An improved protocol for the selective hydroaminomethylation of arylethylenes

Article abstract of DOI:10.1016/j.tetlet.2005.08.107

The hydroaminomethylation of arylethylenes with anilines proceeds under mild conditions in the presence of [Rh(cod)₂BF₄] and dppf as catalyst system to give the corresponding branched amphetamine derivatives in good selectivity and y

Full text of DOI:10.1016/j.tetlet.2005.08.107

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7401–7405
An improved protocol for the selective hydroaminomethylation
of arylethylenes
Lucie Routaboul, Cathleen Buch, Holger Klein, Ralf Jackstell and Matthias Beller*
Leibniz-Institut fu¨r Organische Katalyse (IfOK) an der Universita¨t Rostock e.V., Albert-Einstein Straße 29a,
D-18059 Rostock, Germany
Received 30 May 2005; revised 17 August 2005; accepted 22 August 2005
Available online 12 September 2005
Abstract—The hydroaminomethylation of arylethylenes with anilines proceeds under mild conditions in the presence of
[Rh(cod)2BF4] and dppf as catalyst system to give the corresponding branched amphetamine derivatives in good selectivity and
yield.
Ó 2005 Elsevier Ltd. All rights reserved.
Amines are important products for bulk as well as fine
chemical and pharmaceutical industries. Among the var-
ious methods known for the synthesis of amines the so-
called hydroaminomethylation of olefines is highly
atom-economic and efficient. This domino reaction con-
sists of an initial hydroformylation followed by a reduc-
tive amination (Scheme 1).1 Although the method is
known for more than 50 years, only in the last decade
the potential of this transformation has been explored
in more detail. Here, especially the work of Eilbracht
and co-workers is noteworthy.2
internal olefins.3 The reaction is tolerant to a variety
of potentially reactive functional groups. This aspect
has been utilized, for example, in the hydroaminomethyl-
ation of methallylic alcohols and steroids.4 Despite
recent improvements of hydroaminomethylation cata-
lysts,5 control of all aspects of selectivity (chemo-, regio-
and enantioselectivity) is still a challenge.6
For some time, we are interested in the synthesis of bio-
logically important arylethylamines,7 which are known
to exhibit pharmacological activity such as antihista-
minic and sympathomimetic properties.8 Obviously,
the hydroaminomethylation of styrene offers an easy
access to this class of compounds. However, comparably
In general, hydroaminomethylations permit the synthe-
sis of secondary or tertiary amines from terminal and
R1
R1
NR2R3
R2 = H
HNR2R3
cat.
H2
CHO
R1
NR1R2
R1
NR3
NR2R3
cat.
CO/H2
R1
R1
NR1R2
CHO
HNR2R3
cat.
H2
R2 = H
NR3
R1
R1
R1
condensation / tautomerisation
hydroformylation
hydrogenation
Scheme 1. Hydroaminomethylation of olefins.
Keywords: Amines; Catalysis; Hydroaminomethylation.
*
Corresponding author. Tel.: +49 (0)381 12810; fax: +49 (0)381 12815000; e-mail: matthias.beller@ifok.uni-rostock.de
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.107

7402
L. Routaboul et al. / Tetrahedron Letters 46 (2005) 7401–7405
[Rh(cod)2]BF4
Xantphos
tions (<80 bar; 80 °C), but the observed regioselectivity
towards the branched amines was only moderate to
good. Kostas reported the reaction of styrene with mor-
pholine catalyzed by a cationic rhodium complex with a
P,N-ligand system. Again, the reaction was carried out
at high pressure (100 bar) giving the corresponding
branched amine in good yield and selectivity.10 It is
interesting to note that in all these reactions the
branched amphetamine derivative is formed preferen-
tially due to the increased thermodynamic stability of
the intermediate benzylrhodium complex. However,
the hydroaminomethylation of styrene with piperidine
catalyzed by a cationic rhodium complex in the presence
of Xantphos as ligand gave the linear arylpropylamine
in good yield (Scheme 2).5
R2R3NH
+
NR2R3
Ph
Ph
MeOH/toluene, 125-135 o
C
7 bar CO, 33 bar H2, 5-36 h
n/iso = >80:20
Scheme 2. Hydroaminomethylation to 3-arylpropylamines.
