Metal and organo-catalysed asymmetric hydroaminomethylation of styrenes

Article abstract of DOI:10.1016/S1872-2067(14)60246-1

A new protocol that enables asymmetric hydroaminomethylation of styrenes to afford chiral amines has been developed. Catalysed by an Rh-phosphine species and a chiral phosphoric acid, styrenes are converted into β-chiral amines with good enantioselectivities under syngas in the presence of an amine and Hantzsch ester. The reaction involves two key steps, hydroformylation and reductive amination, with the former catalysed by the Rh species whilst the latter by the phosphoric acid.

Full text of DOI:10.1016/S1872-2067(14)60246-1

Chinese Journal of Catalysis 36 (2015) 106–112
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Article (Special Issue on Catalysis in Organic Synthesis)
Metal and organo‐catalysed asymmetric hydroaminomethylation of
styrenes
Barbara Villa‐Marcos, Jianliang Xiao*
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
A new protocol that enables asymmetric hydroaminomethylation of styrenes to afford chiral amines
has been developed. Catalysed by an Rh‐phosphine species and a chiral phosphoric acid, styrenes
are converted into β‐chiral amines with good enantioselectivities under syngas in the presence of an
amine and Hantzsch ester. The reaction involves two key steps, hydroformylation and reductive
amination, with the former catalysed by the Rh species whilst the latter by the phosphoric acid.
© 2015, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Received 12 September 2014
Accepted 25 October 2014
Published 20 January 2015
Keywords:
Published by Elsevier B.V. All rights reserved.
Asymmetric hydroaminomethylation
Hydroformylation
Chiral amine
Metal catalysis
Organocatalysis
1. Introduction
ble catalyst for hydroaminomethylation must fulfil a number of
requirements (Scheme 2). It must be highly regioselective to
We recently reported that imino bonds can be reduced
highly enantioselectively under metal‐organo cooperative ca‐
talysis [1–5]. Since olefins such as styrenes could be selectively
hydroformylated to the corresponding α‐branched aldehydes
[6], which readily condense with an amine to afford imines, it
became possible to us that β‐chiral amines might be accessible
via a similar strategy (Scheme 1). The enantioselectivity would
be achieved through a dynamic kinetic resolution (DKR) pro‐
cess preceding the reduction. In the presence of a chiral acid
catalyst, imines are expected to undergo fast racemisation by
tautomerisation, and one of the enantiomers of the iminium
cation could be selectively reduced, leading to chiral amines [7].
Hydroformylation of an alkene, followed by reductive ami‐
nation of the resulting aldehyde intermediate with an amine, is
known as hydroaminomethylation [8]. It represents a one‐pot,
atom‐efficient reaction for the synthesis of amines, one of the
most ubiquitous functionalities in chemical synthesis. A suita‐
either the linear or branched aldehyde, depending on the de‐
sired final product. The catalyst must be active for the
enamine/imine hydrogenation, as a slow hydrogenation leads
to aldol‐type side reactions [9]. Finally, the catalyst must be
selective for enamine/imine hydrogenation over hydrogena‐
tion of aldehydes. In addition, the enamine/imine isomerisation
must be faster than the subsequent hydrogenation to ensure
efficient DKR.
The first example of hydroaminomethylation was reported
by Reppe et al. at BASF in the early 1950s [10]. Simple alkenes,
like ethene or propene, were converted to secondary and ter‐
tiary amines in low yields, with ammonia under harsh condi‐
tions of up to 390 °C and 950 bar H2 using [Fe(CO)5] in almost
stoichiometric quantity. Significant progress has been made
since, with notable contributions being made by the groups of
Eilbracht and Beller [8,11–13]. There are, however, few studies
concerning asymmetric hydroaminomethylation, with none
* Corresponding author. Tel: +44‐1517942937; E‐mail: jxiao@liv.ac.uk
DOI: 10.1016/S1872‐2067(14)60246‐1 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 36, No. 1, January 2015

Barbara Villa‐Marcos et al. / Chinese Journal of Catalysis 36 (2015) 106–112
107
H
H2/CO, [M]
R
NH2, Chiral acid, [H]
Reductive amination
H
N
Ar
Ar
Ar
R
Hydroformylation
*
O
Chiral acid
[H]
R
NH2
H
R
H
H
Ar
Ar
Ar
N
HN
R
N
R
Scheme 1. Asymmetric hydroaminomethylation via tandem hydroformylation‐asymmetric reductive amination.
Scheme 2. Chemo‐ and i/n regio‐selectivity issues in the hydroaminomethylation sequence.
reporting significant enantioselectivities [14,15].
