (4) was studied. The tetrahydroquinoline (37) underwent a highly regioselective
corresponding results for various amines are summarized in hydroaminoalkylation reaction with 4 to give the branched
Table 3. As can be seen from Table 3, Entries 1–3 and 9, the product 48a as a mixture of two diastereomers (dr = 84:16)
catalyst [Ta(NMe2)5] is very sensitive to bulky substituents in 73% yield (Table 3, Entry 10). To the best of our knowl-
bound to the nitrogen atom of the amine substrate. For ex- edge, this reaction represents the first example of a success-
ample, the sterically less-hindered para-methyl- and meta- ful metal-catalyzed hydroaminoalkylation of a styrene de-
methyl-substituted N-methylanilines 28 and 29 exclusively rivative with a biologically interesting 1,2,3,4-tetrahydro-
gave the desired branched hydroaminoalkylation products quinoline building block. Additional reactions of 4 with the
39a and 40a in excellent yields of 84 and 93%, respectively. para-fluoro-, para-chloro-, and para-bromo-substituted N-
On the other hand, the corresponding ortho-methyl-substi- methylanilines 31–33 (Table 3, Entries 4–6) then revealed
tuted derivative 30 as well as the slightly more sterically that halogen substituents are tolerated under the reaction
demanding substrate N-ethylaniline 36 did not react at all conditions. Correspondingly, the halogenated branched hy-
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Catalyst for Intermolecular Hydroaminoalkylation
droaminoalkylation products 42a–44a, which offer the pos- atom; this protecting group can be readily cleaved under
sibility of further metal-catalyzed functionalization, were oxidative conditions.[10] In contrast to the electron-rich sub-
obtained in good yields (71–81%). From a synthetic point strate 35, the electron-poor para-trifluoromethyl-substituted
of view, it is particularly promising that the electron-rich aniline 34 did not undergo successful hydroaminoalkylation
substrate 4-methoxy-N-methylaniline (35) also underwent with styrene (Table 3, Entry 7). However, a corresponding
high-yielding [Ta(NMe2)5]-catalyzed hydroaminoalkylation lack of reactivity of this substrate has already been ob-
with 4 to give the branched regioisomer 46a as the single served before with titanium catalysts.[7d] Finally and in
product of the reaction (Table 3, Entry 8). Product 46a was good agreement with the report by Hartwig on the
obtained in 91% yield and contains the well-established [Ta(NMe2)5]-catalyzed hydroaminoalkylation of alkenes,[8c]
para-methoxyphenyl protecting group on the nitrogen attempted reactions of styrene 4 with N-methylcyclohex-
ylamine (38; Table 3, Entry 11) and other dialkylamines
(pyrrolidine, piperidine, N-methylbenzylamine, and 1,2,3,4-
tetrahydroisoquinoline) did not give access to the desired
hydroaminoalkylation products.
Table 3. [Ta(NMe2)5]-catalyzed hydroaminoalkylation of styrene
(4) with various secondary amines.
Conclusions
We have shown for the first time that commercially avail-
able [Ta(NMe2)5] is a competent catalyst for the intermo-
lecular hydroaminoalkylation of styrenes. The new process
delivers the corresponding branched hydroaminoalkylation
products with excellent regioselectivities (Ն98:2) and can be
used for reactions of electron-rich and electron-poor as well
as ortho- and ortho,ortho-disubstituted styrenes. In addition,
an α-methylstyrene was found to be a suitable substrate,
whereas trans-β-methylstyrene failed to react. On the other
hand, the reaction is limited to 1,2,3,4-tetrahydroquinoline
and ortho-unsubstituted N-methylaniline derivatives that
possess methyl, halogen, or methoxy substituents on the
benzene ring. In contrast, electron-acceptor-substituted 4-
triflouromethyl-N-methylaniline as well as dialkylamines
and N-alkylanilines bearing alkyl groups larger than a
methyl group do not undergo successful hydroaminoalkyl-
ation reactions in the presence of [Ta(NMe2)5].
Experimental Section
General: All reactions were performed under an inert atmosphere
of nitrogen in oven-dried Schlenk tubes (Duran glassware, 100 mL,
ø = 30 mm) equipped with Teflon® stopcocks and magnetic stirring
bars (15ϫ4.5 mm). The [Ta(NMe2)5] (99.99% purity) was pur-
chased from Sigma–Aldrich and used without any further purifica-
tion. Hexane was used as a mixture of isomers (hexanes) and was
purified by distillation (50 cm Vigreux column) from molten so-
dium and degassed. Prior to use, all styrenes and amines were puri-
fied by kugelrohr distillation and degassed. All other chemicals
were purchased from commercial sources and were used without
further purification. The styrenes, amines, [Ta(NMe2)5], and hex-
anes were stored in a nitrogen-filled glovebox (M. Braun, Unilab).
Unless otherwise noted, yields refer to isolated yields of pure com-
pounds as gauged by thin layer chromatography (TLC) and 1H and
13C NMR spectroscopy. The ratio of regioisomers was determined
by gas chromatography prior to flash chromatography. For thin
layer chromatography, silica on TLC aluminium foil with a fluores-
cent indicator (254 nm) from Fluka was used. The substances were
detected by exposure to UV light and/or iodine. For flash
chromatography, silica gel from Fluka (particle size 0.037–
0.063 mm) was used. Prior to use, hexanes and ethyl acetate were
distilled for flash chromatography. All products that have already
[a] Reaction conditions: amine (2.0 mmol), 4 (313 mg, 3.0 mmol),
[Ta(NMe2)5] (64 mg, 0.16 mmol, 8 mol-%), hexanes (1.0 mL),
140 °C, 96 h, yields refer to the yield of the isolated branched prod-
uct. [b] Determined by GC analysis prior to chromatography. [c]
Product 48a was obtained as a mixture of two diastereomers in a
ratio of 84:16 (determined by GC analysis).