few investigations have been carried out so far. For
example, Rische and Eilbracht reported very good yield
and selectivity to the corresponding branched amines at
high pressure and temperature (110 bar; 110 °C) in the
presence of [Rh(cod)Cl]2.2e Later on, Alper and co-
workers have used a zwitterionic rhodium complex as
catalyst.9 This system was active under milder condi-
Table 1. Hydroaminomethylation of styrene with anilinea
Here, we present for the first time the use of a rhodium/
diphosphine catalyst system for the hydroaminomethyl-
ation of arylethylenes with anilines.
H
N
As a start of our investigation, we tested different com-
binations of [Rh(cod)2BF4] with phosphines in the mod-
el reaction of styrene with aniline (Table 1).11 It is
important to note that only 2% of amines 3a and 4a
were obtained when the reaction was carried out in the
absence of phosphine.
branched amine
3a
+
CO / H2
1a
2a
+
ligand
[Rh(cod)2BF4]
NH2
N
H
linear amine
3b
Interestingly, in all cases the addition of a catalytic
amount of tetrafluoroboric acid significantly enhanced
the yield of amines with a slight increase in the iso/n-
ratio. Although the effectiveness of the acid is not fully
known, the enhancement of the yield can be partly
attributed to the formation of iminium ions, which are
smoothly reduced to the corresponding amines. It is
likely that this effect will be useful for other hydroamino-
methylations, too.
Entry Ligand
Additive Yield of aminesb (%) iso/n-ratioc
1
—
HBF4
—
2
7
85:15
98:2
2
PPh3
3
PPh3
HBF4
—
52
29
94
12
49
10
35
30
96
99:1
4
Xantphos
78:22
85:15
61:39
86:14
93:7
>99:1
80:20
88:12
5
Xantphos HBF4
6
dppe
—
HBF4
—
HBF4
—
HBF4
7
dppe
8
9
10
11
dppent
dppent
dppf
Apart from the acid, the nature of the phosphine ligand
influences both the selectivity and the yield of amines. A
cationic rhodium precursor in association with the
ligand dppf allowed us vide supra to obtain amines 3a,
4a in almost quantitative yield with a good iso/n-ratio.
dppf
a Reaction conditions: 10 mmol styrene, 10 mmol aniline, 0.25 mol %
[Rh(cod)2BF4], 0.25 mol % diphosphine or 0.5 mol % PPh3, 30 mL
THF, 1 mmol HBF4, 5 bar PCO, 25 bar PH2, 60 °C, 18 h.
b Yield was determined by GC analysis with iso-octane as internal
standard.
Next, the rhodium-catalyzed hydroaminomethylation
of styrene with aniline in the presence of dppf was
c Selectivity was determined by GC analysis.
Table 2. Variation of reaction conditionsa
Entry
Rhodium precursor
CO/H2 (bar)
Temperature (°C)
Solvent
Yield of amineb (%)
iso/n-ratioc
1
2
3
4
5
6
7
8
[Rh(cod)2BF4]
[Rh(cod)2BF4], H2O
[Rh(nbd)2BF4]
[Rh(acac)(CO)2]
[Rh(cod)2BF4]
[Rh(cod)2BF4]
[Rh(cod)2BF4]
[Rh(cod)2BF4]
[Rh(cod)2BF4]
[Rh(cod)2BF4]
[Rh(cod)2BF4]
5/25
5/25
5/25
5/25
5/25
5/25
3.5/26.5
3.5/50
15/15
5/25
60
60
60
60
40
120
60
60
60
60
60
THF
THF
THF
THF
THF
THF
THF
THF
THF
MeOH
Toluene
96
20
97
74
81
99
99
89
99
88
96
88:12
74:26
93:7
92:8
92:8
66:34
91:9
90:10
86:14
95:5
9
10
11
5/25
90:10
a Reaction conditions: 10 mmol styrene, 10 mmol aniline, 0.25 mol % of rhodium precursor, 0.25 mol % dppf, 30 mL of solvent, 1 mmol HBF4, 18 h.