Et‐HEH (0.6 mol), TRIP (12.5 μmol), and toluene (2 mL). The
glass liner was then placed into an autoclave, followed by de‐
gassing with syngas three times. The reaction was carried out
at 11 bar syngas with stirring at 50 °C for 3 d. The stirring was
then stopped, and the autoclave allowed to cool down to room
temperature. The syngas was then carefully released in a fume
hood and the solution was filtered through celite, transferred to
a flask, and concentrated to afford the crude product. Flash
chromatography purification with a column of silica gel eluted
with petroleum ether/ethyl acetate (40/1 to 30/1) yielded the
desired amine product.
2. Experimental
2.1. General procedure for the synthesis of racemic mixtures of
1a–p
To a glass liner equipped with a stir bar was added styrene
(5 mmol), [Rh(acac)(CO)2] (25 μmol), (4‐MeOC6H4)3P (50
μmol), and toluene (2 mL). The glass liner was then placed into
an autoclave, followed by degassing with syngas three times.
The reaction was carried out at 11 bar syngas with stirring at
50 °C overnight. The stirring was then stopped, and the auto‐
clave allowed to cool down to room temperature. The syngas
was then carefully released in a fume hood and the solution
was filtered through celite, transferred to a flask, and concen‐
trated to afford the crude product. Flash chromatography puri‐
fication with a column of silica gel eluted with petroleum
ether/ethyl acetate (50/1) yielded the desired aldehyde prod‐
uct.
To an oven‐dried Schlenk tube equipped with a stir bar was
added the aldehyde prepared (0.5 mmol), amine (0.5 mmol)
and an Iridicycle catalyst (5 μmol) [25]. The tube was degassed
with nitrogen three times. MeOH (4 mL) was then added with
syringe, followed by HCOOH/Et3N (5:2, 1 mL). The resulting
mixture was stirred at 80 °C for 3 h. The stirring was then
stopped, and the reaction mixture allowed to cool down to
room temperature. The reaction was then quenched with water
and basified with saturated KOHaq solution, extracted with
ethyl acetate and dried over MgSO4. Flash chromatography
purification with a column of silica gel eluted with petroleum
ether/ethyl acetate (15/1) yielded the racemic mixtures of
1a–p.
2.3. Analytical data
4‐Methoxy‐N‐(2‐p‐tolylpropyl)aniline, 1a [17]. The product
(50 mg, 79% yield, 80% ee) was obtained as a colourless oil
according to the general procedure in 3 d; 1H NMR (400 MHz,
CDCl3) δ 1.30 (d, J = 7.0 Hz, 3H), 2.33 (s, 3H), 2.98–3.05 (m, 1H),
3.16 (dd, A of ABX, JAB = 12.1 Hz, JAX = 8.4 Hz, 1H), 3.28 (dd, B of
ABX, JAB = 12.1 Hz, JBX = 6.2 Hz, 1H), 3.74 (s, 3H), 3.53–6.57 (m,
2H), 6.74–6.78 (m, 2H), 7.10–7.15 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 20.0, 21.1, 38.8, 52.1, 55.8, 114.4, 114.9, 127.2, 129.4,
136.1, 141.6, 142.4, 152.1; C17H22NO [M+H]+: m/z Calcd.:
256.1701; Found: 256.1706; HPLC (Chiralcel OJ, hexane:iso‐
propanol = 90:10, flow rate 0.5 mL/min, λ = 254 nm): tR = 16.5
min (minor), tR = 18.7 min (major).
3‐Methoxy‐N‐(2‐p‐tolylpropyl)aniline, 1b. The product (53
mg, 83% yield, 84% ee) was obtained as a colourless oil
according to the general procedure in 3 d; 1H NMR (400 MHz,
CDCl3) δ 1.31 (d, J = 6.9 Hz, 3H), 2.33 (s, 3H), 2.97–3.06 (m, 1H),
3.19 (dd, A of ABX, JAB = 12.2 Hz, JAX = 8.3 Hz, 1H), 3.30 (dd, B of
ABX, JAB = 12.2 Hz, JBX = 6.2 Hz, 1H), 3.75 (s, 3H), 6.13 (t, J = 2.1
Hz, 1H), 6.18 (dd, J = 8.1, 2.1 Hz, 1H), 8.25 (dd, J = 8.1, 2.1 Hz,
1H), 7.05 (t, J = 8.1 Hz, 1H), 7.10–7.15 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 18.5, 21.0, 38.8, 50.9, 55.1, 98.8, 102.4, 106.1,
127.1, 129.3, 129.9, 136.1, 141.4, 149.5, 160.8; HPLC (Chiralcel
OD‐H, hexane:isopropanol = 98:2, flow rate 0.5 mL/min, λ =
254 nm): tR = 30.1 min (minor), tR = 37.2 min (major).
