Base-catalyzed anti-Markovnikov hydroamination of vinylarenes - Scope, limitations and computational studies

Article abstract of DOI:10.1002/ejoc.200700147

The hydroamination of vinylarenes with primary and secondary amines was studied with catalytic amounts as low as 2 mol-% of LiN(SiMe₃) ₂/TMEDA. Reactions proceeded readily at 120°C in the absence of solvent to give selective anti-Markovnikov addition. Slow addition was observed at 25°C with either electron-deficient p-chlorostyrene or secondary cyclic amines such as pyrrolidine, piperidine, or morpholine. Primary amines were prone to a second hydroamination reaction to form tertiary amine byproducts. The selectivity for the mono(hydroamination) products could be improved with a two-fold excess of the amine. KN(SiMe₃)₂ showed higher catalytic activity but lower selectivity in comparison to that of LiN(SiMe ₃)₂, resulting in undesired C-H-activation by-products. The mechanism of the lithium-catalyzed hydroamination and the influence of TMEDA was studied with density functional theory. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700147

FULL PAPER
DOI: 10.1002/ejoc.200700147
Base-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes – Scope,
Limitations and Computational Studies
Patricia Horrillo-Martínez,[a] Kai C. Hultzsch,*[a] Adrià Gil,[b] and Vicenç Branchadell[b][‡]
Keywords: Phenethylamines / Hydroamination / Homogeneous catalysis / Lithium / Density functional calculations / Reac-
tion mechanisms
The hydroamination of vinylarenes with primary and second-
ary amines was studied with catalytic amounts as low as
2 mol-% of LiN(SiMe3)2/TMEDA. Reactions proceeded read-
ily at 120 °C in the absence of solvent to give selective anti-
Markovnikov addition. Slow addition was observed at 25 °C
with either electron-deficient p-chlorostyrene or secondary
cyclic amines such as pyrrolidine, piperidine, or morpholine.
Primary amines were prone to a second hydroamination re-
action to form tertiary amine byproducts. The selectivity for
the mono(hydroamination) products could be improved with
a two-fold excess of the amine. KN(SiMe3)2 showed higher
catalytic activity but lower selectivity in comparison to that
of LiN(SiMe3)2, resulting in undesired C–H-activation by-
products. The mechanism of the lithium-catalyzed hydro-
amination and the influence of TMEDA was studied with
density functional theory.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Despite its high synthetic value, hydroamination has
found significant attention only in recent years with the de-
velopment of more efficient transition-metal-based catalyst
systems.[2] Although alkali metals have been used as hy-
droamination catalysts for more than fifty years,[3] the over-
all number of reports is limited.[1,4] Base-catalyzed hydro-
amination reactions have been reported predominantly for
activated olefins such as vinylarenes and 1,3-dienes,[5] and
to some extent, simple unactivated olefins.[6–8] Industrial
applications have remained scarce, with one prominent ex-
ample being the base-catalyzed hydroamination of myrcene
with diethylamine as part of the industrial-scale synthesis
of (–)-menthol.[5b,9] The anti-Markovnikov addition of
amines to vinylarenes leads to β-arylethylamines, which are
lead structures for psychodysleptics, strong analgesics, ana-
leptics, antihistaminics, and anorectics (Figure 1).[5e,10–13]
However, there have only been a few reports on the scope
and limitations of this base-catalyzed process.
Introduction
The importance of nitrogen-containing compounds in
biological systems, as pharmaceuticals and industrially rel-
evant basic and fine chemicals, has led to significant re-
search efforts toward their efficient syntheses. Although
many synthetic methods have been devised over the last
century, one of the simplest synthetic approaches, hydro-
amination, has only become the focus of attention with the
advent of transition-metal catalysts. The addition of amines
to unsaturated carbon–carbon bonds, either in an intermo-
lecular [Equation (1)] or intramolecular [Equation (2)] fash-
ion, generates amines in a waste-free, highly atom-economi-
cal manner, starting from simple and inexpensive precur-
sors.[1]
[a] Institut für Organische Chemie, Friedrich-Alexander Uni-
versität Erlangen-Nürnberg,
Henkestr. 42, 91054 Erlangen, Germany
Fax: +49-9131-8526865
E-mail: hultzsch@chemie.uni-erlangen.de
[b] Departament de Química, Universitat Autònoma de Barcelona,
08193 Bellaterra, Barcelona, Spain
E-mail: vicenc@klingon.uab.es
[‡] Corresponding author for inquiries related to the computa-
tional study
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Pharmaceutically active β-arylethylamines.
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Herein, we wish to report a more detailed investigation 7), in which the formation of a lithium–TMEDA chelate
on the scope and limitations of the alkali-metal-catalyzed complex, R2NLi·TMEDA (A), has been postulated.[6,15–17]
hydroamination of vinylarenes, as well as the influence of
additives such as TMEDA on catalyst activity. Further-
more, the mechanism and effect of the additive was studied
with computational methods.
Several substituted vinylarenes were hydroaminated with
2 mol-% of LiN(SiMe3)2 at 120 °C in a similar fashion with
primary (Table 2) or secondary amines (Table 3). Reactions
were generally monitored until the vinylarene had been con-
sumed completely; however, in some cases, the isolated
yields suffered from the formation of the bis(adduct) and/
or formation of poly(vinylarenes).
Results and Discussion
Scope and Limitations of Alkali-Metal-Catalyzed
Hydroamination of Vinylarenes
As a model system for the application of alternative base
catalysts, we investigated the reaction of styrene and ben-
zylamine, catalyzed by LiN(SiMe3)2 in the presence or ab-
sence of chelating diamine donor additives such as
TMEDA and (–)-sparteine (Table 1). A 1.5:1 styrene/ben-
zylamine mixture was allowed to react at 120 °C in the pres-
ence of 2–15 mol-% of precatalyst and a small amount of
C6D6 as an NMR lock solvent.[14] A slight excess of styrene
was employed in these initial experiments in order to com-
pensate for polystyrene formed as a byproduct. It is impor-
tant to note that hexamethyldisilazane itself did not add to
styrene [5 mol-% LiN(SiMe3)2, 150 °C, 16 h; only the for-
mation of polystyrene was observed].
As before, the addition of TMEDA resulted in improved
reaction rates and conversions. The reactions could be per-
formed in bulk without additional solvent (Table 2, En-
tries 8, 10, and 15 and Table 3, Entries 1, 7, and 10).[14]
Electron-deficient p-chlorostyrene reacted slowly but selec-
tively at room temperature, while catalyst deactivation and
low conversion was observed at elevated temperatures. Elec-
tron-donating substituents in the vinylarene decreased turn-
over rates (Table 2, Entry 1 vs. Entries 5 and 9). The effect
is opposite for benzylamines, leading to increased rates for
p-methoxybenzylamine (Table 1, Entry 4 vs. Table 2, En-
try 2), especially in the presence of TMEDA. As observed
earlier in lithium-catalyzed intermolecular hydroamina-
tions,[5c,5d,5l] the reactions displayed a first-order rate depen-
dence on styrene concentration (see the Supporting Infor-
mation).
Table 1. Variation of the base-catalyzed intermolecular hydro-
amination of styrene and benzylamine.[a]
The reaction of 2-vinylnaphthalene with benzylamine re-
quired 10 mol-% of LiN(SiMe3)2/TMEDA and resulted in
a 7.5:1 ratio of the mono- and bis(adducts) 3e and 4e,
respectively (Table 2, Entry 6). However, this ratio improved
to 12:1 when the reaction was carried out with a two-fold
excess of the amine (Table 2, Entry 7). The addition of ben-
zylamines to α- and β-methylstyrene produced selectively
the mono(adducts), though only in moderate yields.
Attempts to perform asymmetric hydroamination reac-
tions with chiral additives have been rather unsuccessful so
far. Reactions involving (–)-sparteine[18] or α-isospart-
eine[18–20] proceeded with slightly slower rates than with
TMEDA; however, little or no enantioselectivity was ob-
served (Յ 14% ee, see Table 2, Entries 14, 16, 17, 19, and
20). Another commonly applied additive for lithium-cata-
lyzed asymmetric reactions, (R,R)-2,2Ј-isopropylidenebis(4-
phenyl-2-oxazoline),[20b,21] displayed strong binding to LiN-
(SiMe3)2 (as observed by NMR spectroscopy); however, no
catalytic hydroamination reaction was observed.
Entry Catalyst
(mol-%)
Additive
1a/2a t (h) Yield
Ratio
(%)[b] (3a/4a)[c]
1
2
3
4
5
6
7
15
2.5
2
2
2
2
2
–
–
–
3:2
3:2
3:2
3:2
1:1
1:2
1:1
19
13
2
51
67
1.5:1
2:1
1.6:1
2.6:1
5:1
20:1
6:1
44
TMEDA
TMEDA
TMEDA
(–)-sparteine
1
73[d]
62
2.5
0.75 67[d]
1.25
74
[a] Reaction conditions: 2–3 mmol of styrene, 2–4 mmol of amine,
and 0.1 mL of C6D6 at 120 °C. [b] Determined by GC chromatog-
raphy with octadecane as an internal standard. [c] Determined by
1H NMR spectroscopy. [d] Determined by column chromatog-
raphy.