b Yield was determined by GC analysis with iso-octane as internal standard.
c Selectivity was determined by GC analysis.

L. Routaboul et al. / Tetrahedron Letters 46 (2005) 7401–7405
Table 3. Hydroaminomethylation of styrenes with various aminesa
7403
[Rh(cod)2]BF4
dppf, 10 mol% HBF4
NR2R3
3a-m
R2R3NH
NR2R3
+
Ar
Ar
+
Ar
60 ˚C, 30 bar (CO/H2 = 1:5)
4a-m
Entry
1
Olefin
Amine
Major product
Yield of aminesb (%)
iso/n-ratioc
H
N
96
88:12
H2N
3a, 4a
H
N
2
3
4
98
3b, 4b
85:15
88:12
59:41
H2N
H2N
H2N
Cl
Cl
H
N
97
3c, 4c
MeO
MeO
MeO
MeO
H
N
17
3d, 4d
5
6
66
3e, 4e
99:1
N
O
N
N
N
O
H
N
Fe
55
81:19
H2N
Fe
3f, 4f
H
7d
50
93:7
N
H2N
3g, 4g
H
N
N
8
75
85:15
3h, 4h
NH2
OMe
H
N
OMe
9
97
88:12
3i, 4i
H
N
10
65
60
3j, 4j
90:10
96:4
OMe
H2N
11e
OMe
CF3
H
N
12
99
3k, 4k
83:17
CF3
CN
H2N
H2N
H
N
13
14f
59
99
3l, 4l
78:22
80:20
CN
CN
CN
N
15f
98
3m, 4m
85:15
H2N
a Reaction conditions: 10 mmol olefin, 10 mmol amine, 0.25 mol % [Rh(cod)2BF4], 0.275 mol % dppf, 30 mL THF, 1 mmol HBF4, 5 bar PCO, 25 bar
P
H2, 60 °C, 18 h.
b Yield was determined by GC analysis with iso-octane as internal standard.
c Selectivity was determined by GC analysis.
d 72 h, 0.5 mol % [Rh(cod)2BF4], 0.55 mol % dppf.
e 40 °C.
f 74 h.

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L. Routaboul et al. / Tetrahedron Letters 46 (2005) 7401–7405
investigated with regard to critical reaction parameters
such as solvent, temperature, rhodium precursor and
pressure. Selected results are shown in Table 2. The
purity of the rhodium precursor strongly influences the
yield of the reaction (Table 2, entries 1 and 2). In gen-
eral, yields of amines are better when the reaction was
carried out in the presence of a cationic rhodium precur-
sor. It is important to note that our catalytic system is
efficient even at 40 °C (Table 2, entry 5), which is impor-
tant because the regioselectivity towards the branched
amine is significantly better at lower temperature (Table
2, compare entries 1 and 6). Modification of the total
pressure seems to have only a slight effect on both the
yield and the regioselectivity.
should be useful for the synthesis of a wide variety of
known and new amphetamine derivatives.
Acknowledgements
This work has been supported by the State of Mecklen-
burg-Western Pommerania, and the ÔBundesministerium
fur Bildung und Forschung (BMBF)Õ. We thank Mrs. C.
¨
Mewes, Mrs. H. Baudisch, Mrs. A. Lehmann and Mrs.