2.2. General procedure for asymmetric hydroaminomethylation
To a glass liner equipped with a stir bar was added 4 Å MS
(100 mg), alkene (0.4 mmol), amine (0.25 mmol),
[Rh(acac)(CO)2] (1.25 μmol), (4‐MeO‐C6H4)3P (2.5 μmol),
3‐Methyl‐N‐(2‐p‐tolylpropyl)aniline, 1c. The product (52

108
Barbara Villa‐Marcos et al. / Chinese Journal of Catalysis 36 (2015) 106–112
mg, 87% yield, 78% ee) was obtained as a clear yellow oil
according to the general procedure in 3 d; 1H NMR (400 MHz,
CDCl3) δ 1.31 (d, J = 7.0 Hz, 3H), 2.26 (s, 3H), 2.34 (s, 3H),
2.97–3.05 (m, 1H), 3.19 (dd, A of ABX, JAB = 12.2 Hz, JAX = 8.3 Hz,
1H), 3.31 (dd, B of ABX, JAB = 12.2 Hz, JBX = 6.2 Hz, 1H), 3.52 (brs,
1H), 6.38–6.39 (m, 2H), 6.51 (d, J = 7.4 Hz, 1H), 7.02–7.06 (m,
1H), 7.11–7.15 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 20.0, 21.2,
21.8, 39.0, 51.1, 110.2, 113.9, 118.4, 127.3, 129.2, 129.5, 136.2,
139.0, 141.7, 148.4; HRMS for C17H22N [M+H]+: m/z Calcd.:
240.1747; Found: 240.1744; HPLC (Chiralcel OD‐H, hexane:
isopropanol = 99.8:0.2, flow rate 1 mL/min, λ = 254 nm): tR =
20.2 min (minor), tR = 20.9 min (major).
2‐Methyl‐N‐(2‐p‐tolylpropyl)aniline, 1d. The product (36
mg, 61% yield, 86% ee) was obtained as a colourless oil
according to the general procedure in 3 d; 1H NMR (400 MHz,
CDCl3) δ 1.34 (d, J = 6.9 Hz, 3H), 1.93 (s, 3H), 2.33 (s, 3H),
3.04–3.09 (m, 1H), 3.19 (dd, A of ABX, JAB = 11.9 Hz, JAX = 8.4 Hz,
1H), 3.37 (dd, B of ABX, JAB = 12.2 Hz, JBX = 5.8 Hz, 1H), 3.43 (brs,
1H), 6.64 (d, J = 7.7 Hz, 2H), 7.00, (d, J = 7.4 Hz, 1H), 7.10–7.12
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 17.2, 19.6, 21.0, 38.7,
51.0, 109.9, 116.8, 122.1, 127.1, 129.4, 129.5, 130.0, 136.2,
141.4, 146.1; HRMS for C17H22N [M+H]+: m/z Calcd.: 240.1747;
Found: 240.1746; HPLC (Chiralcel OD‐H, hexane:isopropanol =
99:1, flow rate 1 mL/min, λ = 254 nm): tR = 7.2 min (major), tR =
7.9 min (minor).
126.2, 126.5, 129.9, 130.5, 136.2, 142.6, 149.6, 160.9; C17H22NO
[M+H]+: m/z Calcd.: 256.1701; Found: 256.1703; HPLC
(Chiralcel OD‐H, hexane:isopropanol = 98:2, flow rate 0.5
mL/min, λ = 254 nm): tR = 41.3 min (minor), tR = 52.7 min
(major).
4‐Methoxy‐N‐(2‐m‐tolylpropyl)aniline, 1h. The product (39
mg, 61% yield, 80% ee) was obtained as a pale yellow oil
according to the general procedure in 3 d; 1H NMR (400 MHz,
CDCl3) δ 1.31 (d, J = 7.0 Hz, 3H), 2.35 (s, 3H), 2.97–3.03 (m, 1H),
3.18 (dd, A of ABX, JAB = 12.1 Hz, JAX = 8.3 Hz, 1H), 3.28 (dd, B of
ABX, JAB = 12.1 Hz, JBX = 6.1 Hz, 1H), 3.74 (s, 3H), 6.53–6.57 (m,
2H), 6.74–6.78 (m, 2H), 7.01–7.06 (m, 3H), 7.21 (d, J = 8.2 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 20.0, 21.6, 39.3, 52.1, 55.9,
114.5, 115.0, 124.4, 127.5, 128.1, 128.7, 138.4, 142.5, 144.7,
152.2; HRMS for C17H22NO [M+H]+: m/z Calcd.: 256.1701;
Found: 256.1700; HPLC (Chiralcel OD‐H, hexane:isopropanol =
99:1, flow rate 0.5 mL/min, λ = 254 nm): tR = 42.7 min (major),
tR = 49.9 min (minor).