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J. Dörfler, S. Doye
FULL PAPER
been reported in the literature were characterized by 1H NMR, 13
C
to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.19 (d, 3JH,H
NMR, and infrared (IR) spectroscopy and GC–MS. New com-
pounds were additionally characterized by high resolution mass
spectrometry (HRMS). NMR spectra were recorded with Bruker
Avance DRX 500 MHz and Bruker Avance III 500 MHz spectrom-
= 6.3 Hz, 3 H), 2.19 (s, 3 H), 2.22 (s, 3 H), 3.15–3.27 (m, 3 H), 3.56
3
3
(br s, 1 H), 6.49 (d, JH,H = 7.7 Hz, 2 H), 6.61 (t, JH,H = 7.3 Hz,
1 H), 6.90–6.96 (m, 2 H), 7.01–7.10 (m, 3 H) ppm. 13C NMR
(125 MHz, DEPT, CDCl3, 25 °C): δ = 19.4 (CH3), 19.7 (CH3), 20.9
(CH3), 33.8 (CH), 50.2 (CH2), 112.9 (CH), 117.3 (CH), 125.2 (CH),
127.1 (CH), 129.2 (CH), 131.3 (CH), 135.6 (C), 136.0 (C), 139.5
1
eters. All H NMR spectra are reported in δ (ppm) relative to the
signal of tetramethylsilane (TMS) at δ = 0.00 ppm, J values are
given in Hz. All 13C NMR spectra are reported in δ (ppm) relative
to the central line of the triplet for CDCl3 at δ = 77.0 ppm. Infrared
spectra were recorded with a Bruker Vector 22 spectrometer. Mass
spectra were recorded with a Finnigan MAT 95 spectrometer [EI
with an ionization potential of 70 eV or chemical ionization (CI)
with isobutane as the ionization gas]. GC–MS analyses were per-
(C), 148.2 (C) ppm. IR (NaCl): ν = 3414, 3049, 3017, 2962, 2923,
˜
1603, 1504, 1320, 1257, 991 cm–1. GC–MS: m/z (%) = 239 (6)
[M]+, 106 (100) [C7H8N]+, 77 (10) [C6H5]+.
Amine 19a: The general procedure was used to synthesize 19a from
1
(214 mg, 2.0 mmol) and 2,4,6-trimethylstyrene (8; 439 mg,
3.0 mmol). After purification by flash chromatography (hexanes/
EtOAc 30:1), 19a (258 mg, 1.02 mmol, 51%) was isolated as a yel-
low oil. Prior to chromatography, the 19a/19b ratio was determined
to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.29 (d, 3JH,H
= 7.2 Hz, 3 H), 2.18 (s, 3 H), 2.24 (br s, 6 H), 3.36–3.41 (m, 2 H),
formed with
a Thermo Finnigan Focus gas chromatograph
equipped with a DSQ mass detector and Agilent DB-5 column
(length: 30 m, inner diameter: 0.32 mm, film thickness: 0.25 μm,
94% methyl-/5% phenyl-/1% vinylpolysiloxane). GC analyses were
performed with a Shimadzu GC-2010 plus gas chromatograph
equipped with a flame ionization detector.
3
3
3.49 (sext, JH,H = 7.4 Hz, 1 H), 3.72 (br s, 1 H), 6.50 (d, JH,H
=
3
7.8 Hz, 2 H), 6.63 (t, JH,H = 7.3 Hz, 1 H), 6.76 (br s, 2 H), 7.08
(t, 3JH,H = 7.9 Hz, 2 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3,
25 °C): δ = 17.3 (CH3), 20.6 (CH3), 21.4 (CH3), 34.6 (CH), 48.3
(CH2), 113.0 (CH), 117.3 (CH), 129.2 (CH), 135.6 (C), 136.8 (C),
General Procedure for the Hydroaminoalkylation of Styrenes, as Ex-
emplified by the Reaction of N-Methylaniline (1) with Styrene (4):
(Table 1, Entry 7): 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 [Ta(NMe2)5] (64 mg,
0.16 mmol, 8 mol-%), hexanes (0.5 mL), 1 (214 mg, 2.0 mmol), 4
(313 mg, 3.0 mmol), and an additional amount of hexanes
(0.5 mL). The Schlenk tube was then sealed, and the mixture was
heated to 140 °C for 96 h.[11] Finally, the crude product was purified
by flash chromatography (SiO2, hexanes/EtOAc 30:1) to give 5a[7g]
(388 mg, 1.84 mmol, 92%) as a yellow oil. Prior to chromatog-
148.0 (C) ppm. IR (NaCl): ν = 3413, 3050, 2964, 2923, 2871, 1603,
˜
1505, 1430, 1256, 844 cm–1. GC–MS: m/z (%) = 253 (8) [M]+, 147
(11) [C11H15]+, 106 (100) [C7H8N]+, 77 (22) [C6H5]+. HRMS (CI):
calcd. for C18H24N [M + H]+ 254.1909; found 254.1912.