S. Buchholz (all IfOK) for their excellent support.
References and notes
Finally, we tested the efficiency of the catalytic system in
the hydroaminomethylation of arylethylenes with vari-
ous amines. The results are summarized in Table 3.
para-Substituted styrenes react with aniline in the pres-
ence of the catalytic system quantitatively to give the
corresponding amines (Table 3, entries 2 and 3). Appar-
ently, electronic effects of the substituents in the 4-posi-
tion of styrene have only little influence on the yield and
selectivity of the reaction. However, hydroamino-meth-
ylation of 4-methoxystyrene with cyclohexylamine affor-
ded only 17% of 3d and 4d with a low iso/n-ratio (Table
3, entry 4).
1. For an excellent review see: Eilbracht, P.; Ba¨rfacker, L.;
Buss, C.; Hollmann, C.; Kitsos-Rzychon, B. E.; Krane-
mann, C.; Rische, T.; Roggenbuck, R.; Schimdt, A. Chem.
Rev. 1999, 99, 3329.
2. (a) Ko¨hling, P.; Schmidt, A. M.; Eilbracht, P. Org. Lett.
2003, 18, 3213; (b) Rische, T.; Ba¨rfacker, L.; Eilbracht, P.
Eur. J. Org. Chem. 1999, 3, 653; (c) Rische, T.; Kitsos-
Rzychon, B.; Eilbracht, P. Tetrahedron 1998, 54, 2723; (d)
Kranemann, C. L.; Eilbracht, P. Synthesis 1998, 71; (e)
Rische, T.; Eilbracht, P. Synthesis 1997, 1331.
3. Selected examples: (a) Ahmed, M.; Seayad, A. M.;
Jackstell, R.; Beller, M. Angew. Chem., Int. Ed. 2003, 42,
5615; (b) Seayad, A. M.; Selvakumar, K.; Ahmed, M.;
Beller, M. Tetrahedron Lett. 2003, 44, 1679; (c) Seayad, A.
M.; Ahmed, M.; Klein, H.; Jackstell, R.; Gross, T.; Beller,
M. Science 2002, 297, 1676; (d) Zimmermann, B.; Herwig,
J.; Beller, M. Angew. Chem., Int. Ed. 1999, 38, 2372; (e)
Schaffrath, H.; Keim, W. J. Mol. Catal. 1999, 140, 107; (f)
Brunet, J. J.; Neibecker, D.; Agbossou, F.; Srivastav, R. S.
J. Mol. Catal. 1994, 87, 223; (g) Baig, T.; Molinier, J.;
Kalck, P. J. Organomet. Chem. 1993, 455, 219; (h) To¨ro¨s,
S.; Gemes-Pesci, I.; Heil, B.; Maho, S.; Tubar, Z. J. Chem.
Soc., Chem. Commun. 1992, 585; (i) Baig, T.; Kalck, P. J.
Chem. Soc., Chem. Commun. 1992, 1373.
4. (a) Breit, B. Tetrahedron Lett. 1998, 39, 5163; (b) Nagy, E.;
Heil, B.; Toro¨s, S. J. Organomet. Chem. 1999, 586, 10.
5. Ahmed, M.; Seayad, A. M.; Jackstell, R.; Beller, M. J.
Am. Chem. Soc. 2003, 125, 10311.
6. Seayad, J.; Tillack, A.; Beller, M. Angew. Chem., Int. Ed.
2004, 43, 3368.
7. (a) Tewari, A.; Hein, M.; Zapf, A.; Beller, M. Tetrahedron
Lett. 2004, 45, 7703; (b) Michalik, D.; Kumar, K.; Fun
Lo, W.; Tillack, A.; Zapf, A.; Arlt, M.; Heinrich, T.;
Beller, M. Tetrahedron Lett. 2004, 45, 2057; (c) Kumar,
K.; Michalik, D.; Garcia Castro, Y.; Tillack, A.; Zapf, A.;
Arlt, M.; Heinrich, T.; Bo¨ttcher, H.; Beller, M. Chem. Eur.