3‐Methoxy‐N‐(2‐(m‐tolyl)propyl)aniline, 1i. The product
(50 mg, 78% yield, 84% ee) was obtained as a pale yellow oil
according to the general procedure in 3 d; 1H NMR (400 MHz,
CDCl3) δ 1.24 (d, J = 7.0 Hz, 3H), 2.27 (s, 3H), 2.89–2.98 (m, 1H),
3.14 (dd, A of ABX, JAB = 12.3 Hz, JAX = 8.3 Hz, 1H), 3.23 (dd, B of
ABX, JAB = 12.3 Hz, JBX = 6.2 Hz, 1H), 3.53 (brs, 1H), 3.68 (s, 3H),
6.06 (t, J = 2.3 Hz, 1H), 6.11 (dd, J = 8.1, 1.5 Hz, 1H), 6.18 (dd, J =
4‐Bromo‐N‐(2‐p‐tolylpropyl)aniline, 1e. The product (34
mg, 45% yield, 79% ee) was obtained as a clear oilaccording to
the general procedure in 3 d; 1H NMR (400 MHz, CDCl3) δ 1.30
(d, J = 7.0 Hz, 3H), 2.33 (s, 3H), 2.95–3.03 (m, 1H), 3.15 (dd, A of
8.1, 2.3 Hz, 1H), 6.94–7.00 (m, 4H), 7.15 (t, J = 7.7 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 19.3, 21.4, 38.6, 50.9, 55.7, 101.9,
103.2, 124.3, 127.4, 128.0, 128.9, 129.9, 130.3, 138.3, 144.5,
149.6, 160.9; C17H22NO [M+H]+: m/z Calcd.: 256.1701; Found:
256.1703; HPLC (Chiralcel OD‐H, hexane:isopropanol = 98:2,
flow rate 0.5 mL/min, λ = 254 nm): tR = 37.8 min (minor), tR =
47.9 min (major).
N‐(2‐m‐Tolylpropyl)aniline, 1j. The product (32 mg, 56%
yield, 80% ee) was obtained as a colourless oilaccording to the
general procedure in 3 d; 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J
= 7.0 Hz, 3H), 2.27 (s, 3H), 2.89–2.98 (m, 1H), 3.14 (dd, A of
ABX, JAB = 12.3 Hz, JAX = 8.5 Hz, 1H), 3.28 (dd, B of ABX, JAB
=
12.3 Hz, JBX = 6.0 Hz, 1H), 3.57 (brs, 1H), 6.41–6.44 (m, 2H),
7.08–7.14 (m, 4H), 7.19–7.23 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 19.8, 21.0, 38.7, 50.9, 108.8, 114.5, 127.5, 129.4, 131.9,
136.3, 141.1, 147.1; C16H1979BrN [M+H]+: m/z Calcd.: 304.0701;
Found: 304.0704; HPLC (Chiralcel OD‐H, hexane:isopropanol =
98:2, flow rate 0.5 mL/min, λ = 254 nm): tR = 14.7 min (minor),
tR = 15.3 min (major).
ABX, JAB = 12.1 Hz, JAX = 8.3 Hz, 1H), 3.24 (dd, B of ABX, JAB
=
4‐Methoxy‐N‐(2‐phenylpropyl)aniline, 1f [17]. The product
(45 mg, 74% yield, 83% ee) was obtained as a colourless oil
according to the general procedure in 3 d; 1H NMR (400 MHz,
CDCl3) δ 1.32 (d, J = 7.0 Hz, 3H), 3.00–3.08 (m, 1H), 3.19 (dd, A
12.2 Hz, JBX = 6.2 Hz, 1H), 3.49 (brs, 1H), 6.49 (dd, J = 8.4, 0.9 Hz,
2H), 6.61 (t, J = 7.3 Hz, 1H), 6.96 (t, J = 8.4 Hz, 3H), 7.08–7.12
(m, 2H), 7.14–7.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 19.9,
21.5, 39.2, 50.9, 113.0, 117.3, 124.3, 127.4, 128.0, 128.6, 129.3,
138.3, 144.5, 148.2; MS (CI) for C16H20N [M+H]+: m/z 226
(100%); Anal. Calcd. for C16H19N: C, 85.28; H, 8.50; N, 6.22.
Found: C, 84.71; H, 8.83; N, 6.42. HPLC (Chiralcel OD‐H,
hexane:isopropanol = 99.5:0.5, flow rate 4 mL/min, λ = 254
nm): tR = 11.3 min (minor), tR = 12.3 min (major).