Amine 20a:[7d] The general procedure was used to synthesize 20a
from 1 (214 mg, 2.0 mmol) and 4-tert-butylstyrene (9; 481 mg,
3.0 mmol). After purification by flash chromatography (hexanes/
EtOAc 30:1), 20a (443 mg, 1.66 mmol, 83%) was isolated as a yel-
low oil. Prior to chromatography, the 20a/20b ratio was determined
to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.25 (s, 9
1
raphy, the 5a/5b ratio was determined to be 98:2 by GC. H NMR
3
(500 MHz, CDCl3, 25 °C): δ = 1.26 (d, JH,H = 7.0 Hz, 3 H), 2.99
3
2
3
(sext, JH,H = 7.0 Hz, 1 H), 3.16 (dd, JH,H = 12.3 Hz, JH,H
=
3
H), 1.26 (d, JH,H = 7.0 Hz, 3 H), 2.96 (sext, 3JH,H = 7.0 Hz, 1 H),
8.3 Hz, 1 H), 3.26 (dd, 2JH,H = 12.4 Hz, JH,H = 6.2 Hz, 1 H), 6.51
3
2
3
2
3.15 (dd, JH,H = 12.2 Hz, JH,H = 8.0 Hz, 1 H), 3.25 (dd, JH,H
=
=
3
3
(d, JH,H = 7.8 Hz, 2 H), 6.63 (t, JH,H = 7.3 Hz, 1 H), 7.09 (t,
3
3
12.2 Hz, JH,H = 6.4 Hz, 1 H), 3.67 (br s, 1 H), 6.51 (d, JH,H
3JH,H = 7.7 Hz, 2 H), 7.13–7.19 (m, 3 H), 7.25 (t, JH,H = 7.3 Hz,
3
3
8.3 Hz, 2 H), 6.62 (t, JH,H = 7.3 Hz, 1 H), 6.99–7.14 (m, 4 H),
2 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3, 25 °C): δ = 19.7
(CH3), 39.1 (CH), 51.0 (CH2), 113.1 (CH), 117.5 (CH), 126.6 (CH),
127.2 (CH), 128.6 (CH), 129.2 (CH), 144.4 (C), 147.8 (C) ppm. IR
7.28 (d, JH,H = 8.3 Hz, 2 H) ppm. 13C NMR (125 MHz, DEPT,
3
CDCl3, 25 °C): δ = 19.7 (CH3), 31.4 (CH3), 34.4 (C), 38.6 (CH),
50.9 (CH2), 112.9 (CH), 117.2 (CH), 125.5 (CH), 126.8 (CH), 129.2
(NaCl): ν = 3414, 3082, 2961, 1602, 1507, 1320, 1257 cm–1. GC–
˜
(CH), 141.3 (C), 148.1 (C), 149.3 (C) ppm. IR (NaCl): ν = 3413,
˜
MS: m/z (%) = 221 (9) [M]+, 106 (100) [C7H8N]+, 77 (19) [C6H5]+.
3051, 3022, 2955, 2869, 1603, 1506, 1320, 1267, 1014 cm–1. GC–
MS: m/z (%) = 267 (4) [M]+, 106 (100) [C7H8N]+, 77 (6) [C6H5]+.
Amine 17a:[7d] The general procedure was used to synthesize 17a
from 1 (214 mg, 2.0 mmol) and para-methylstyrene (6; 355 mg,
3.0 mmol). After purification by flash chromatography (hexanes/
EtOAc 30:1), 17a (396 mg, 1.75 mmol, 88%) was isolated as a yel-
low oil. Prior to chromatography, the 17a/17b ratio was determined
to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.24 (d, 3JH,H
= 7.0 Hz, 3 H), 2.26 (s, 3 H), 2.95 (sext, 3JH,H = 7.1 Hz, 1 H), 3.13
Amine 21a:[7d] The general procedure was used to synthesize 21a
from 1 (214 mg, 2.0 mmol) and 4-vinylbiphenyl (10; 541 mg,
3.0 mmol). After purification by flash chromatography (hexanes/
EtOAc 30:1), 21a (350 mg, 1.22 mmol, 61%) was isolated as a white
solid. Prior to chromatography, the 21a/21b ratio was determined
to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.30 (d, 3JH,H
2
3
2
3
2
(dd, JH,H = 12.3 Hz, JH,H = 8.3 Hz, 1 H), 3.24 (dd, JH,H
=
=
= 7.0 Hz, 3 H), 3.04 (sext, JH,H = 7.0 Hz, 1 H), 3.20 (dd, JH,H
=
=
3
3
3
2
3
12.3 Hz, JH,H = 6.2 Hz, 1 H), 3.55 (br s, 1 H), 6.49 (d, JH,H
12.4 Hz, JH,H = 8.2 Hz, 1 H), 3.30 (dd, JH,H = 12.4 Hz, JH,H
6.2 Hz, 1 H), 3.77 (br s, 1 H), 6.53 (d, JH,H = 7.8 Hz, 2 H), 6.63
(t, JH,H = 7.3 Hz, 1 H), 7.10 (t, JH,H = 7.9 Hz, 2 H), 7.20–7.29
3
3
7.7 Hz, 2 H), 6.61 (t, JH,H = 7.3 Hz, 1 H), 7.02–7.10 (m, 6 H)
ppm. 13C NMR (125 MHz, DEPT, CDCl3, 25 °C): δ = 19.9 (CH3),
21.0 (CH3), 38.8 (CH), 50.9 (CH2), 113.0 (CH), 117.3 (CH), 127.1
(CH), 129.2 (CH), 129.3 (CH), 136.1 (C), 141.4 (C), 148.1 (C) ppm.
3
3
3
(m, 3 H), 7.36 (t, JH,H = 7.7 Hz, 2 H) 7.46–7.55 (m, 4 H) ppm.
13C NMR (125 MHz, DEPT, CDCl3, 25 °C): δ = 19.8 (CH3), 38.8
(CH), 51.0 (CH2), 113.1 (CH), 117.5 (CH), 127.0 (CH), 127.2 (CH),
127.4 (CH), 127.7 (CH), 128.7 (CH), 129.2 (CH), 139.6 (C), 140.9
IR (NaCl): ν = 3413, 3050, 3019, 2960, 2923, 1603, 1506, 1320,
˜
992 cm–1. GC–MS: m/z (%) = 225 (11) [M]+, 106 (100) [C7H8N]+,
77 (17) [C6H5]+.
(C), 143.6 (C), 147.9 (C) ppm. IR (KBr): ν = 3401, 3027, 2955,
˜
2926, 1601, 1510, 1484, 1323, 1260, 1026 cm–1. GC–MS: m/z (%)
Amine 18a:[7d] The general procedure was used to synthesize 18a
from 1 (214 mg, 2.0 mmol) and 2,4-dimethylstyrene (7; 397 mg,
3.0 mmol). After purification by flash chromatography (hexanes/
= 287 (3) [M]+, 106 (100) [C7H8N]+, 77 (12) [C6H5]+.