J. 2004, 10, 746; (d) Seayad, J.; Tillack, A.; Hartung, C.
G.; Beller, M. Adv. Synth. Catal. 2002, 344, 795; (e) Beller,
M.; Breindl, C. Chemosphere 2001, 43, 21; (f) Hartung, C.
G.; Breindl, C.; Tillack, A.; Beller, M. Tetrahedron 2000,
56, 5157; (g) Beller, M.; Breindl, C.; Riermeier, T. H.;
Eichberger, M.; Trauthwein, H. Angew. Chem., Int. Ed.
1998, 37, 3389.
Reaction of 2-vinylpyridine with morpholine proceeds
with an excellent regioselectivity to give 66% of 3e and
4e (Table 3, entry 5). This is a rare successful example
of using a heteroaromatic olefin as substrate in hydro-
aminomethylations. In the reaction of vinylferrocene
with aniline amines, 3f, 4f are obtained in 55% with a
good iso/n-ratio (Table 3, entry 6). In case of sterically
more demanding b-methylstyrene, longer reaction time
and more catalyst are necessary to obtain a reasonable
yield (50%) of 3g, 4g (Table 3, entry 7). It is noteworthy
that the hydroaminomethylation of this internal olefin
occurs with high regioselectivity. Hydroaminomethyl-
ation of styrene with N-methylaniline afforded 3h, 4h in
75% (Table 3, entry 8). This demonstrated the feasibility
of using secondary amines in the reaction. In addition,
different substituted anilines have been hydroaminome-
thylated easily (Table 3, entries 9–11). 2-Anisidine affor-
ded 97% of 3i and 4i with an iso/n-ratio of 88:12. Under
the same reaction conditions, 65% of 3j and 4j are ob-
tained from 4-anisidine. Here, side-products formed by
bishydroaminomethylation were observed. Amine 3k
and 4k are obtained in excellent yield from styrene
and 4-trifluoromethylaniline (Table 3, entry 12). Finally,
reaction of styrene with 3- and 4-aminobenzonitrile
afforded 3l and 3m. A longer reaction time allowed us
to obtain both products nearly quantitatively (Table 3,
entries 13–15).
8. Seijas, A. J.; Vazquez-Tato, M. P.; Martinez, M. M.
Synlett 2001, 875.
9. Lin, Y. S.; El Ali, B.; Alper, H. Tetrahedron Lett. 2001, 42,
2423.
In conclusion, we have shown that [Rh(cod)2BF4]/dppf
in the presence of HBF4 catalyzes the hydroaminome-
thylation of aromatic olefins with different amines with
good regioselectivity towards the branched products.
The described catalyst system permits for the first time
hydroaminomethylation of styrenes under mild condi-
tions (low pressure; 60 °C). The reported procedure
10. Kostas, I. D. J. Chem. Res. (S) 1999, 630.
11. General procedure: Hydroaminomethylation reactions
were carried out in a Parr stainless steel autoclave
(100 mL). In a typical experiment (Table 1, entry 10), a
Schlenk flask was charged with [Rh(cod)2BF4] (0.25 mol %),

L. Routaboul et al. / Tetrahedron Letters 46 (2005) 7401–7405
7405
dppf (0.25 mol %) and THF (30 mL) under argon atmo-
sphere. The solution was stirred at room temperature for
1 h, then styrene (10 mmol), aniline (10 mmol) and tetra-
fluoroboric acid (0.2 mL 54% wt % solution in diethyl ether)
were added. The solution was transferred to the autoclave
and the autoclave was pressurized with CO (5 bar) and
hydrogen (25 bar). The reaction was carried out at 60 °C for
18 h. Then, the autoclave was cooled at 5 °C and depres-
surized. After transfer to a Schlenk flask, the mixture was
analyzed by gas chromatography using iso-octan as internal
standard. All branched amines were fully characterized by
1H NMR, 13C NMR, MS and HRMS.