N‐(2‐(4‐Methoxyphenyl)propyl)‐4‐methylaniline, 1k. The
product (39 mg, 61% yield, 82% ee) was obtained as a
colourless oil according to the general procedure in 3 d; 1H
NMR (400 MHz, CDCl3) δ 1.29 (d, J = 6.9 Hz, 3H), 2.23 (s, 3H),
2.96–3.04 (m, 1H), 3.15 (dd, A of ABX, JAB = 12.2 Hz, JAX = 8.4 Hz,
1H), 3.29 (dd, B of ABX, JAB = 12.2 Hz, JBX = 6.0 Hz, 1H), 3.80 (s,
3H), 6.48–6.51 (m, 2H), 6.85–6.88 (m, 2H), 6.97 (d, J = 8.4 Hz,
2H), 7.12–7.16 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 20.0, 21.2,
38.9, 51.5, 55.9, 114.0, 114.1, 126.5, 128.2, 129.8, 136.6, 145.9,
158.2, 158.3; HRMS for C17H22NO [M+H]+: m/z Calcd.:
256.1701; Found: 256.1700; HPLC (Chiralcel OD‐H,
of ABX, JAB = 12.2 Hz, JAX = 8.3 Hz, 1H), 3.30 (dd, B of ABX, JAB
=
12.2 Hz, JBX = 6.1 Hz, 1H), 3.74 (s, 3H), 6.52–6.56 (m, 2H),
6.74–6.77 (m, 2H), 7.21–7.25 (m, 3H), 7.30–7.35 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 19.8, 39.2, 52.0, 55.8, 114.4, 114.9,
126.6, 127.3, 128.7, 142.4, 144.6, 152.1; C16H20NO [M+H]+: m/z
Calcd.: 242.1539; Found: 242.1537; HPLC (Chiralcel OJ, hexane
:isopropanol = 90:10, flow rate 0.5 mL/min, λ = 254 nm): tR =
19.6 min (minor), tR = 23.1 min (major).
3‐Methoxy‐N‐(2‐(o‐tolyl)propyl)aniline, 1g. The product (31
mg, 49% yield, 91% ee) was obtained a pale yellow oil
according to the general procedure in 3 d; 1H NMR (400 MHz,
CDCl3) δ 1.21 (d, J = 6.4 Hz, 3H), 2.24 (s, 3H), 3.18–3.32 (m, 3H),
3.54 (brs, 1H), 3.68 (s, 3H), 6.06 (t, J = 2.2 Hz, 1H), 6.11 (dd, J =
8.0, 1.5 Hz, 1H), 6.18 (dd, J = 8.0, 2.2 Hz, 1H), 6.98 (t, J = 8.0 Hz,
1H), 7.04–7.11 (m, 2H), 7.13–7.15 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 19.6 (2C), 34.2, 50.2, 55.1, 98.8, 102.5, 106.0, 125.3,

Barbara Villa‐Marcos et al. / Chinese Journal of Catalysis 36 (2015) 106–112
109
hexane:isopropanol = 98.5:1.5, flow rate 0.5 mL/min, λ = 254
tR = 39.3 min (minor).
nm): tR = 19.9 min (minor), tR = 22.2 min (major).
4‐Bromo‐N‐(2‐(4‐methoxyphenyl)propyl)aniline, 1l. The
product (41 mg, 51% yield, 84% ee) was obtained as a pale
yellow oil according to the general procedure in 3 d; H NMR
3. Results and discussion
1
Hydroformylation usually affords a linear aldehyde. How‐
ever, it is the branched aldehyde that could lead to a chiral
amine. Hence, in order to turn the product of hydroam‐
inomethylation into highly optically active, one must first
maximise the i/n selectivity of the transformation (Scheme 2).
Li and co‐workers [16] reported the selective hydroformylation
of styrene to the corresponding α‐branched aldehyde with a Rh
catalyst containing a triarylphosphine ligand possessing a
long‐chain alkoxy group. The reaction takes place in toluene,
with 0.2 mol% [Rh(acac)(CO)2] and 0.4 mol% phosphine ligand
at 15 bar syngas and 50 °C. As a starting point, we decided to
use these conditions for our hydroaminomethylation sequence,
with p‐anisidine as the model amine. A range of phosphine
ligands were initially tested. Disappointedly, we quickly found
that although the Rh‐phosphine catalyst promoted the hydro‐
formylation of styrene and the enamine was formed, hydro‐
genation of the latter was never observed, even in the presence
of an acid (Scheme 1). This may not be surprising as one of the
main problems with the hydroaminomethylation protocols is
the slow hydrogenation of the enamine/imine intermediate [9].
Knowing that the imine hydrogenation could be effected by
other catalysts, we then focused on the idea of using two dif‐
ferent catalysts, one for the hydroformylation and the other for
the hydrogenation step. In particular, List et al. [17] had devel‐
oped a protocol on asymmetric reductive amination of
α‐branched aldehydes via DKR, in which a chiral phosphoric
acid acted as the organocatalyst and a Hantzsch ester (HEH) as
the hydrogen source. This became our choice to effect the re‐
ductive amination step.