Amine 22a:[7d] The general procedure was used to synthesize 22a
EtOAc 30:1), 18a (334 mg, 1.40 mmol, 70%) was isolated as a yel- from 1 (214 mg, 2.0 mmol) and 4-methoxystyrene (11; 403 mg,
low oil. Prior to chromatography, the 18a/18b ratio was determined 3.0 mmol). After purification by flash chromatography (hexanes/
2794
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2790–2797

Catalyst for Intermolecular Hydroaminoalkylation
EtOAc 30:1), 22a (274 mg, 1.14 mmol, 57%) was isolated as a yel- (CH), 129.2 (CH), 132.5 (C), 133.6 (C), 141.9 (C), 148.1 (C) ppm.
low oil. Prior to chromatography, the 22a/22b ratio was determined
IR (NaCl): ν = 3413, 3053, 2986, 1602, 1508, 1265, 1179, 989 cm–1.
˜
to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.23 (d, 3JH,H
GC–MS: m/z (%) = 261 (6) [M]+, 155 (4) [C12H11]+, 106 (100)
[C7H8N]+, 77 (15) [C6H5]+. HRMS (EI): calcd. for C19H19N [M]+
261.1518; found 261.1511.
3
2
= 7.0 Hz, 3 H), 2.94 (sext, JH,H = 7.0 Hz, 1 H), 3.10 (dd, JH,H
=
=
3
2
3
12.3 Hz, JH,H = 8.4 Hz, 1 H), 3.24 (dd, JH,H = 12.3 Hz, JH,H
6.1 Hz, 1 H), 3.57 (br s, 1 H), 3.72 (s, 3 H), 6.50 (d, 3JH,H = 7.8 Hz,
Amine 26a: The general procedure was used to synthesize 26a from
1 (214 mg, 2.0 mmol) and 1-methyl-4-(propen-2-yl)benzene (15;
397 mg, 3.0 mmol). After purification by flash chromatography
(hexanes/EtOAc 30:1), 26a (393 mg, 1.64 mmol, 82%) was isolated
as a yellow oil. Prior to chromatography, the 26a/26b ratio was
3
3
2 H), 6.61 (t, JH,H = 7.3 Hz, 1 H), 6.79 (d, JH,H = 8.6 Hz, 2 H),
7.04–7.11 (m, 4 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3,
25 °C): δ = 19.9 (CH3), 38.3 (CH), 51.0 (CH2), 55.2 (CH3), 113.0
(CH), 114.0 (CH), 117.3 (CH), 128.1 (CH), 129.2 (CH), 136.4 (C),
148.1 (C), 158.2 (C) ppm. IR (NaCl): ν = 3412, 3050, 3020, 2958,
˜
1
determined to be Ͼ99:1. H NMR (500 MHz, CDCl3, 25 °C): δ =
2930, 1603, 1511, 1248, 1179, 1037, 991 cm–1. GC–MS: m/z (%) =
1.32 (s, 6 H), 2.26 (s, 3 H), 3.17 (s, 2 H), 3.27 (br s, 1 H), 6.45 (d,
241 (4) [M]+, 106 (100) [C7H8N]+, 77 (24) [C6H5]+.
3
3JH,H = 8.3 Hz, 2 H), 6.58 (t, JH,H = 7.3 Hz, 1 H), 7.02–7.10 (m,
3
4 H), 7.20 (d, JH,H = 8.2 Hz, 2 H) ppm. 13C NMR (125 MHz,
Amine 23a:[7g] The general procedure was used to synthesize 23a
from 1 (214 mg, 2.0 mmol) and 4-(trifluoromethyl)styrene (12;
517 mg, 3.0 mmol). After purification by flash chromatography
(hexanes/Et2O 9:1Ǟ8:2Ǟ7:3Ǟ6:4), 23a (463 mg, 1.66 mmol,
83%) was isolated as a yellow oil. Prior to chromatography, the
23a/23b ratio was determined to be 96:4. 1H NMR (500 MHz,
DEPT, CDCl3, 25 °C): δ = 20.9 (CH3), 27.5 (CH3), 38.5 (C), 55.7
(CH2), 112.7 (CH), 117.0 (CH), 126.0 (CH), 129.1 (CH), 129.2
(CH), 135.7 (C), 143.6 (C), 148.7 (C) ppm. IR (NaCl): ν = 3411,
˜
3052, 3021, 2964, 2922, 1603, 1506, 1430, 1320, 1179, 1155,
993 cm–1. GC–MS: m/z (%) = 239 (7) [M]+, 133 (4) [C10H13]+, 106
(100) [C7H8N]+, 77 (11) [C6H5]+. HRMS (EI): calcd. for C17H21N
[M]+ 239.1674; found 239.1671.