The reaction gave predominantly the secondary amine
Aniline added rather sluggishly to styrene even at 150 °C
mono(adduct) 3a, as well as the tertiary amine bis(adduct) (Table 2, Entry 21), but the more nucleophilic N-methylani-
4a as a byproduct. Both hydroamination products were line reacted faster (Table 3, Entry 10).
formed exclusively as anti-Markovnikov adducts. The ratio
The reaction of styrene with benzhydrylamine (2o) in the
between secondary and tertiary amine could be improved presence of 2 mol-% of LiN(SiMe3)2/TMEDA proceeded to
by increasing the amine/styrene ratio (Table 1, Entries 4–6). 78% conversion at 120 °C within 19 h. However, C–H acti-
The addition of TMEDA or (–)-sparteine resulted in a vation of benzhydrylamine produced a small amount of the
ligand-accelerated catalytic reaction (Table 1, Entries 4 and primary amine 5o as a byproduct [Equation (3)].
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Base-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes
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erate to excellent yields (Table 3).[5j] Loss of product in these
cases resulted primarily from polymeric byproducts or cata-
lyst deactivation. The addition of cyclic secondary amines
proceeded slowly at 25 °C with significantly improved yields
for piperidine and morpholine (Table 3, Entries 2 and 6). It
is noteworthy that benzylmethylamine and benzylamine
add to styrene at similar rates, despite the increased steric
demand of the secondary amine. Note also that dibenzyl-
amine adds significantly more rapidly to styrene than diethyl-
amine, most likely due to the higher volatility of diethyl-
amine under the reaction conditions employed.
(3)
Secondary amines reacted cleanly and efficiently at
120 °C with 5 mol-% of LiN(SiMe3)2/TMEDA to produce
the desired anti-Markovnikov tertiary amines 6a–j in mod-
Table 2. LiN(SiMe3)2-catalyzed intermolecular hydroamination of vinylarenes with primary amines.[a]
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Table 2. (continued)
[a] Reaction conditions: 2 mmol of vinylarene, 2 mmol of amine, 2 mol-% of LiN(SiMe3)2, 2 mol-% of additive, and 0.1 mL of C6D6 at
120 °C. [b] Isolated yield by column chromatography. [c] Determined by 1H NMR spectroscopy. [d] Vinylarene/amine = 3:2. [e] Vinylarene/
amine = 1:2. [f] 10 mol-% of LiN(SiMe3)2 and 10 mol-% of TMEDA. [g] Using a sealed capillary of C6D6. [h] Reaction at 25 °C. [i]
Racemic product. [j] 7% ee. [k] 14% ee. [l] Reaction at 150 °C.
Table 3. Lithium amide catalyzed intermolecular hydroamination of vinylarenes with secondary amines.[a]
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Table 3. (continued)
[a] Reaction conditions: 2 mmol of vinylarene, 2 mmol of amine, 5 mol-% of LiN(SiMe3)2, 5 mol-% of TMEDA, and 0.1 mL of C6D6 at
120 °C. [b] Isolated yield by column chromatography. [c] Using a sealed capillary of C6D6. [d] Reaction at 25 °C. [e] 2 mol-% of LiN-
(SiMe3)2 and 2 mol-% of TMEDA. [f] Reaction at 150 °C.
The addition of piperidine to α-methylstyrene (Table 3,
Entry 12) required a more forcing reaction temperature
(150 °C). Although the addition of N-methylaniline to sty-
rene (Table 3, Entry 10) proceeded more smoothly than did
the addition of aniline (Table 2, Entry 21), the reaction was
significantly slower than the addition of more nucleophilic
secondary alkylamines.
Table 4. KN(SiMe3)2-catalyzed intermolecular hydroamination of
styrene.[a]
It has been observed previously that potassium bases
commonly exhibit higher reactivity in base-catalyzed hy-
droamination reactions.[5e] Indeed, KN(SiMe3)2/TMEDA
displayed improved catalytic activity in the intermolecular
hydroamination of styrene (Table 4) than did LiN(SiMe3)2/
TMEDA, and reactions could be performed under milder
reaction conditions. However, selectivity towards the sec-
ondary amine products 3a,b decreased, and a significant
amount of the C–H activation byproduct 5a was formed
(Table 4, Entry 1).
Entry Alkene Amine t (h) T (°C) Conversion
Ratio
(%)[b]
(3/4/5)[b]
1
2
1a
1a
2a
2b
1.5
16.5
45
60
99
99
2.3:1:1.5
2:1:0
Computational Study of the Catalytic Cycle
[a] Reaction conditions: 2 mmol of vinylarene, 2 mmol of amine,
2 mol-% of KN(SiMe3)2, 2 mol-% of TMEDA, and 0.1 mL of
C6D6. [b] Determined by H NMR spectroscopy.
The proposed catalytic cycle for the base-catalyzed hy-
droamination of vinylarenes is based on an ionic mecha-
1
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P. Horrillo-Martínez, K. C. Hultzsch, A. Gil, V. Branchadell
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nism (Scheme 1).[1,4] Alkali metals, their alkyl and aryl salts,
hydrides, and amides deprotonate the reacting amine to give
strongly nucleophilic metal amides (I0), which can add to
the olefin more easily. Nevertheless, the activation energy
for this step is large due to the unfavorable interaction be-
tween the nitrogen lone pair and the π-system of the alkene.
The resulting polar (2-aminoalkyl)metal complexes (I1) are
highly reactive and form the product immediately upon
protonation by the starting amine, regenerating the metal
amide.
There are several thermodynamic and kinetic aspects
that restrain the direct nucleophilic addition of amines ac-
ross C–C multiple bonds.[1a,1b] One of them is low exo-
thermicity, and these reactions are sometimes even thermo-
neutral.
Scheme 1.
sence of TMEDA with DFT methods. As noted above, the
In this study, the lithium-catalyzed addition of benzyl- catalytic cycle of our reaction begins with [Li]NHBn (I0),
amine to styrene was investigated in the presence and ab- which is generated from [Li]N(SiMe3)2 and benzylamine by
Figure 2. Gibbs energy profile in benzene solution for the catalytic anti-Markovnikov hydroamination of styrene with benzylamine,
catalyzed by LiN(SiMe3)2 (solid line) or (TMEDA)LiN(SiMe3)2 (dashed line). The relative Gibbs energies at 298.15 K and 1 molL–1 in
kcalmol–1 are given. The corresponding profile for the Markovnikov addition is given in grey.
Figure 3. Transition states [TS1 and (TMEDA)TS1] for the lithium/proton exchange between LiN(SiMe3)2 and benzylamine in the absence
(left) and presence of TMEDA (interatomic distances in Å).
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Base-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes
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proton/lithium exchange (Scheme 1). Taking this into ac- transfer from benzylamine to [Li]N(SiMe3)2 {[Li] = Li or
count, the whole catalytic cycle has been found slightly ex- (TMEDA)Li} to form [Li]NHBn and HN(SiMe3)2. In the
ergonic (Figure 2), in agreement with results found pre- second step, [Li]NHBn undergoes nucleophilic attack on
viously.[1a,1b]
styrene to form the intermediate I1. This nucleophilic at-
The calculated Gibbs energy profile for the hydroamin- tack can be Markovnikov or anti-Markovnikov and deter-
ation reaction of styrene with benzylamine with either LiN- mines the regioselectivity of the process. Both possibilities
(SiMe3)2 or the TMEDA adduct (TMEDA)LiN(SiMe3)2 as have been studied in the Gibbs energy profile of Figure 2,
the catalyst is depicted in Figure 2. The global process in- and it is observed that anti-Markovnikov structures are
volves three elementary steps. The first consists of a proton more stable than the Markovnikov ones in all cases. Thus,
Figure 4. Transition states [TS2 and (TMEDA)TS2] of the anti-Markovnikov nucleophilic attack of the lithium amide on styrene (top)
as well as the resulting anti-Markovnikov intermediates [I1 and (TMEDA)I1] formed in this attack (center). The transition states for the
Markovnikov nucleophilic attack [TS2Ј and (TMEDA)TS2Ј] are depicted in the bottom row (all interatomic distances in Å).
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the discussion below will be mainly based on the anti-Mar- TS3), the rate-determining step of the catalytic cycle is TS2.
kovnikov pathway. The third and final step involves an ex- In the presence of TMEDA, (TMEDA)TS1 has the largest
change of lithium in I1 by a proton from free benzylamine, Gibbs activation energy (24.3 kcalmol–1) in the whole pro-
releasing the hydroamination product and regenerating the cess. However, the rate-determining step considering only
lithium benzylamide catalyst. The coordination by the catalytic cycle is the formation of (TMEDA)TS2
TMEDA stabilizes all stationary points.
(19.9 kcalmol–1). Therefore, coordination of TMEDA de-
The first step is endergonic and involves the late transi- creases the Gibbs activation energy for the rate-determining
tion states TS1 and (TMEDA)TS1, respectively (Figure 3). step by 2.4 kcalmol–1 for the formation of (TMEDA)TS2
The proton of benzylamine has already been transferred to versus that for TS2.
the nitrogen atom of [Li]N(SiMe3)2, whereas the lithium
In the third and final step, the hydroamination product
cation is halfway between both nitrogen atoms. The N–H is formed in another proton/lithium exchange reaction, in
distances are similar for both transition states, while the Li– which benzylamine acts as an acid. We have also considered
N distances are larger for (TMEDA)TS1 than they are for the possibility that I1 is protonated by HN(SiMe3)2, formed
TS1.