We combined the [Rh(acac)(CO)2] catalyst precursor with
PPh3, Et‐HEH and the phosphoric acid TRIP in toluene to ex‐
amine the reaction of p‐methylstyrene with p‐anisidine at 11
bar syngas and 50 °C (Scheme 3). The reaction mixture was left
stirring for 2 d. Delightfully, after flash chromatography purifi‐
cation, a promising 41% isolated yield was obtained for the
desired product 1a with a good enantioselectivity of 81% ee.
Encouraged by this result, optimisation of the conditions
was then undertaken, aiming to improve the yield and enanti‐
oselectivity. First, the effect of the HEH was studied. The results
are shown in Table 1. The reaction takes place under a syngas
pressure; therefore H2 could act as the reductant for the hy‐
drogenation step. However, the presence of HEH is essential in
this reaction, suggesting that the hydrogen source for the re‐
ductive amination or more precisely the reduction of the imino
bond comes from the HEH (entry 1). An excess of Et‐HEH pro‐
vides a positive effect on the yield (entry 2 vs entry 3). Whilst a
bulkier tBu‐HEH afforded an increase in the enantioselectivity
of the reductive amination of α‐branched aldehydes [17], very
low yield was obtained in our case (entry 5). A decrease in the
activity with bulkier HEH’s was also observed by List et al. [17].
The effect of the temperature was next examined. Although
better enantioselectivities were obtained at a low temperature
of 6 °C for the reductive amination step [17], the hydroam‐
(400 MHz, CDCl3) δ 1.30 (d, J = 6.9 Hz, 3H), 2.94–3.03 (m, 1H),
3.13 (dd, A of ABX, JAB = 12.2 Hz, JAX = 8.6 Hz, 1H), 3.28 (dd, B of
ABX, JAB = 12.2 Hz, JBX = 6.0 Hz, 1H), 3.80 (s, 3H), 6.41–6.45 (m,
2H), 6.86–6.88 (m, 2H), 7.11–7.14 (m, 2H), 7.20–7.24 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 20.3, 38.7, 51.4, 55.7, 109.2, 114.5,
114.9, 128.5, 132.3, 136.6, 147.5, 158.8; HRMS for C16H19BrNO
[M+H]+: m/z Calcd.: 320.0650; Found: 320.0659; HPLC
(Chiralcel OD‐H, hexane:isopropanol = 98:2, flow rate 0.5
mL/min, λ = 254 nm): tR = 23.0 min (minor), tR = 27.3 min
(major).
4‐Methoxy‐N‐(2‐(4‐(trifluoromethyl)phenyl)propyl)aniline,
1m. The product (54 mg, 70% yield, 81% ee) was obtained as a
colourless oil according to the general procedure in 3 d; 1H
NMR (400 MHz, CDCl3) δ 1.34 (d, J = 6.9 Hz, 3H), 3.08–3.17 (m,
1H), 3.22 (dd, A of ABX, JAB = 12.4 Hz, JAX = 8.2 Hz, 1H), 3.33 (dd,
B of ABX, JAB = 12.4 Hz, JBX = 6.0 Hz, 1H), 3.75 (s, 3H), 6.52–6.56
(m, 2H), 6.75–6.79 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.58 (d, J =
8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 19.5, 39.2, 51.8, 55.8,
114.5, 115.0, 124.3 (q, JCF = 268.9 Hz) 125.6 (q, JCF = 3.6 Hz),
127.8, 128.9 (q, JCF = 21.1 Hz), 141.9, 148.9, 152.3; HRMS for
C16H19BrNO [M+H]+: m/z Calcd.: 310.1419; Found: 310.1419;
HPLC (Chiralcel OD‐H, hexane:isopropanol = 98:2, flow rate 0.5
mL/min, λ = 254 nm): tR = 27.1 min (major), tR = 29.9 min
(minor).
N‐(2‐(4‐(Trifluoromethyl)phenyl)propyl)aniline, 1n. The
product (39 mg, 56% yield, 79% ee) was obtained as a
1
colourless oil according to the general procedure in 3 d; H
NMR (400 MHz, CDCl3) δ 1.35 (d, J = 6.9 Hz, 3H), 3.09–3.18 (m,
1H), 3.26 (dd, A of ABX, JAB = 12.6 Hz, JAX = 8.3 Hz, 1H), 3.37 (dd,
B of ABX, JAB = 12.6 Hz, JBX = 6.2 Hz, 1H), 3.52 (brs, 1H),
6.56–6.59 (m, 2H), 6.64–6.72 (m, 1H), 7.14–7.19 (m, 2H), 7.33
(d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 19.6, 38.6, 50.7, 112.9, 117.6, 125.6 (q, JCF = 3.8 Hz),
127.6, 129.0 (q, JCF = 30.6 Hz), 129.3, 147.7, 148.7 (The carbon
resonance CF3 was not observed, possibly due to overlap with
other aromatic carbon resonances); C16H17F3N [M+H]+: m/z
Calcd.: 280.1313; Found: 280.1307; HPLC (Chiralcel OD‐H,
hexane:isopropanol = 98:2, flow rate 0.5 mL/min, λ = 254 nm):
tR = 29.3 min (minor), tR = 33.7 min (major).