3
3
CDCl3, 25 °C): δ = 1.27 (d, JH,H = 6.9 Hz, 3 H), 3.06 (sext, JH,H
2
3
= 7.0 Hz, 1 H), 3.18 (dd, JH,H = 12.4 Hz, JH,H = 8.2 Hz, 1 H),
2
3
3.29 (dd, JH,H = 12.7 Hz, JH,H = 6.2 Hz, 1 H), 3.56 (br s, 1 H),
Amine 39a: The general procedure was used to synthesize 39a from
4-methyl-N-methylaniline (28; 242 mg, 2.0 mmol) and 4 (313 mg,
3.0 mmol). After purification by flash chromatography (hexanes/
EtOAc 30:1), 39a (379 mg, 1.68 mmol, 84%) was isolated as a yel-
low oil. Prior to chromatography, the 39a/39b ratio was determined
to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.24 (d, 3JH,H
3
3
6.50 (d, JH,H = 7.8 Hz, 2 H), 6.64 (t, JH,H = 7.3 Hz, 1 H), 7.09
3
3
(t, JH,H = 7.9 Hz, 2 H), 7.25 (d, JH,H = 8.1 Hz, 2 H), 7.50 (d,
3JH,H = 8.2 Hz, 2 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3,
25 °C): δ = 19.4 (CH3), 39.1 (CH), 50.7 (CH2), 113.0 (CH), 117.6
1
3
(CH), 124.2 (q, JC,F = 272 Hz, CF3), 125.6 (q, JC,F = 3.6 Hz,
2
CH), 127.6 (CH), 128.9 (q, JC,F = 32 Hz, C), 129.3 (CH), 147.7
3
= 7.0 Hz, 3 H), 2.14 (s, 3 H), 2.95 (sext, JH,H = 7.0 Hz, 1 H), 3.12
(C), 148.7 (C) ppm. IR (NaCl): ν = 3416, 3052, 3022, 2965, 2931,
˜
2
3
2
(dd, JH,H = 12.3 Hz, JH,H = 8.2 Hz, 1 H), 3.23 (dd, JH,H
=
=
1603, 1507, 1421, 1327, 1164, 1122, 991 cm–1. GC–MS: m/z (%) =
279 (6) [M]+, 133 (3) [C9H11N]+, 106 (100) [C7H8N]+, 77 (21)
[C6H5]+.
3
3
12.4 Hz, JH,H = 6.3 Hz, 1 H), 3.58 (br s, 1 H), 6.43 (d, JH,H
3
8.4 Hz, 2 H), 6.89 (d, JH,H = 8.2 Hz, 2 H), 7.10–7.17 (m, 3 H),
7.20–7.26 (m, 2 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3,
25 °C): δ = 19.7 (CH3), 20.4 (CH3), 39.1 (CH), 51.5 (CH2), 113.4
(CH), 126.5 (CH), 126.8 (C), 127.2 (CH), 128.6 (CH), 129.7 (CH),
Amine 24a:[12] The general procedure was used to synthesize 24a
from 1 (214 mg, 2.0 mmol) and 4-chlorostyrene (13; 416 mg,
3.0 mmol). After purification by flash chromatography (hexanes/
EtOAc 30:1), 24a (348 mg, 1.42 mmol, 71%) was isolated as a yel-
low oil. Prior to chromatography, the 24a/24b ratio was determined
144.5 (C), 145.5 (C) ppm. IR (NaCl): ν = 3411, 3025, 2961, 2869,
˜
1618, 1521, 1318, 1253, 1182, 1130, 998 cm–1. GC/MS: m/z (%) =
225 (7) [M]+, 120 (100) [C8H10N]+, 91 (13) [C7H7]+, 77 (12)
[C6H5]+. HRMS (CI): calcd. for C16H20N [M + H]+ 226.1596;
found 226.1600.
1
3
to be 97:3. H NMR (500 MHz, CDCl3, 25 °C): δ = 1.24 (d, JH,H
3
2
= 7.0 Hz, 3 H), 2.97 (sext, JH,H = 7.0 Hz, 1 H), 3.12 (dd, JH,H
12.6 Hz, JH,H = 8.2 Hz, 1 H), 3.25 (dd, JH,H = 12.6 Hz, JH,H
6.2 Hz, 1 H), 3.57 (br s, 1 H), 6.49 (d, JH,H = 7.1 Hz, 2 H), 6.63
=
=
3
2
3
Amine 40a: The general procedure was used to synthesize 40a from
3-methyl-N-methylaniline (29; 242 mg, 2.0 mmol) and 4 (313 mg,
3.0 mmol). After purification by flash chromatography (hexanes/
EtOAc 30:1), 40a (419 mg, 1.86 mmol, 93%) was isolated as a yel-
low oil. Prior to chromatography, the 40a/40b ratio was determined
to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.26 (d, 3JH,H
3
3
(t, JH,H = 7.3 Hz, 1 H), 7.04–7.12 (m, 4 H), 7.19–7.24 (m, 2 H)
ppm. 13C NMR (125 MHz, DEPT, CDCl3, 25 °C): δ = 19.6 (CH3),
38.7 (CH), 50.9 (CH2), 113.0 (CH), 117.6 (CH), 128.6 (CH), 128.8
(CH), 129.3 (CH), 132.3 (C), 143.0 (C), 147.8 (C) ppm. IR (NaCl):
3
ν = 3414, 3051, 3022, 2963, 2928, 1603, 1506, 1410, 1320, 1179,
˜
= 7.0 Hz, 3 H), 2.18 (s, 3 H), 2.97 (sext, JH,H = 7.1 Hz, 1 H), 3.15
1153, 991 cm–1. GC–MS: m/z (%) = 245 (4) [M]+, 106 (100)
2
3
2
(dd, JH,H = 12.3 Hz, JH,H = 8.2 Hz, 1 H), 3.25 (dd, JH,H
=
[C7H8N]+, 77 (22) [C6H5]+.
3
3
12.3 Hz, JH,H = 6.2 Hz, 1 H), 6.29–6.34 (m, 2 H), 6.44 (d, JH,H
= 7.3 Hz, 1 H), 6.94–7.00 (m, 1 H), 7.12–7.19 (m, 3 H), 7.21–7.28
(m, 2 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3, 25 °C): δ =
19.8 (CH3), 21.6 (CH3), 39.2 (CH), 51.0 (CH2), 110.2 (CH) 113.8
(CH), 118.4 (CH), 126.6 (CH), 127.2 (CH), 128.6 (CH), 129.1
Amine 25a: The general procedure was used to synthesize 25a from
1
(214 mg, 2.0 mmol) and 2-vinylnaphthalene (14; 463 mg,
3.0 mmol). After purification by flash chromatography (hexanes/
EtOAc 30:1), 25a (136 mg, 0.52 mmol, 26%) was isolated as a yel-
low oil. Prior to chromatography, the 25a/25b ratio was determined
to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.42 (d, 3JH,H
(CH), 139.0 (C), 144.5 (C), 148.0 (C) ppm. IR (NaCl): ν = 3413,
˜
3082, 3027, 2961, 2870, 1605, 1510, 1326, 1267, 1180, 1122,
908 cm–1. GC–MS: m/z (%) = 225 (5) [M]+, 120 (100) [C8H10N]+,
91 (15) [C7H7]+, 77 (7) [C6H5]+. HRMS (EI): calcd. for C16H19N
[M]+ 225.1517; found 225.1512.