N-(2-Pyridin-2-yl-propyl)morpholine (3e): 1H NMR (400
MHz, CDCl3): d 7.55–7.45 (m, 1H, CH), 7.11–7.06 (m, 2H, 2
CH), 7.06–7.01 (m, 1H, CH), 3.67–3.63 (m, 2H, CH2N),
3.59–3.54 (m, 2H, CH2N), 3.10–3.01 (m, 1H, CHCH3),
2.72–2.67 (m, 1H, CH2N), 2.60 (dd, 1J = 12.2 Hz,
2J = 6.9 Hz, 1H, CH2N), 2.49–2.42 (m, 2H, CH2O), 2.38–
2.33 (m, 2H, CH2O), 1.23 (d, J = 6.9 Hz, 3H, CH3). 13C
NMR (161 MHz, CDCl3): d 164.8 (Py), 148.9 (CH), 136.0
(CH), 122.9 (CH), 121.8 (2Ph), 66.8 (CH2N), 64.7 (CH2N),
58.6 (CH2N), 53.7 (CH2O), 53.4 (CH2O), 35.4(CHCH3),
18.8 (CH3). GC–MS (EI, 70 eV): m/z = 206 [M+], 188, 174,
161, 132, 120, 106, 100, 93, 78, 70, 52, 42, 28. HRMS Calcd
for C12H18N2O: 206.14191. Found 206.14180.
N-Phenyl-2-(4-methoxyphenyl)propylamine (3c): 1H NMR
(400 MHz, CDCl3): d 7.51–7.41 (m, 4H, Ph), 7.21–7.18 (m,
2H, Ph), 7.02 (tt, J = 1.0 and 7.3 Hz, 1H, Ph), 6.90–6.85 (m,
2H, Ph), 4.1 (s, 3H, OCH3), 3.90 (br s, 1H, NH), 3.56 (dd,
J = 12.3 and 6.2 Hz, 1H, CH2–N), 3.56 (dd, J = 12.3 and
8.3 Hz, 1H, CH2N), 3.31 (m, 1H, CH–CH3), 1.62 (d,
J = 7.1 Hz, 3H, CH3). 13C NMR (161 MHz, CDCl3): d
158.0 (Ph), 148.1 (Ph), 136.3 (Ph), 129.0 (2Ph), 127.9 (2Ph),
117.0 (Ph), 113.9 (2Ph), 112.8 (2Ph), 55.0 (O–CH3), 50.1
(CH2–NH), 38.1 (CH–CH3), 19.8 (CH3). GC–MS (EI,
70 eV) m/z = 241 [M+], 181, 135, 106, 91, 69, 65, 52. HRMS
Calcd for C16H19NO: 241.14627. Found 241.14627.
N-Phenyl(2-ferrocenylpropyl)amine (3f): 1H NMR (400
MHz, d6-acetone) d 7.2–7.1 (m, 2H, Ph), 6.7–6.6 (m, 3H,
Ph), 4.7 (m, 1H, NH), 4.16 (m, 7H, 5H Cp+2H subst Cp),
4.12 (m, 2H, subst Cp), 3.22 (m, 1H, CH2–NH), 3.09 (m, 1H,
CH2–NH), 2.82 (m, 1H, CHCH2), 1.34 (d, J = 6.9 Hz, 2H,
CH2). 13C NMR (161 MHz, d6-acetone) d 149.5 (quat Ph),
129.7 (Ph), 116.9 (Ph), 113.1 (Ph), 93.6 (quat Cp), 69.0 (Cp),
67.94 (subst Cp), 67.84 (subst Cp), 67.76 (subst Cp), 66.4
(subst Cp), 51.9 (CH2), 33.2 (CH), 19.1 (CH3). GC–MS (EI,
70 eV) m/z = 319 [M+], 213, 153, 106, 89, 77, 46, 28. HRMS
Calcd for C19H21NFe: 319.10233. Found 319.10198.