The nucleophilic attack of [Li]NHBn on styrene is as- thermodynamically more favorable (∆G = –15.1 kcalmol–1)
sisted by the lithium cation, as indicated by the coordina- than the protonation involving benzylamine (∆G
in the first step, instead of benzylamine. This process is
=
tion of the lithium ion to both reactants observed in the –8.2 kcalmol–1). However, the Gibbs activation energies for
structures of the stationary points corresponding to the the reactions of I1 and (TMEDA)I1 with HN(SiMe3)2 are
transitions states TS2 and (TMEDA)TS2 (Figure 4). The ∆G‡ = 20.9 kcalmol–1 and ∆G‡ = 24.8 kcalmol–1, respec-
resulting intermediates I1 and (TMEDA)I1 are stabilized by tively. These Gibbs activation energies are clearly larger
an intramolecular amine coordination to the lithium ion, than those corresponding to protonation by benzylamine
thereby increasing the stiffness of the molecule (Figure 4). (∆G‡ = 15 kcalmol–1 and ∆G‡ = 14.5 kcalmol–1), which is
This second step is also thermodynamically unfavorable, es- due to the large steric congestion in the transition state of
pecially in the presence of TMEDA, and has a Gibbs free the proton transfer involving HN(SiMe3)2. Therefore, ki-
energy cost of ∆G = 11.0 kcalmol–1 (with TMEDA) or ∆G netic control predominates in this process over thermo-
= 6.3 kcalmol–1 (in the absence of TMEDA). Thus, the co- dynamic control, and the proton is transferred from ben-
ordination of TMEDA does not seem to have any role from zylamine via the transition state depicted in Figure 5. From
a thermodynamic point of view. Moreover, as observed in a thermodynamic point of view, this last step is more favor-
Figure 4, TMEDA has almost no effects in the N–C dis- able in the presence of TMEDA (∆G = –12.9 kcalmol–1)
tance since this distance is almost the same in both transi- than in the absence of TMEDA (∆G = –8.2 kcalmol–1).
tion states (2.091 Å in the absence of TMEDA and 2.102 Å From a kinetic point of view, coordination of TMEDA de-
in the presence of TMEDA).
creases the Gibbs activation energy by only 0.5 kcalmol–1
As observed in Figure 2, in the absence of TMEDA the (Figure 2). The most important geometrical parameters for
activation energies for the transition states TS1 the transition state are the C–H distance, which is shorter
(21.5 kcalmol–1) and TS2 (22.3 kcalmol–1) differ by only by 0.083 Å in the presence of TMEDA (1.469 Å vs. 1.552 Å,
0.8 kcalmol–1 when looking at the entire process. When Figure 5), and the C–Li distance, which is longer in the ab-
considering only the catalytic cycle (involving only TS2 and sence of TMEDA (2.985 Å vs. 3.275 Å).
Figure 5. Transition states [TS3 and (TMEDA)TS3] for the lithium/proton exchange between I1 and (TMEDA)I1, respectively, and
benzylamine in the absence (left) and presence of TMEDA (right). Interatomic distances are given in Å.
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Base-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes
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Regioselectivity of Base-Catalyzed Hydroamination of
Vinylarenes
Conclusions
LiN(SiMe3)2/TMEDA is a convenient catalyst system for
the intermolecular hydroamination of vinylarenes with pri-
mary and secondary alkylamines in a 1:1 ratio. Reactions
could be performed effectively in the absence of solvent.
While reactions generally required elevated temperatures
(120 °C), several activated substrates were shown to react at
room temperature. Primary amines were prone to a second
hydroamination reaction to give tertiary amine byproducts.
However, the secondary amine mono(adducts) could be ob-
tained with good selectivity if a two-fold excess of the amine
was employed.
One important aspect of base-catalyzed hydroamination
of vinylarenes is the high anti-Markovnikov regioselectivity
observed.[22] The regioselectivity is determined in the sec-
ond step of the global process involving the addition of [Li]-
NHCH2Ph (I0) to styrene. Therefore, the bonding of the
lithium ion was analyzed through Wiberg indexes[23] for the
anti-Markovnikov and Markovnikov transition states TS2
and TS2Ј (see Figure 4) and were evaluated with the natural
bond orbital (NBO)[24] method.
All Markovnikov stationary points (Figure 2, grey pro-
file) are higher in energy than the corresponding anti-
Markovnikov points (Figure 2, black profile) in the pres-
ence of TMEDA (dashed lines) as well as in the absence of
TMEDA (solid lines). In the nucleophilic attack, the lith-
ium ion has a tendency to interact with the aromatic ring
of styrene in the anti-Markovnikov transition state TS2 in
the absence of TMEDA (Figure 4, top), as confirmed by
the bond-order values for Li–C3 (0.0134) and Li–C4
(0.0133), which are similar to the bond-order value of Li–
C2 (0.0181).[25] The Markovnikov transition state TS2Ј
(Figure 4, bottom), on the other hand, shows significantly
larger distances between lithium and the aromatic ring car-
bon atoms, and the bond orders are smaller due to the ori-
entation of the system. Coordination of TMEDA to the
lithium ion in the anti-Markovnikov transition state
(TMEDA)TS2 and the Markovnikov transition state
(TMEDA)TS2Ј (Figure 4) results in longer Li–C(aryl) dis-
tances and reduced bond orders in comparison to TS2 and
TS2Ј, respectively.
The Gibbs energy difference between (TMEDA)TS2 and
(TMEDA)TS2Ј is 10.4 kcalmol–1, with the anti-Markovni-
kov transition state (TMEDA)TS2 being more stable. On
the other hand, in the absence of TMEDA the difference
between TS2 and TS2Ј is only 3.5 kcalmol–1. This is due to
a solvent effect, because lithium is more accessible to the
solvent in TS2Ј than it is in TS2 (Figure 4). This increased
solvent–ion interaction results in a larger electrostatic term
and stabilizes TS2Ј. When TMEDA is introduced, the lith-
ium ion is equally accessible in (TMEDA)TS2 and
(TMEDA)TS2Ј, resulting in similar solvent effects for the
Markovnikov and anti-Markovnikov transition states. The
anti-Markovnikov intermediates I1 and (TMEDA)I1 are
both ca. 12.5 kcalmol–1 more stable than the corresponding
Markovnikov intermediates.
Finally, we have investigated the mechanism of the lith-
ium-catalyzed hydroamination of styrene with benzylamine
with computational methods. The anti-Markovnikov ad-
dition is favored over the Markovnikov pathway both by
thermodynamic and kinetic factors governing the regiose-
lectivity-determining addition step of the addition of the
lithium amide to the vinylarene. The aromatic ring plays an
important role since its interaction with the lithium ion fa-
vors the anti-Markovnikov mechanism. Within the catalytic
cycle, coordination of TMEDA decreases the Gibbs acti-
vation energy for the rate-determining nucleophilic addition
step of [Li]NHBn to styrene by 2.4 kcalmol–1 in compari-
son to that of the reaction in the absence of TMEDA.
Therefore coordination of TMEDA results in an increase in
the rate of the reaction.
Experimental Section
General Considerations: All operations were carried out with stan-
dard Schlenk and glove-box inert-gas techniques under dry nitro-
gen or argon, unless otherwise stated. Hexane was purified by dis-
tillation from sodium/triglyme/benzophenone ketyl. Deuterated
benzene was dried with sodium/benzophenone ketyl and distilled
in vacuo. nBuLi (2.5  in hexanes) and (R)-O-acetylmandelic acid
were used as received. N,N,NЈ,NЈ-Tetramethylethylenediamine
(TMEDA), (–)-sparteine, and other commercially available amines
and vinylarenes were distilled from finely powdered CaH2 and were
stored over molecular sieves. α-Isosparteine was prepared accord-
ing to a published procedure.[26] LiN(SiMe3)2 was prepared by the
addition of nBuLi to a solution of hexamethyldisilazane in hexane
at 0 °C. 1H, 13C, and 19F NMR spectra were recorded with a
Bruker Avance 300 or Avance 400 spectrometer. Mass spectra were
recorded with a Micromass Zabspec instrument (FAB, 3-nitroben-
zyl alcohol) and Finnigan MAT 95XP instrument (EI) for High
Resolution Mass Spectrum. Gas chromatography was conducted
with a ThermoQuest Trace GC 2000 (OPTIMA-5, 0.25 µm capil-
lary column, 25 mϫ0.32 mm). Elemental analyses were deter-
mined with a Carlo Erba EA1110 CHN instrument by the Micro-
analytical Laboratory of this department.
In the last step leading to the hydroamination product,
the anti-Markovnikov pathway is clearly favored over the
Markovnikov one. Both anti-Markovnikov transition states
TS3 and (TMEDA)TS3 are ca. 10–12 kcalmol–1 more
stable than the corresponding Markovnikov transition
states. On the other hand, the anti-Markovnikov hydro-
amination product is also favored by 1.9 kcalmol–1 over
the Markovnikov hydroamination product. Therefore,
thermodynamic as well as kinetic factors favor the anti-
Markovnikov products, both in the presence and absence of
TMEDA.