3
2
= 6.9 Hz, 3 H), 3.23 (sext, JH,H = 7.0 Hz, 1 H), 3.34 (dd, JH,H
=
=
3
2
3
12.3 Hz, JH,H = 8.4 Hz, 1 H), 3.43 (dd, JH,H = 12.4 Hz, JH,H
6.0 Hz, 1 H), 3.58 (br s, 1 H), 6.57 (d, JH,H = 8.1 Hz, 2 H), 6.69
3
3
3
(t, JH,H = 7.3 Hz, 1 H), 7.15 (t, JH,H = 7.7 Hz, 2 H), 7.37 (d, Amine 42a: The general procedure was used to synthesize 42a from
3JH,H = 8.4 Hz, 1 H), 7.41–7.50 (m, 2 H), 7.66 (s, 1 H), 7.77–7.85 4-fluoro-N-methylaniline (31; 250 mg, 2.0 mmol) and 4 (313 mg,
(m, 3 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3, 25 °C): δ = 3.0 mmol). After purification by flash chromatography (hexanes/
19.8 (CH3), 39.4 (CH), 50.8 (CH2), 113.0 (CH), 117.4 (CH), 125.5 EtOAc 30:1), 42a (367 mg, 1.60 mmol, 80%) was isolated as a yel-
(CH), 125.8 (CH), 126.1 (CH), 127.6 (CH), 127.6 (CH), 128.4
low oil. Prior to chromatography, the 42a/42b ratio was determined
Eur. J. Org. Chem. 2014, 2790–2797
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2795

J. Dörfler, S. Doye
FULL PAPER
to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.24 (d, 3JH,H
Amine 48a:[13] The general procedure was used to synthesize 48a
from 1,2,3,4-tetrahydroquinoline (37; 266 mg, 2.0 mmol) and 4
(313 mg, 3.0 mmol). After purification by flash chromatography
(hexanes/EtOAc 30:1), a mixture of two diastereomers of 48a
3
2
= 7.0 Hz, 3 H), 2.95 (sext, JH,H = 7.1 Hz, 1 H), 3.10 (dd, JH,H
=
=
=
3
2
3
12.2 Hz, JH,H = 8.4 Hz, 1 H), 3.21 (dd, JH,H = 12.3 Hz, JH,H
3
6.1 Hz, 1 H), 3.35 (br s, 1 H), 6.36–6.44 (m, 2 H), 6.78 (t, JH,H
3
8.7 Hz, 2 H), 7.10–7.19 (m, 3 H), 7.25 (t, JH,H = 7.5 Hz, 2 H) (347 mg, 1.46 mmol, 73%) was isolated as a yellow oil. The ratio
ppm. 13C NMR (125 MHz, DEPT, CDCl3, 25 °C): δ = 19.7 (CH3), of the two diastereomers was determined by GC analysis to be
3
39.1 (CH), 51.6 (CH2), 113.7 (d, JC,F = 7.4 Hz, CH), 115.6 (d, 84:16. Prior to chromatography, the 48a/48b ratio was determined
2JC,F = 22 Hz, CH), 126.6 (CH), 127.2 (CH), 128.7 (CH), 144.4 to be Ͼ99:1. 1H NMR (500 MHz, CDCl3, 25 °C, signals of the
1
3
(C), 155.7 (d, JC,F = 235 Hz, C) ppm. IR (NaCl): ν = 3411, 3060,
major diastereomer): δ = 1.30 (d, JH,H = 7.0 Hz, 3 H), 1.47–1.58
˜
3029, 2963, 2873, 1613, 1510, 1453, 1318, 1255, 1155, 1121,
(m, 1 H), 1.63–1.73 (m, 1 H), 2.59–2.67 (m, 2 H), 2.71–2.81 (m, 1
1017 cm–1. GC–MS: m/z (%)
=
229 (11) [M]+, 124 (100)
H), 3.30 (td, 3JH,H = 8.2 Hz, 3JH,H = 3.0 Hz, 1 H), 3.93 (br s, 1 H),
[C7H7NF]+, 95 (8) [C6H4F]+. HRMS (EI): calcd. for C15H16NF
[M]+ 229.1267; found 229.1261.
6.42 (d, JH,H = 7.9 Hz, 1 H), 6.53 (t, JH,H = 7.9 Hz, 1 H), 6.84–
3
3
3
6.91 (m, 2 H), 7.13–7.19 (m, 3 H), 7.26 (t, JH,H = 7.6 Hz, 2 H)
ppm. 13C NMR (125 MHz, DEPT, CDCl3, 25 °C, signals of the
major diastereomer): δ = 16.8 (CH3), 25.9 (CH2), 26.0 (CH2), 44.2
(CH), 56.9 (CH), 114.4 (CH), 117.1 (CH), 121.5 (C), 126.4 (CH),
126.7 (CH), 127.6 (CH), 128.5 (CH), 129.2 (CH), 144.4 (C), 144.4
Amine 43a:[7g] The general procedure was used to synthesize 43a
from 4-chloro-N-methylaniline (32; 283 mg, 2.0 mmol) and 4
(313 mg, 3.0 mmol). After purification by flash chromatography
(hexanes/EtOAc 30:1), 43a (398 mg, 1.62 mmol, 81%) was isolated
as a yellow oil. Prior to chromatography, the 43a/43b ratio was
(C) ppm. IR (NaCl): ν = 3415, 3055, 3025, 2960, 2842, 1605, 1586,
˜
1451, 1376, 1120, 1022 cm–1. GC–MS: m/z (%) = 237 (5) [M]+, 132
1
determined to be Ͼ99:1. H NMR (500 MHz, CDCl3, 25 °C): δ =
(100) [C9H10N]+, 77 (9) [C6H5]+.