4‐Methoxy‐N‐(2‐(naphthalen‐2‐yl)propyl)aniline, 1p [17].
The product (59 mg, 81% yield, 83% ee) was obtained as a pale
1
yellow oil according to the general procedure in 3 d; H NMR
(400 MHz, CDCl3) δ 1.41 (d, J = 6.8 Hz, 3H), 3.18–3.26 (m, 1H),
3.29 (dd, A of ABX, JAB = 12.0 Hz, JAX = 8.4 Hz, 1H), 3.39 (dd, B of
ABX, JAB = 12.0 Hz, JBX = 5.7 Hz, 1H), 3.74 (s, 3H), 6.52–6.56 (m,
2H), 6.74–6.78 (m, 2H), 7.37 (dd, J = 8.5, 1.7 Hz, 1H), 7.43–7.50
(m, 2H), 7.66 (s, 1H), 7.81 (t, J = 8.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 19.9, 39.4, 51.8, 55.8, 114.4, 114.9, 125.5, 125.9, 126.1,
127.6(2), 127.6(4), 128.4, 130.2, 132.5, 133.6, 142.0, 142.3,
152.1; HRMS for C20H22NO [M+H]+: m/z Calcd: 292.1701;
Found: 292.1711; HPLC (Chiralcel OD‐H, hexane:isopropanol =
98:2, flow rate 0.5 mL/min, λ = 254 nm): tR = 36.4 min (major),

110
Barbara Villa‐Marcos et al. / Chinese Journal of Catalysis 36 (2015) 106–112
R
H
0.2 mol% [Rh(acac)(CO)2]
0.4 mol% PPh3, 5 mol% TRIP
OMe
O
N
O
O
P
+
OH
Et-HEH, 4
Å MS, toluene
H2N
OMe
11 bar syngas, 50 oC, 2 d
1a
41% yield, 81% ee
R
R: 2,4,6(C3H7)3-C6H2
TRIP
Scheme 3. Preliminary study of the metal‐ and organo‐catalysed asymmetric hydroaminomethylation.
inomethylation in question became much slower when the
temperature was dropped to 25 °C (3 d, 24% yield, 83% ee). As
maybe expected, a higher temperature of 80 °C led to a higher
yield but a slight decrease in enantioselectivity (2 d, 55% yield,
79% ee). Thus, a temperature of 50 °C was chosen which of‐
fered good enantioselectivities whilst maintaining a reasonable
rate of reaction.
asymmetric reductive amination of ketones [19,20]. Lower
yield was obtained when using electron‐deficient p‐bromoan‐
iline (entry 5), reflecting presumably the difficulty encountered
in the aldehyde‐amine condensation step. This was also ob‐
served by List et al. [17] in the organocatalytic reductive ami‐
nation of α‐branched aldehydes via DKR and in transition met‐
al‐ [2] and organo‐catalysed [21,22] asymmetric reductive
amination of ketones.
We next investigated the asymmetric hydroaminomethyla‐
tion of different derivatives of styrene with aniline and its ana‐
logues (Table 4). Good yields and enantioselectivities were
obtained in general. A lower yield was obtained when using an
ortho‐substituted styrene (entry 2). This is due to the i/n selec‐
tivity in the hydroformylation step being lower as a result of
steric effects, with the ortho substituent inhibiting the for‐
mation of the benzylic Rh species that would favour producing
the branched aldehyde [23,24]. In fact, when hydroformylation
of p‐methyl and o‐methylstyrene was compared, the i/n selec‐
tivity decreased from 13:1 to 7:1. Similar to what is shown in
Table 3, electron‐deficient groups in the aniline ring have a
detrimental effect on the yield (Table 4, entries 7 and 10). As
mentioned, this is likely to result from an inefficient condensa‐
tion step [17,22]. The same could be expected from elec‐
tron‐deficient groups in the styrene ring (entries 8–10) [17].
Table 2 shows the effect of phosphine ligands in this asym‐
metric hydroaminomethylation. Monophosphine ligands are in
general superior compared to diphosphines (entries 1–3 vs
4–8). Within the derivatives of PPh3, a more electron‐donating
substituent in the ligand leads to an increase in yield (entry 8),
whilst an electron‐deficient substituent has a negative effect on
the yield (entry 7). The increase in yield stems from a higher
selectivity for the branched aldehyde in the hydroformylation
step. Moser and co‐workers [18] showed that p‐electron‐do‐
nating groups in the phosphine increase the basicity of the
phosphine and the selectivity for α‐branched aldehydes.