Typical Catalytic Intermolecular Hydroamination Reactions: In a
glove box, a screw-cap NMR tube was charged with the catalyst
precursors (0.04 mmol, 2 mol-%), C6D6 (0.1 mL or sealed capil-
lary), TMEDA (0.04 mmol, 2 mol-%) or chiral additive
(0.04 mmol, 2 mol-%), the olefin (2.0 mmol), and the amine
(2.0 mmol). The NMR tube was then placed in a preheated oil bath
1
(25–150 °C), and conversion was monitored by H and 13C NMR
spectroscopy. Final conversions were determined by the disappear-
Eur. J. Org. Chem. 2007, 3311–3325
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3319

P. Horrillo-Martínez, K. C. Hultzsch, A. Gil, V. Branchadell
FULL PAPER
ance of characteristic olefinic signals. Et2O (ca. 2 mL) was added
to the reaction mixture, and the mixture was then filtered through
a pad of silica gel to remove polymeric byproducts, and the pad was
washed with Et2O (2ϫ2 mL). The solvent was carefully removed in
a rotary evaporator to give the crude products. The products were
purified by column chromatography on silica gel (CH2Cl2 + a few
drops of Et3N, CH2Cl2/MeOH, 95:5 + a few drops of Et3N, or
EtOAc/hexane, 4:1).
7.17 (m, 3 H, aryl-H), 3.77 (s, 2 H, NHCH2Ph), 2.95 (s, 4 H,
ArCH2CH2NH), 1.49 (br. s, 1 H, NH) ppm. 13C{1H} NMR
(100.6 MHz, CDCl3): δ = 140.0, 137.4, 133.5, 132.1, 128.4, 128.1,
127.6, 127.4, 127.3, 127.0, 126.9, 126.9, 125.9, 125.3 (aryl), 53.8
(NHCH2Ph), 50.2 (ArCH2CH2NH), 36.4 (ArCH2CH2NH) ppm.
MS (FAB, 3-NBA): m/z (%) = 262 (100) [M]+, 120 (38) [M –
C10H7CH2]+. C19H20ClN (3e·HCl) (297.83): calcd. C 76.62, H 6.77,
N 4.70; found C 76.13, H 6.82, N 4.79.
Benzyl(phenethyl)amine (3a): Purification by column chromatog-
raphy on silica gel (CH2Cl2 + a few drops of Et3N, Rf = 0.02). H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.32–7.19 (m, 10 H, aryl-H),
Benzyl[2-(4-methoxyphenyl)ethyl]amine (3f): Purification by column
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
1
1
0.05). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.33–7.22 (m, 5 H,
3
3
3
3.80 (s,
2
H, NHCH2Ph), 2.91 (t, JH,H
=
6.4 Hz,
2
H,
aryl-H), 7.12 (d, JH,H = 8.4 Hz, 2 H, aryl-H), 6.83 (d, JH,H =
3
PhCH2CH2NH), 2.83 (t, JH,H = 6.3 Hz, 2 H, PhCH2CH2NH), 8.6 Hz, 2 H, aryl-H), 3.80 (s, 2 H, NHCH2Ph), 3.79 (s, 3 H, OCH3),
1.52 (br. s, 1 H, NH) ppm. 13C{1H} NMR (100.6 MHz, CDCl3, 2.87 (t, JH,H = 7.0 Hz, 2 H, ArCH2CH2NH), 2.77 (t, JH,H
25 °C): δ = 140.2, 140.0, 128.7, 128.4, 128.3, 128.0, 126.9, 126.1
7.0 Hz, 2 H, ArCH2CH2NH), 1.42 (br. s, 1 H, NH) ppm. 13C{1H}
(aryl), 53.8 (NHCH2Ph), 50.5 (PhCH2CH2NH), 36.3 NMR (100.6 MHz, CDCl3, 25 °C): δ = 158.0, 140.3, 132.0, 129.6,
=
3
3
(PhCH2CH2NH) ppm. MS (FAB, 3-NBA): m/z (%) = 212 (100)
[M]+, 120 (16) [M – CH2Ph]+. C15H17N (211.31): calcd. C 85.26,
H 8.11, N 6.63; found C 85.24, H 7.87, N 6.39. The spectroscopic
data are in agreement with previously published data.[5l,27]
128.4, 128.1, 126.9, 113.9 (aryl), 55.2 (OCH3), 53.9 (NHCH2Ph),
50.8 (ArCH2CH2NH), 35.4 (ArCH2CH2NH) ppm. MS (FAB, 3-
NBA): m/z (%) = 242 (100) [M]+, 120 (42) [M – MeOC6H4CH2]+.
HRMS (EI): calcd. for C16H19NO 241.1461; found 241.1455.
(4-Methoxybenzyl)(phenethyl)amine (3b): Purification by column
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
0.02). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.30–7.26 (m, 2 H,
(4-Methoxybenzyl)[2-(4-methoxyphenyl)ethyl]amine (3g): Purifica-
tion by column chromatography on silica gel (CH2Cl2/MeOH, 95:5
+ a few drops of Et3N, Rf = 0.91).1H NMR (400 MHz, CDCl3,
1
3
3
aryl-H), 7.21–7.18 (m, 5 H, aryl-H), 6.86–6.83 (m, 2 H, aryl-H),
25 °C): δ = 7.18 (d, JH,H = 8.6 Hz, 2 H, aryl-H), 7.09 (d, JH,H =
3.78 (s, 3 H, OMe), 3.73 (s, 2 H, NHCH2Ar), 2.91–2.87 (m, 2 H, 8.6 Hz, 2 H, aryl-H), 6.82 (m, 4 H, aryl-H), 3.78 (s, 3 H, OCH3),
PhCH2CH2NH), 2.83–2.80 (m, 2 H, PhCH2CH2NH), 1.49 (br. s, 1
3.77 (s, 3 H, OCH3), 3.72 (s, 2 H, NHCH2Ar), 2.84 (m, 2 H,
H, NH) ppm. 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = ArCH2CH2NH), 2.75 (m, 2 H, ArCH2CH2NH), 1.41 (br. s, 1 H,
158.5, 140.0, 132.4, 129.2, 128.7, 128.4, 126.1, 113.7 (aryl), 55.2 NH) ppm. 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = 158.6,
(OMe), 53.2 (NHCH2Ar), 50.4 (PhCH2CH2NH), 36.3 158.0, 132.5, 132.1, 129.6, 129.2, 113.8, 113.7 (aryl), 55.2 (OCH3),
(PhCH2CH2NH) ppm. MS (FAB, 3-NBA): m/z (%) = 242 (50)
[M]+, 150 (22) [M – CH2Ph]+, 136 (16) [M – CH2CH2Ph]+, 121
(100) [M – NHCH2CH2Ph]+. HRMS (EI): calcd. for C16H19NO
241.1461; found 241.1466. The spectroscopic data are in agreement
with previously published data.[5l,28]
53.3 (NHCH2Ar), 50.7 (ArCH2CH2NH), 35.4 (ArCH2CH2NH)
ppm. MS (FAB, 3-NBA): m/z (%) = 272 (15) [M]+, 121 (100)
[MeOC6H4CH2]+. C17H21NO2 (271.36): calcd. C 75.25, H 7.80, N
5.16; found C 75.71, H 7.54, N 4.91.
Benzyl[2-(4-chlorphenyl)ethyl]amine (3h): Purification by column
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
0.04).1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.34–7.21 (m, 7 H,
Benzyl[2-(p-tolyl)ethyl]amine (3c): Purification by column
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
1
3
0.06). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.32–7.23 (m, 5 H,
aryl-H), 7.12 (d, JH,H = 8.4 Hz, 2 H, aryl-H), 3.79 (s, 2 H,
aryl-H), 7.09 (s, 4 H, aryl-H), 3.80 (s, 2 H, NHCH2Ph), 2.89 (m, 2 NHCH2Ph), 2.88 (m, 2 H, PhCH2CH2NH), 2.79 (m, 2 H,
H, MePhCH2CH2NH), 2.79 (m, 2 H, MePhCH2CH2NH), 2.32 (s, PhCH2CH2NH), 1.32 (br. s, 1 H, NH) ppm. 13C{1H} NMR
3 H, CH3C6H4), 1.34 (br. s, 1 H, NH) ppm. 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = 140.2, 138.5, 131.9, 130.0, 128.5,
(100.6 MHz, CDCl3, 25 °C): δ = 140.4, 136.9, 135.5, 128.9, 128.6,
128.3, 128.0, 126.8 (aryl), 53.9 (NHCH2Ph), 50.7 (ArCH2CH2NH),
128.4, 128.0, 126.9 (aryl), 53.8 (NHCH2Ph), 50.3 (ArCH2CH2NH),
35.7 (ArCH2CH2NH) ppm. MS (FAB, 3-NBA): m/z (%) = 246
35.9 (ArCH2CH2NH), 21.0 (CH3C6H4) ppm. MS (FAB, 3-NBA): (100) [M]+, 154 (52) [M – CH2Ph]+, 120 (85) [M – ClC6H4CH2]+.
m/z (%) = 226 (100) [M]+, 120 (32) [M – NHCH2Ph]+. HRMS (EI): C15H16ClN (245.75): calcd. C 73.31, H 6.56, N 5.70; found C 73.48,
calcd. for C16H19N 225.1512; found 225.1501.
H 6.49, N 5.89.