1.25 (d, 3JH,H = 7.0 Hz, 3 H), 2.95 (sext, 3JH,H = 7.0 Hz, 1 H), 3.11
2
3
2
Supporting Information (see footnote on the first page of this arti-
(dd, JH,H = 12.3 Hz, JH,H = 8.4 Hz, 1 H), 3.22 (dd, JH,H
=
=
1
cle): Copies of the H and 13C NMR spectra of all products.
3
3
12.4 Hz, JH,H = 6.1 Hz, 1 H), 3.51 (br s, 1 H), 6.39 (d, JH,H
3
8.5 Hz, 2 H), 7.01 (d, JH,H = 8.7 Hz, 2 H), 7.10–7.19 (m, 3 H),
7.24 (t, JH,H = 7.5 Hz, 2 H) ppm. 13C NMR (125 MHz, DEPT,
3
Acknowledgments
CDCl3, 25 °C): δ = 19.7 (CH3), 39.1 (CH), 51.0 (CH2), 114.0 (CH),
121.9 (C), 126.7 (CH), 127.2 (CH), 128.7 (CH), 129.0 (CH), 144.2
We thank the Deutsche Forschungsgemeinschaft (DFG) for finan-
cial support of our research.
(C), 146.5 (C) ppm. IR (NaCl): ν = 3416, 3060, 3027, 2962, 2872,
˜
1600, 1501, 1453, 1318, 1256, 1177, 1128, 1091 cm–1. GC–MS: m/z
(%) = 245 (6) [M]+, 140 (100) [C7H7NCl]+, 77 (11) [C6H5]+.
[1] For reviews on catalytic C–H activation in the α position to a
nitrogen atom, see: a) K. R. Campos, Chem. Soc. Rev. 2007,
36, 1069–1084; b) S. Doye, Angew. Chem. Int. Ed. 2001, 40,
3351–3353; Angew. Chem. 2001, 113, 3455–3457.
[2] For selected examples of catalytic C–H activation in the α posi-
tion to a nitrogen atom, see: a) Y. Zhang, H. Peng, M. Zhang,
Y. Cheng, C. Zhu, Chem. Commun. 2011, 47, 2354–2356; b) M.
Ghorbial, K. Harhammer, M. D. Milhovilovic, M. Schnürch,
Chem. Commun. 2010, 46, 8836–8838; c) F. Yang, J. Li, J. Xie,
Z.-Z. Huang, Org. Lett. 2010, 12, 5214–5217; d) M.-Z. Wang,
C.-Y. Zhou, M.-K. Wong, C.-M. Che, Chem. Eur. J. 2010, 16,
5723–5735; e) D. Sureshkumar, A. Sud, M. Klussmann, Synlett
2009, 1558–1561.
[3] For a review on the hydroaminoalkylation of alkenes, see: P. W.
Roesky, Angew. Chem. Int. Ed. 2009, 48, 4892–4894; Angew.
Chem. 2009, 121, 4988–4991.
[4] For ruthenium catalysts, see: a) C.-H. Jun, D.-C. Hwang, S.-J.
Na, Chem. Commun. 1998, 1405–1406; b) N. Chatani, T.
Asaumi, S. Yorimitsu, T. Ikeda, F. Kakiuchi, S. Murai, J. Am.
Chem. Soc. 2001, 123, 10935–10941.
Amine 44a: The general procedure was used to synthesize 44a from
4-bromo-N-methylaniline (33; 372 mg, 2.0 mmol) and 4 (313 mg,
3.0 mmol). After purification by flash chromatography (hexanes/
EtOAc 30:1), 44a (412 mg, 1.42 mmol, 71%) was isolated as a dark
yellow oil. Prior to chromatography, the 44a/44b ratio was deter-
1
mined to be Ͼ99:1. H NMR (500 MHz, CDCl3, 25 °C): δ = 1.33
(d, 3JH,H = 7.0 Hz, 3 H), 3.03 (sext, 3JH,H = 7.2 Hz, 1 H), 3.19 (dd,
3
2
2JH,H = 12.4 Hz, JH,H = 8.4 Hz, 1 H), 3.30 (dd, JH,H = 12.4 Hz,
3JH,H = 6.1 Hz, 1 H), 3.59 (br s, 1 H), 6.39–6.46 (m, 2 H), 7.18–
7.26 (m, 5 H), 7.33 (t, JH,H = 7.5 Hz, 2 H) ppm. 13C NMR
3
(125 MHz, DEPT, CDCl3, 25 °C): δ = 19.7 (CH3), 39.1 (CH), 50.8
(CH2), 108.8 (C), 114.5 (CH), 126.7 (CH), 127.2 (CH), 128.7 (CH),
131.9 (CH), 144.2 (C), 147.0 (C) ppm. IR (NaCl): ν = 3414, 3026,
˜
2961, 2928, 2870, 1594, 1496, 1453, 1318, 1257, 1178, 1128,
1072 cm–1. GC–MS: m/z (%)
=
289 (9) [M]+, 184 (100)
[C7H7NBr]+, 105 (39) [C8H9]+. HRMS (EI): calcd. for C15H16NBr
[M]+ 289.0466; found 289.0455.
[5] For iridium catalysts, see: S. Pan, K. Endo, T. Shibata, Org.
Lett. 2011, 13, 4692–4695.
[6] For zirconium catalysts, see: J. A. Bexrud, P. Eisenberger, D. C.
Leitch, P. R. Payne, L. L. Schafer, J. Am. Chem. Soc. 2009, 131,
2116–2118.