With the outcome of optimisation in hand, we then explored
the scope of the methodology using a range of styrenes and
anilines. Table 3 shows the effect of substituents at the aniline
on the hydroaminomethylation of p‐methylstyrene. All the
products 1a–e were obtained with good enantioselectivity
(78%–86% ee). Better enantioselectivities were obtained when
more sterically‐hindered anilines were used (entry 1 vs 2, entry
3 vs 4), and this observation was previously noted in the
Table 2
Effect of ligands on the model asymmetric hydroaminomethylation.
Table 1
Effect of Hantzsch esters on the model asymmetric hydroaminomethyl‐
ation.
Entry
Ligand
DPPP
DPPB
XANTPHOS
A
Isolated yield (%)
1
2
3
4
5
6
7
8
N.R.a
N.R.a
20
<5
43
eea (%)
N.D.c
81
Isolated yield
Entry
Eqs. Et‐HEH
1
2
3
4
5
—
N.R.b
40
1.2
2.2
4.0
1.2d
67
64
< 10
80
80
N.D.c
B
PPh3
30
P(4‐CF3C6H4)3
P(4‐MeOC6H4)3
25
48
Reaction conditions: 0.4 mmol p‐methylstyrene, 0.25 mmol p‐anisidine,
1.25 μmol [Rh(acac)(CO)2], 2.5 μmol PPh3, Et‐HEH (unless otherwise
specified), 12.5 μmol TRIP, 100 mg 4 Å MS, 4 mL toluene, 11 bar CO/H2
1:1, 50 °C, 2 d.
Reactions conditions: the same as those in Table 1 except with different
phosphine ligand, 0.6 mmol Et‐HEH and 17 h reaction time.
a No desired reaction; only linear product observed.
a Determined by HPLC. b No reaction. c Not determined. d tBu‐HEH used.

Barbara Villa‐Marcos et al. / Chinese Journal of Catalysis 36 (2015) 106–112
111
Table 3
Table 4
Asymmetric hydroaminomethylation of p‐methylstyrene with different
Asymmetric hydroaminomethylation of different derivatives of styrene.
anilines.
H
N
[Rh]
R
+
R'
R'
R
HEH, CO/H2
H2N
Isolated ee a
yield (%) (%)
Entry
1
R
R’
Product
Isolated ee a
yield (%) (%)
Entry
1
R
Product
H
p‐OMe
80
83
p‐OMe
79
83
87
61
80
84
78
86
2
3
4
o‐Me m‐OMe
m‐Me p‐OMe
m‐Me m‐OMe
49
61
78
91
80
84
2
3
4
m‐OMe
m‐Me
o‐Me
5
m‐Me
H
56
80
5
p‐Br
45
79
6
7
8
p‐OMe p‐Me
p‐OMe p‐Br
p‐CF3 p‐OMe
61
51
70
82
84
81
Reactions conditions: the same as those in Table 1 except with 0.25
mmol aniline derivative, 2.5 μmol P(4‐CH3OC6H4)3, 0.6 mmol Et‐HEH
and 3 d reaction time.
a Determined by HPLC.
4. Conclusions
We have developed a new protocol that enables asymmetric
hydroaminomethylation of styrenes, affording β‐chiral amines
with good yields and enantioselectivities. To the best of our
knowledge, this is the first example of an asymmetric version of
this tandem reaction where significant enantioselectivities
have been achieved. The transformation is made possible by
combining metal‐ and organo‐catalysis, with the former cata‐
lysing the hydroformylation while the latter reductive amina‐
tion via DKR. The protocol provides an attractive pathway for
the synthesis of β‐chiral amines, as they can be obtained in one
step from easily available starting materials. The main draw‐
back of the protocol is the use of HEH as hydrogen source. A
single chiral metal complex to catalyse both steps will be more
desirable, and lead to a greener procedure with H2 as the only
hydrogen source.
9
p‐CF3
H
56
<5
81
79
N.D.b
83
10
11
p‐CF3 p‐Br
Rc p‐OMe
Reaction conditions: the same as those in Table 1 except with 0.4 mmol
styrene derivative, 0.25 mmol aniline derivative, 2.5 μmol
P(4‐CH3OC6H4)3, 0.6 mmol Et‐HEH and 3 d reaction time.
a Determined by HPLC.
b Not determined.
c 2‐Vinylnaphthalene (R: 3,4‐C4H4) used.
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Barbara Villa‐Marcos et al. / Chinese Journal of Catalysis 36 (2015) 106–112
Graphical Abstract
Chin. J. Catal., 2015, 36: 106–112 doi: 10.1016/S1872‐2067(14)60246‐1
Metal and organo‐catalysed asymmetric hydroaminomethylation of styrenes
Barbara Villa‐Marcos, Jianliang Xiao*
University of Liverpool, UK
H
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