(4-Methoxybenzyl)[2-(p-tolyl)ethyl]amine (3d): Purification by col-
Benzyl(2-phenylpropyl)amine (3i): Purification by column
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
0.02). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.30 (m, 4 H, aryl-
umn chromatography on silica gel (CH2Cl2/MeOH, 95:5 + a few
drops of Et3N, Rf = 0.15).1H NMR (400 MHz, CDCl3, 25 °C): δ =
1
3
7.20 (d, JH,H = 8.6 Hz, 2 H, aryl-H), 7.10 (s, 4 H, aryl-H), 6.85 H), 7.22 (m, 6 H, aryl-H), 3.77 (d, 2JH,H = 13.4 Hz, 1 H, NCH2Ph),
3
2
(d, JH,H = 8.7 Hz, 2 H, aryl-H), 3.79 (s, 3 H, OCH3), 3.74 (s, 2 H,
3.72 (d, JH,H = 13.4 Hz, 1 H, NCH2Ph), 3.01–2.93 (m, 1 H,
3
NHCH2Ar), 2.88 (m, 2 H, ArCH2CH2NH), 2.79 (m, 2 H, PhCH(CH3)CH2NH), 2.79 (d, JH,H = 7.5 Hz, 2 H, PhCH(CH3)-
ArCH2CH2NH), 2.32 (s, 3 H, CH3C6H4), 1.46 (br. s, 1 H, NH) CH2NH), 1.36 (br. s, 1 H, NH), 1.25 (d, 3JH,H = 6.9 Hz, 3 H, CH3)
ppm. 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = 158.5, 136.9, ppm. 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = 145.3, 140.4,
135.5, 132.4, 129.2, 129.1, 128.5, 113.7 (aryl), 55.2 (OCH3), 53.2
(NHCH2Ar), 50.5 (ArCH2CH2NH), 35.8 (ArCH2CH2NH), 21.0 (NHCH2Ph), 53.8 (PhCH(Me)CH2NH), 40.0 (PhCH(Me)-
(CH3C6H4) ppm. MS (FAB, 3-NBA): m/z (%) = 256 (48) [M]+, 121
CH2NH), 20.1 (CH3) ppm. MS (FAB, 3-NBA): m/z (%) = 226 (100)
128.5, 128.3, 128.0, 127.4, 127.2, 126.8, 126.3 (aryl), 56.3
(100) [CH3OC6H4CH2]+. C17H21NO (255.36): calcd. C 79.96, H [M]+. The spectroscopic data are in agreement with previously pub-
8.29, N 5.49; found C 79.94, H 8.35, N 5.61.
lished data.[29]
Benzyl[2-(naphthalen-2-yl)ethyl]amine (3e): Purification by column
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
0.04). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.77–7.71 (m, 4 H,
(4-Methoxybenzyl)(2-phenylpropyl)amine (3j): Purification by col-
umn chromatography on silica gel (CH2Cl2/MeOH, 95:5 + a few
1
1
drops of Et3N, Rf = 0.53). H NMR (400 MHz, CDCl3, 25 °C): δ
3
aryl-H), 7.60 (s, 1 H, aryl-H), 7.43–7.33 (m, 4 H, aryl-H), 7.31–
= 7.34 (m, 2 H, aryl-H), 7.24 (m, 3 H, aryl-H), 7.18 (d, JH,H
=
3320
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3311–3325

Base-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes
FULL PAPER
8.6 Hz, 2 H, aryl-H), 6.86 (d, 3JH,H = 8.6 Hz, 2 H, aryl-H), 3.82 (s,
(NHCH2CH2CH3) ppm. MS (FAB, 3-NBA): m/z (%) = 164 (100)
[M]+. C11H17N (163.26): calcd. C 80.93, H 10.50, N 8.58; found C
80.77, H 10.28, N 8.39. The spectroscopic data are in agreement
2
3 H, OCH3), 3.75 (d, JH,H = 13.1 Hz, 1 H, NHCH2Ar), 3.70 (d,
2JH,H = 13.1 Hz, 1 H, NHCH2Ar), 3.00 (m, 1 H, PhCH(CH3)-
3
CH2NH), 2.81 (d, JH,H = 4.5 Hz, 2 H, PhCH(CH3)CH2NH), 1.45 with previously published data.[11]
(br. s, 1 H, NH), 1.29 (d, 3JH,H = 6.9 Hz, 3 H, CH3) ppm. 13C{1H}
(Benzhydryl)(phenethyl)amine (3o): Purification by column
NMR (100.6 MHz, CDCl3, 25 °C): δ = 158.5, 145.4, 132.4, 129.1,
128.5, 127.2, 126.3, 113.7 (aryl), 56.2 (NHCH2Ar), 55.2 (OCH3),
53.2 (PhCH(CH3)CH2NH), 40.0 (PhCH(CH3)CH2NH), 20.1
(CH3) ppm. MS (FAB, 3-NBA): m/z (%) = 256 (18) [M]+, 121 (100)
[CH3OC6H4CH2]+. C17H21NO (255.36): calcd. C 79.96, H 8.29, N
5.49; found C 80.00, H 8.01, N 5.42.
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
1
0.45). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.36–7.34 (m, 4 H,
aryl-H), 7.28–7.24 (m, 6 H, aryl-H), 7.20–7.16 (m, 5 H, aryl-H),
4.82 (s, 1 H, NHCHPh2), 2.84–2.80 (s, 4 H, PhCH2CH2NH), 1.57
(br. s, 1 H, NH) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ =
144.1, 140.1, 128.7, 128.43, 128.37, 127.2, 126.9, 126.0 (aryl), 67.3
(NHCHPh2), 49.3 (PhCH2CH2NH), 36.5 (PhCH2CH2NH) ppm.
MS (FAB, 3-NBA): m/z (%) = 288 (22) [M]+, 210 (10) [M – Ph]+,
167 (100) [M – NHCH2CH2Ph]+. C21H21N (287.40): calcd. C 87.76,
H 7.36, N 4.87; found C 87.76, H 7.41, N 4.78.
Benzyl(1-methyl-2-phenylethyl)amine (3k): Purification by column
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
0.02). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.30–7.15 (m, 10
H, aryl-H), 3.85 (d, 2JH,H = 13.3 Hz, 1 H, NCH2Ph), 3.74 (d, 2JH,H
= 13.3 Hz, 1 H, NCH2Ph), 3.01–2.90 (m, 1 H, PhCH2CH(CH3)-
Benzylbis(phenethyl)amine (4a): Purification by column chromatog-
raphy on silica gel (CH2Cl2 + a few drops of Et3N, Rf = 0.09).
NH), 2.78 (m,
1
H, PhCH2CH(CH3)NH), 2.65 (m,
1
H,
=
3
PhCH2CH(CH3)NH), 1.63 (br. s, 1 H, NH), 1.10 (d, JH,H
1
Isolated yield: 21% (based on the amine for Table 1, Entry 4). H
6.2 Hz, 3 H, CH3) ppm. 13C{1H} NMR (100.6 MHz, CDCl3,
NMR (400 MHz, CDCl3, 25 °C): δ = 7.29–7.12 (m, 10 H, aryl-H),
3.73 (s, 2 H, NCH2Ph), 2.79 (s, 8 H, PhCH2CH2N) ppm. 13C{1H}
NMR (100.6 MHz, CDCl3, 25 °C): δ = 140.6, 139.6, 128.8, 128.7,
128.3, 128.1, 126.8, 125.8 (aryl), 58.5 (NCH2Ph), 55.7
(PhCH2CH2N), 33.6 (PhCH2CH2N) ppm. MS (FAB, 3-NBA): m/z
(%) = 316 (76) [M]+, 224 (100) [M – CH2Ph]+. HRMS (EI): calcd.
for C23H25N 315.1982; found 315.1950. The spectroscopic data are
in agreement with previously published data.[5l]
25 °C): δ = 140.4, 139.4, 129.3, 128.3, 127.9, 126.8, 126.1 (aryl),
53.7
(NHCH2Ph),
51.2
(PhCH2CH(CH3)NH),
43.5
(PhCH2CH(CH3)NH), 20.2 (CH3) ppm. MS (FAB, 3-NBA): m/z
(%) = 226 (100) [M]+, 134 (52) [M – CH2Ph]+. The spectroscopic
data are in agreement with previously published data.[5h,13c]
(4-Methoxybenzyl)(1-methyl-2-phenylethyl)amine (3l): Purification
by column chromatography on silica gel (CH2Cl2 + a few drops of
Et3N, Rf = 0.42). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.30 (m,
2 H, aryl-H), 7.23 (m, 1 H, aryl-H), 7.17 (m, 4 H, aryl-H), 6.84 (d,
3JH,H = 8.4 Hz, 2 H, aryl-H), 3.82 (d, 1 H, NCH2Ar, obscured by
(4-Methoxybenzyl)bis(phenethyl)amine (4b): Purification by column
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
0.07). Isolated yield: 20% (based on the amine for Table 2, En-
2
3
try 2). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.28 (t, JH,H
=
another signal), 3.80 (s, 3 H, OCH3), 3.69 (d, JH,H = 12.9 Hz, 2
H, NHCH2Ar), 3.00–2.92 (m, 1 H, PhCH2CH(CH3)NH), 2.79 (m,
1 H, PhCH2CH(CH3)NH), 2.66 (m, 1 H, PhCH2CH(CH3)NH),
7.4 Hz, 4 H, aryl-H), 7.22–7.18 (m, 4 H, aryl-H), 7.16–7.14 (m, 4
3
H, aryl-H), 6.84 (d, JH,H = 8.6 Hz, 2 H, aryl-H), 3.82 (s, 3 H,
3
1.51 (br. s, 1 H, NH), 1.11 (d, JH,H = 6.2 Hz, 3 H, CH3) ppm.