Amine 46a:[7g] The general procedure was used to synthesize 46a
from 4-methoxy-N-methylaniline (35; 274 mg, 2.0 mmol) and 4
(313 mg, 3.0 mmol). After purification by flash chromatography
(hexanes/EtOAc 30:1), 46a (439 mg, 1.83 mmol, 91%) was isolated
as a yellow oil. Prior to chromatography, the 46a/46b ratio was
[7] For titanium catalysts, see: a) C. Müller, W. Saak, S. Doye, Eur.
J. Org. Chem. 2008, 2731–2739; b) R. Kubiak, I. Prochnow, S.
Doye, Angew. Chem. Int. Ed. 2009, 48, 1153–1156; Angew.
Chem. 2009, 121, 1173–1176; c) I. Prochnow, R. Kubiak, O. N.
Frey, R. Beckhaus, S. Doye, ChemCatChem 2009, 1, 162–172;
d) R. Kubiak, I. Prochnow, S. Doye, Angew. Chem. Int. Ed.
2010, 49, 2626–2629; Angew. Chem. 2010, 122, 2683–2686; e)
I. Prochnow, P. Zark, T. Müller, S. Doye, Angew. Chem. Int.
Ed. 2011, 50, 6401–6405; Angew. Chem. 2011, 123, 6525–6529;
f) D. Jaspers, W. Saak, S. Doye, Synlett 2012, 23, 2098–2102;
g) J. Dörfler, S. Doye, Angew. Chem. Int. Ed. 2013, 52, 1806–
1809; Angew. Chem. 2013, 125, 1851–1854; h) T. Preuß, W.
Saak, S. Doye, Chem. Eur. J. 2013, 19, 3833–3837.
1
determined to be Ͼ99:1. H NMR (500 MHz, CDCl3, 25 °C): δ =
1.25 (d, 3JH,H = 7.0 Hz, 3 H), 2.97 (sext, 3JH,H = 7.1 Hz, 1 H), 3.12
2
3
2
(dd, JH,H = 12.3 Hz, JH,H = 8.4 Hz, 1 H), 3.22 (dd, JH,H
=
3
12.3 Hz, JH,H = 6.1 Hz, 1 H), 3.66 (s, 3 H), 6.45–6.49 (m, 2 H),
3
6.67–6.71 (m, 2 H), 7.13–7.18 (m, 3 H), 7.25 (t, JH,H = 7.4 Hz, 2
H) ppm. 13C NMR (125 MHz, DEPT, CDCl3, 25 °C): δ = 19.8
(CH3), 39.2 (CH), 52.0 (CH2), 55.8 (CH3), 114.4 (CH), 114.8 (CH),
126.6 (CH), 127.2 (CH), 128.6 (CH), 142.2 (C), 144.6 (C), 152.1
(C) ppm. IR (NaCl): ν = 3399, 3060, 3027, 2958, 2871, 1602, 1512,
˜
1453, 1377, 1236, 1155, 1128, 1038 cm–1. GC–MS: m/z (%) = 241
(14) [M]+, 136 (100) [C6H10NO]+, 77 (6) [C6H5]+.
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Eur. J. Org. Chem. 2014, 2790–2797

Catalyst for Intermolecular Hydroaminoalkylation
[8] For group 5 metal catalysts, see: a) M. G. Clerici, F. Maspero,
Synthesis 1980, 305–306; b) W. A. Nugent, D. W. Ovenall, S. J.
Holmes, Organometallics 1983, 2, 161–162; c) S. B. Herzon,
J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 6690–6691; d) S. B.
Herzon, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 14940–
14941; e) P. Eisenberger, R. O. Ayinla, J. M. P. Lauzon, L. L.
Schafer, Angew. Chem. Int. Ed. 2009, 48, 8361–8365; Angew.
Chem. 2009, 121, 8511–8515; 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. Reznich-
enko, T. J. Emge, S. Audörsch, E. G. Klauber, K. C. Hultzsch,
B. Schmidt, Organometallics 2011, 30, 921–924; i) A. L.
Reznichenko, K. C. Hultzsch, J. Am. Chem. Soc. 2012, 134,
3300–3311; j) P. Garcia, Y. Y. Lau, M. R. Perry, L. L. Schafer,
Angew. Chem. Int. Ed. 2013, 52, 9144–9148; Angew. Chem.
2013, 125, 9314–9318; k) Z. Zhang, J.-D. Hamel, L. L. Schafer,
Chem. Eur. J. 2013, 19, 8751–8754.
references cited therein; b) T. Rische, P. Eilbracht, Tetrahedron
1999, 55, 1915–1920, and references cited therein.
P. Bravo, M. Guidetti, F. Viani, M. Zanda, A. L. Markovsky,
A. E. Sorochinsky, I. V. Soloshonok, V. A. Soloshonok, Tetra-
hedron 1998, 54, 12789–12806.
Owing to the small amount of volatile material and the large
volume of the Schlenk tube (100 mL), it was not necessary to
use a pressure tube. In the past five years, we have performed
several hundred similar experiments and we have not observed
a single explosion of a Schlenk tube.
[10]
[11]
[12] L. Routaboul, C. Buch, H. Klein, R. Jackstell, M. Beller, Tetra-
hedron Lett. 2005, 46, 7401–7405.
[13] T. Wang, L.-G. Zhuo, Z. Li, F. Chen, Z. Ding, Y. He, Q.-H.
Fan, J. Xiang, Z.-X. Yu, A. S. C. Chan, J. Am. Chem. Soc.
2011, 133, 9878–9891.
Received: January 17, 2014
Published Online: March 4, 2014
[9] a) G. B. Shinde, N. C. Niphade, S. P. Deshmukh, R. B. Toche,
V. T. Mathad, Org. Process Res. Dev. 2011, 15, 455–461, and
Eur. J. Org. Chem. 2014, 2790–2797
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www.eurjoc.org
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