OMe), 3.69 (s, 2 H, NCH2Ar), 2.80 (s, 8 H, PhCH2CH2N) ppm.
13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = 158.5, 140.6,
131.5, 129.8, 128.8, 128.2, 125.8, 113.5 (aryl), 57.7 (NCH2Ar), 55.4
(OMe), 55.2 (PhCH2CH2N), 33.5 (PhCH2CH2N-) ppm. MS (FAB,
3-NBA): m/z (%) = 346 (8) [M]+, 344 (24) [M – H2]+, 254 (24) [M –
CH2Ph]+, 121 (100) [CH3C6H4CH2]+. C24H27NO (345.49): calcd.
C 83.44, H 7.88, N 4.05; found C 83.21, H 7.96, N 3.91. The spec-
troscopic data are in agreement with previously published data.[5l]
13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = 158.5, 139.4,
132.6, 129.1, 129.0, 128.3, 126.1, 113.7 (aryl), 55.2 (OCH3), 53.6
(PhCH2CH(CH3)NH), 50.6 (NHCH2Ar), 43.5 (PhCH2CH(CH3)-
NH), 20.1 (CH3) ppm. MS (FAB, 3-NBA): m/z (%) = 256 (38)
[M]+, 121 (100) [CH3OC6H4CH2]+. C17H21NO (255.36): calcd. C
79.96, H 8.29, N 5.48; found C 79.87, H 8.38, N 5.42. The spectro-
scopic data are in agreement with previously published data.[13d]
(Phenethyl)phenylamine (3m): Purification by column chromatog-
raphy on silica gel (CH2Cl2/MeOH, 95:5 + a few drops of Et3N, Rf
Benzylbis[2-(p-tolyl)ethyl]amine (4c): Purification by column
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
1
1
= 0.65). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.38–7.34 (m, 2
0.05). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.30–7.20 (m, 5 H,
3
3
3
H, aryl-H), 7.29–7.20 (m, 5 H, aryl-H), 6.75 (t, JH,H = 7.3 Hz, 1
aryl-H), 7.07 (d, JH,H = 7.9 Hz, 4 H, aryl-H), 7.02 (d, JH,H
8.0 Hz, 4 H, aryl-H), 3.73 (s, 2 H, NCH2Ph), 2.76 (s, 8 H,
CH2CH2N), 2.32 (s,
H, CH3C6H4) ppm. 13C{1H} NMR
=
3
H, aryl-H), 6.65 (d, JH,H = 7.8 Hz, 2 H, aryl-H), 3.69 (br. s, 1 H,
3
3
NH), 3.43 (t, JH,H = 6.8 Hz, 2 H, PhCH2CH2N), 2.95 (t, JH,H
=
3
7.1 Hz, 2 H, PhCH2CH2N) ppm. 13C{1H} NMR (100.6 MHz,
CDCl3, 25 °C): δ = 147.9, 139.3, 129.2, 128.7, 128.5, 126.4, 117.4,
112.9 (aryl), 45.0 (PhCH2CH2N), 35.5 (PhCH2CH2N) ppm. MS
(FAB, 3-NBA): m/z (%) = 198 (98) [M]+, 197 (100) [M – H]+. The
spectroscopic data are in agreement with previously published
data.[12b,13b]
(100.6 MHz, CDCl3, 25 °C): δ = 139.7, 137.5, 135.3, 129.0, 128.7,
128.6, 128.1, 126.7 (aryl), 58.5 (NHCH2Ph), 55.8 (CH2CH2N), 33.2
(CH2CH2N), 21.0 (CH3C6H4) ppm. MS (FAB, 3-NBA): m/z (%) =
344 (32) [M]+, 342 (52) [M – H2]+, 238 (100) [M – CH2C6H4-
CH3]+, 119 (48) [CH3C6H4CH2CH2]+. HRMS (EI): calcd. for
C25H27N [M – 2 H]+ 341.2138; found 341.2125.
(Phenethyl)propylamine (3n): Purification by column chromatog-
raphy on silica gel (CH2Cl2/MeOH, 95:5 + a few drops of Et3N, Rf
= 0.1). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.21–7.15 (m, 2
(4-Methoxybenzyl)bis[2-(p-tolyl)ethyl]amine (4d): Purification by
column chromatography on silica gel (CH2Cl2/MeOH, 95:5 + a few
drops of Et3N, Rf = 0.79). Isolated yield: 19% (based on the amine
H, aryl-H), 7.11–7.08 (m,
PhCH2CH2NH), 2.70 (m, 2 H, PhCH2CH2NH), 2.48 (t, JH,H
7.3 Hz, H, NHCH2CH2CH3), 1.43–1.33 (m,
3
H, aryl-H), 2.77 (m,
2
H, for Table 2, Entry 5). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.20
3
3
=
(d, JH,H = 8.6 Hz, 2 H, aryl-H), 7.09–7.01 (m, 8 H, aryl-H), 6.82
2
2
H, (d, 3JH,H = 8.7 Hz, 2 H, aryl-H), 3.80 (s, 3 H, OCH3), 3.67 (s, 2 H,
NHCH2CH2CH3), 1.00 (br. s, 1 H, NH), 0.78 (t, 3JH,H = 7.4 Hz, 3 NCH2Ar), 2.75 (s, 8 H, ArCH2CH2N), 2.32 (s, 6 H, CH3C6H4)
H, NHCH2CH2CH3) ppm. 13C{1H} NMR (100.6 MHz, CDCl3, ppm. 13C{1H} NMR (75.5 MHz, CDCl3, 25 °C): δ = 158.5, 137.5,
25 °C): δ = 140.2, 128.7, 128.4, 126.1 (aryl), 51.8 (CH2NH), 51.2
(CH2NH), 36.5 (PhCH2), 23.2 (NHCH2CH2CH3), 11.8
135.3, 131.4, 129.9, 129.0, 128.6, 113.5 (aryl), 57.7 (NCH2Ar), 55.6
(ArCH2CH2N), 55.2 (OCH3), 33.0 (ArCH2CH2N), 21.0 (CH3)
Eur. J. Org. Chem. 2007, 3311–3325
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3321

P. Horrillo-Martínez, K. C. Hultzsch, A. Gil, V. Branchadell
FULL PAPER
ppm. MS (FAB, 3-NBA): m/z (%) = 374 (20) [M]+, 121 (100)
[CH3OC6H4CH2]+. C26H31NO (373.54): calcd. C 83.60, H 8.37, N
3.75; found C 83.52, H 8.31, N 3.39.
(%) = 190 (100) [M]+. HRMS (EI): calcd. for C13H19N 189.1512;
found 189.1508. The spectroscopic data are in agreement with pre-
viously published data.[12a,12c]
Benzylbis[2-(naphthalen-2-yl)ethyl]amine (4e): Purification by col-
umn chromatography on silica gel (CH2Cl2 + a few drops of Et3N,
Rf = 0.2). Isolated yield: 9% (based on the amine for Table 2, En-
try 7). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.79–7.77 (m, 2 H,
aryl-H), 7.70–7.68 (m, 4 H, aryl-H), 7.52 (s, 2 H, aryl-H), 7.44–
7.35 (m, 5 H, aryl-H), 7.26 (br. s, 2 H, aryl-H), 7.21 (br. s, 4 H,
aryl-H), 3.78 (s, 2 H, NCH2Ph), 2.93–2.90 (m, 8 H, ArCH2CH2N)
N-Phenethylpyrrolidine (6b): Purification by column chromatog-
raphy on silica gel (CH2Cl2/MeOH, 95:5 + a few drops of Et3N, Rf
= 0.34). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.28–7.24 (m, 2
1
H, aryl-H), 7.20–7.15 (m, 3 H, aryl-H), 2.84–2.80 (m, 2 H,
PhCH2CH2N), 2.70–2.66 (m, 2 H, PhCH2CH2N), 2.58–2.53 (m, 4
H, ring α-CH2), 1.81–1.75 (m, 4 H, ring β-CH2) ppm. 13C{1H}
NMR (100.6 MHz, CDCl3, 25 °C): δ = 140.4, 128.6, 128.3, 125.9
ppm. 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = 133.6, 132.0, (aryl), 58.3 (ArCH2CH2N), 54.2 (ring α-CH2), 35.8 (ArCH2), 23.4
128.8, 128.2, 127.8, 127.6, 127.4, 126.9, 126.8, 125.8, 125.1 (aryl),
(ring β-CH2) ppm. MS (FAB, 3-NBA): m/z (%) = 176 (100) [M]+.
58.6 (NCH2Ph), 55.5 (ArCH2CH2N), 33.8 (ArCH2CH2N) ppm. The spectroscopic data are in agreement with previously published
MS (FAB, 3-NBA): m/z (%) = 416 (42) [M]+, 274 (100) [M –
C10H7CH2]+. C31H29N (415.58): calcd. C 89.60, H 7.03, N 3.37;
found C 89.41, H 7.03, N 3.24.
data.[30]
N-Phenethylmorpholine (6c): Purification by column chromatog-
raphy on silica gel (CH2Cl2/MeOH, 95:5 + a few drops of Et3N, Rf
= 0.05). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.27 (t, JH,H =
7.4 Hz, 2 H, aryl-H), 7.20–7.16 (m, 3 H, aryl-H), 3.73 (m, 4 H,
PhCH2CH2N), 2.79 (m, 2 H, NCH2CH2O), 2.58 (m, 2 H,
1
3
Bis(phenethyl)propylamine (4n): Purification by column chromatog-
raphy on silica gel (CH2Cl2/MeOH, 95:5 + a few drops of Et3N, Rf
= 0.33). Isolated yield: 17% (based on the amine for Table 2, En-
try 22). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.22 (m, 4 H, aryl- NCH2CH2O), 2.52 (br. m, 4 H, NCH2CH2O) ppm. 13C{1H} NMR
H), 7.14–7.11 (m, 6 H, aryl-H), 2.71 (s, 8 H, PhCH2CH2N), 2.48
(100.6 MHz, CDCl3, 25 °C): δ = 140.1, 138.1, 128.7, 128.4, 126.1
3
(t, JH,H = 7.6 Hz, 2 H, NCH2CH2CH3), 1.50–1.38 (m, 2 H, (aryl), 67.0 (NCH2CH2O), 60.9 (PhCH2CH2N), 53.7
3
NCH2CH2CH3), 0.84 (t, JH,H = 7.3 Hz, 3 H, NCH2CH2CH3) (NCH2CH2O), 33.3 (PhCH2CH2N) ppm. MS (FAB, 3-NBA): m/z
ppm. 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = 140.7, 128.7, (%) = 192 (100) [M]+. C12H17NO (191.27): calcd. C 75.35, H 8.96,
128.3, 125.8 (aryl), 56.1 (PhCH2CH2N), 56.0 (NCH2CH2CH3), N 7.32; found C 75.03, H 8.98, N 7.28. The spectroscopic data are
33.7 (PhCH2CH2N), 20.4 (NCH2CH2CH3), 11.9 (NCH2CH2CH3)
ppm. MS (FAB, 3-NBA): m/z (%) = 268 (54) [M]+, 176 (100) [M –
PhCH2]+. C19H25N (267.41): calcd. C 85.34, H 9.42, N 5.24; found
C 85.74, H 9.54, N 5.38.
in agreement with previously published data.[12a,12c,31]
Benzyl(methyl)(phenethyl)amine (6d): Purification by column
chromatography on silica gel (CH2Cl2/MeOH, 95:5 + a few drops
1
of Et3N, Rf = 0.3). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.31–
(1,3-Diphenylpropyl)amine (5a): Purification by column chromatog-
7.28 (m, 7 H, aryl-H), 7.21 (m, 3 H, aryl-H), 3.58 (s, 2 H,
raphy on silica gel (CH2Cl2 + a few drops of Et3N, Rf = 0.07). NCH2Ph), 2.86 (m,
2
H, PhCH2CH2N), 2.68 (m,
2 H,
Isolated yield: 30% (based on the amine for Table 4, Entry 1).1H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.27–7.21 (m, 4 H, aryl-H),
7.19–7.13 (m, 3 H, aryl-H), 7.09–7.05 (m, 3 H, aryl-H), 3.80 (t,
PhCH2CH2N), 2.30 (s, 3
(100.6 MHz, CDCl3, 25 °C): δ = 140.5, 139.0, 129.0, 128.7, 128.3,
128.2, 126.9, 125.9 (aryl), 62.2 (NCH2Ph), 59.2 (PhCH2CH2N),
H, NCH3) ppm. 13C{1H} NMR
3JH,H = 6.8 Hz, 1 H, CHNH2), 2.58–2.43 (m, 2 H, PhCH2CH2CH), 42.2 (NCH3), 33.9 (PhCH2CH2N) ppm. MS (FAB, 3-NBA): m/z
1.95–1.86 (m, 2 H, PhCH2CH2CH), 1.48 (br. s, 2 H, NH2) ppm. (%) = 226 (80) [M]+, 134 (100) [M – PhCH2]+. C16H19N (225.33):
13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = 146.3, 141.9,
calcd. C 85.29, H 8.50, N 6.22; found C 85.21, H 8.41, N 6.32.
128.5, 128.3, 127.0, 126.4, 125.8 (aryl), 55.8 (CHNH2), 41.0 The spectroscopic data are in agreement with previously published
(PhCH2CH2CH), 32.8 (PhCH2CH2CH) ppm. MS (FAB, 3-NBA):
m/z (%) = 212 (100) [M]+. HRMS (EI): calcd. for C15H17N
211.1356; found 211.1360.
data.[12d]
Diethyl(phenethyl)amine (6e): Purification by column chromatog-
raphy on silica gel (CH2Cl2/MeOH, 95:5 + a few drops of Et3N, Rf
= 0.36). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.28–7.24 (m, 2
1
(1,1,3-Triphenylpropyl)amine (5o): Purification by column
chromatography on silica gel (CH2Cl2 + a few drops of Et3N, Rf =
0.15). Isolated yield: 12% (based on the amine). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.37–7.35 (m, 4 H, aryl-H), 7.29–
3
H, aryl-H), 7.18 (d, JH,H = 7.2 Hz, 3 H, aryl-H), 2.77–2.67 (m, 4
3
H, PhCH2CH2N), 2.60 (q, JH,H = 7.2 Hz, 4 H, NCH2CH3), 1.06
3
(t, JH,H = 7.2 Hz, 6 H, NCH2CH3) ppm. 13C{1H} NMR
7.25 (m, 4 H, aryl-H), 7.22–7.08 (m, 7 H, aryl-H), 2.48 (s, 4 H, (100.6 MHz, CDCl3, 25 °C): δ = 140.7, 128.6, 128.3, 125.9 (aryl),
PhCH2CH2), 1.75 (br. s, 2 H, NH2) ppm. 13C{1H} NMR 54.8 (PhCH2CH2N), 46.8 (NCH2CH3), 33.3 (PhCH2CH2N), 11.7
(100.6 MHz, CDCl3, 25 °C): δ = 148.6, 142.5, 128.4, 128.3, 128.2,
126.5, 126.4, 125.8 (aryl), 61.1 (CNH2), 44.7 (PhCH2CH2), 30.7
(PhCH2CH2) ppm. MS (FAB, 3-NBA): m/z (%) = 288 (20) [M]+,
271 (100) [M – NH2]+, 183 (98) [M – PhCH2CH2]+. C21H21N
(287.40): calcd. C 87.76, H 7.36, N 4.87; found C 87.71, H 7.33, N
4.89.
(NCH2CH3) ppm. MS (FAB, 3-NBA): m/z (%) = 178 (100) [M]+.
The spectroscopic data are in agreement with previously published
data.[32]
Dibenzyl(phenethyl)amine (6f): Purification by column chromatog-
raphy on silica gel (CH2Cl2/MeOH, 95:5 + a few drops of Et3N, Rf
1
= 0.19). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.32–7.22 (m, 13
N-Phenethylpiperidine (6a): Purification by column chromatog-
raphy on silica gel (CH2Cl2/MeOH, 95:5 + a few drops of Et3N, Rf
= 0.14). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.26 (m, 2 H,
H, aryl-H), 7.10–7.08 (m, 2 H, aryl-H), 3.65 (br. s, 4 H, NCH2Ph),
2.82–2.80 (m,
2 H, PhCH2CH2N), 2.74–2.70 (m, 2 H,
PhCH2CH2N) ppm. 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ
aryl-H), 7.17 (m, 3 H, aryl-H), 2.80 (m, 2 H, PhCH2CH2N), 2.54 = 140.6, 139.7, 128.8, 128.7, 128.2, 128.1, 126.8, 125.8 (aryl), 58.2
(m, 2 H, PhCH2CH2N), 2.45 (br. s, 4 H, ring α-CH2), 1.64–1.58
(NCH2Ph), 55.1 (PhCH2CH2N), 33.5 (PhCH2CH2N) ppm. MS
(m, 4 H, ring β-CH2) 1.45 (m, 2 H, ring γ-CH2) ppm. 13C{1H}
(FAB, 3-NBA): m/z (%) = 302 (26) [M]+, 300 (44) [M – H2]+, 210
NMR (100.6 MHz, CDCl3, 25 °C): δ = 140.7, 128.7, 128.3, 125.9 (100) [M – CH2Ph]+. C22H23N (301.43): calcd. C 87.66, H 7.69, N
(aryl), 61.4 (PhCH2CH2N), 54.5 (ring α-CH2), 33.7 (PhCH2CH2N), 4.65; found C 87.83, H 7.83, N 4.65. The spectroscopic data are in
26.0 (ring β-CH2), 24.4 (ring γ-CH2) ppm. MS (FAB, 3-NBA): m/z
agreement with previously published data.[32]
3322
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3311–3325

Base-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes
FULL PAPER
Methyl(phenethyl)(phenyl)amine (6g): Purification by column
quencies are real) or transition states (only one imaginary fre-
quency). Thermal corrections to Gibbs free energies were also ob-
chromatography on silica gel (CH2Cl2/EtOAc, 1:1 + a few drops of
1
Et3N, Rf = 0.88). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.38– tained by these unscaled harmonic vibrational frequencies. All cal-
3
7.26 (m, 7 H, aryl-H), 6.81–6.75 (m, 3 H, aryl-H), 3.62 (t, JH,H
=
=
culations were carried out with the GAUSSIAN03 package.[36] The
effect of solvation by benzene was estimated by means of single-
3
7.8 Hz, 2 H, PhCH2CH2N), 2.95 (s, 3 H, NCH3), 2.91 (t, JH,H
7.8 Hz, 2 H, PhCH2CH2N) ppm. 13C{1H} NMR (100.6 MHz, point calculations on the gas-phase-optimized geometries with the
CDCl3, 25 °C): δ = 148.8, 139.8, 129.2, 128.8, 128.5, 126.2, 116.1,
CPCM method.[37] Gibbs energies in solution have been referred to
112.1 (aryl), 54.7 (CH2N), 38.4 (PhCH2), 32.9 (NCH3) ppm. MS 298.15 K and 1 molL–1. Due to the fact that the product of reac-
(FAB, 3-NBA): m/z (%) = 212 (34) [M]+, 120 (100) [M – tion presents many more degrees of freedom than the reactants,
PhCH2]+. C15H17N (211.31): calcd. C 85.26, H 8.11, N 6.63; found
C 85.19, H 8.24, N 6.49. The spectroscopic data are in agreement
with previously published data.[31]
a Monte Carlo Multiple Minimum conformational search[38] was
carried out for it with the MMFF94s force field[39] implemented in
the Macromodel 7.0 package.[40]
1-[2-(4-Chlorophenyl)ethyl]piperidine (6h): Purification by column
Supporting Information (see footnote on the first page of this arti-
cle): Complete list of Cartesian coordinates for all optimized inter-
mediates and transition states, and all bond orders determined for
TS2, TS2Ј, (TMEDA)TS2, and (TMEDA)TS2Ј, and 1H and 13C
NMR spectra of all hydroamination products.
chromatography on silica gel (CH2Cl2/MeOH, 95:5 + a few drops
1
of Et3N, Rf = 0.07). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.19
(d, 3JH,H = 8.3 Hz, 2 H, aryl-H), 7.08 (d, 3JH,H = 8.3 Hz, 2 H, aryl-
H), 2.75 (m, 2 H, ArCH2CH2N), 2.50 (m, 2 H, ArCH2CH2N), 2.43
(br. m, 4 H, ring α-CH2), 1.62–1.56 (m, 4 H, ring β-CH2), 1.45–
1.40 (m, 2 H, ring γ-CH2) ppm. 13C{1H} NMR (100.6 MHz,
Acknowledgments
CDCl3, 25 °C):
δ = 138.9, 131.6, 129.9, 128.3 (aryl), 61.0
(ArCH2CH2N), 54.4 (ring α-CH2), 32.8 (ArCH2), 25.8 (ring β-
CH2), 24.2 (ring γ-CH2) ppm. MS (FAB, 3-NBA): m/z (%) = 224
(100) [M]+. C13H18ClN (223.75): calcd. C 69.79, H 8.11, N 6.26;
found C 69.39, H 8.29, N 6.13.
Generous financial support by the Deutsche Forschungsgemein-
schaft (DFG), the Dr. Otto Röhm Gedächtnisstiftung, and Minis-
terio de Educación y Ciencia of Spain (Project CTQ2005-08797-
C02-02/BQU) is gratefully acknowledged. K. C. H. is a DFG
Emmy Noether fellow and thanks Professor John A. Gladysz for
his continual support. Access to computational facilities of Centre
de Computació de Catalunya (CESCA) is gratefully acknowledged.
N-(2-Phenylpropyl)piperidine (6i): Purification by column
chromatography on silica gel (CH2Cl2/MeOH, 95:5 + a few drops
of Et3N, Rf = 0.06). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.29–
7.26 (m, 2 H, aryl-H), 7.20–7.15 (m, 3 H, aryl-H), 2.93 (sext., 3JH,H
= 7.0 Hz, 1 H, PhCH), 2.46–2.38 (m, 4 H, ring α-CH2), 2.28 (br.
d, 2 H, PhCH(CH3)CH2N), 1.60–1.47 (m, 4 H, ring β-CH2), 1.42–
[1] a) D. Steinborn, R. Taube, Z. Chem. 1986, 26, 349; b) R. Taube
in Applied Homogeneous Catalysis, vol. 1 (Eds.: B. Cornils,
W. A. Herrmann), Wiley-VCH, Weinheim, 1996, pp. 507; c)
T. E. Müller, M. Beller, Chem. Rev. 1998, 98, 675; d) T. E.
Müller, M. Beller, Transition Metals for Organic Synthesis
(Eds.: M. Beller, C. Bolm), Wiley-VCH, Weinheim, 1998, vol.
2, p. 316; e) J. J. Brunet, D. Neibecker in Catalytic Hetero-
functionalization from Hydroamination to Hydrozirconation
(Eds.: A. Togni, H. Grützmacher), Wiley-VCH, Weinheim,
2001, pp. 91.
3
1.36 (m, 2 H, ring γ-CH2) 1.26 (d, JH,H = 6.9 Hz, 3 H, CH3)
ppm. 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ = 146.7, 128.2,
127.2, 125.9 (aryl), 67.1 (PhCH(CH3)CH2N), 55.0 (ring α-CH2),
37.5 (PhCH), 26.1 (ring β-CH2), 24.5 (ring γ-CH2), 20.0 (CH3)
ppm. MS (FAB, 3-NBA): m/z (%) = 204 (100) [M]+. C14H21N
(203.33): calcd. C 82.70, H 10.41, N 6.89; found C 82.40, H 10.39,
N 6.80. The spectroscopic data are in agreement with previously
published data.[33]
[2] a) M. Beller, C. Breindl, M. Eichberger, C. G. Hartung, J.
Seayad, O. R. Thiel, A. Tillack, H. Trauthwein, Synlett 2002,
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g) F. Alonso, I. P. Beletskaya, M. Yus, Chem. Rev. 2004, 104,
3079; h) M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew. Chem.
2004, 116, 3448; Angew. Chem. Int. Ed. 2004, 43, 3368; i) A. L.
Odom, Dalton Trans. 2005, 225; j) K. C. Hultzsch, Adv. Synth.
Catal. 2005, 347, 367; k) K. C. Hultzsch, Org. Biomol. Chem.
2005, 3, 1819.
[3] a) R. Wegler, G. Pieper, Chem. Ber. 1950, 83, 1; b) B. W. Howk,
E. L. Little, S. L. Scott, G. M. Whitman, J. Am. Chem. Soc.
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A. Kolka, J. Org. Chem. 1957, 22, 646.
[4] J. Seayad, A. Tillack, C. G. Hartung, M. Beller, Adv. Synth.
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[5] a) R. J. Schlott, J. C. Falk, K. W. Narducy, J. Org. Chem. 1972,
37, 4243; b) K. Takabe, T. Katagiri, J. Tanaka, Bull. Chem. Soc.
Jpn. 1973, 46, 222; c) T. Narita, N. Imai, T. Tsuruta, Bull.
Chem. Soc. Jpn. 1973, 46, 1242; d) T. Narita, T. Yamaguchi, T.
Tsuruta, Bull. Chem. Soc. Jpn. 1973, 46, 3825; e) M. Beller, C.
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Bis(2-methoxyethyl)(phenethyl)amine (6j): Purification by column
chromatography on silica gel (CH2Cl2/MeOH, 95:5 + a few drops
of Et3N, Rf = 0.14). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.23–
3
7.20 (m, 2 H, aryl-H), 7.14–7.10 (m, 3 H, aryl-H), 3.42 (t, JH,H
=
6.1 Hz, 4 H, NCH2CH2OCH3), 3.29 (s, 6 H, OCH3), 2.78–2.69 (m,
8
H, PhCH2CH2NCH2CH2OCH3) ppm. 13C{1H} NMR
(100.6 MHz, CDCl3, 25 °C): δ = 140.5, 128.7, 128.3, 125.8 (aryl),
71.1 (CH2OCH3), 58.8 (OCH3), 57.2 (PhCH2CH2N), 53.8
(NCH2CH2OCH3), 33.3 (PhCH2CH2N) ppm. MS (FAB, 3-NBA):
m/z (%) = 238 (100) [M]+, 236 (45) [M – H2]+, 192 (35) [M –
CH2OCH3]+. HRMS (EI): calcd. for C14H23NO2 237.1723; found
237.1715.
General Procedure for the Determination of the Enantiomeric Ex-
cess: The amine (0.05 mmol) and (R)-O-acetylmandelic acid
1
(0.06 mmol) were dissolved in CDCl3 or C6D6, and their H NMR
spectrum was recorded either at room temperature or at 0 °C. The
enantiomeric excess was determined by 1H NMR spectroscopy
through the integration of diastereomeric protons in proximity to
the nitrogen atom.
Computational Details: All calculations were performed with the
nonlocal hybrid Becke 3-parameter Lee–Yang–Parr density func-
tional (B3LYP)[34] with the 6-31+G(d) basis set.[35] Harmonic vi-
brational frequencies have been calculated for all structures in or-
der to characterize the stationary points as energy minima (all fre-
Eur. J. Org. Chem. 2007, 3311–3325
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3323

P. Horrillo-Martínez, K. C. Hultzsch, A. Gil, V. Branchadell
FULL PAPER
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3311–3325

Base-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes
FULL PAPER
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Received: February 19, 2007
Published Online: May 10, 2007
Eur. J. Org. Chem. 2007, 3311–3325
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3325