A practical, solvent free, one-pot synthesis of C2-symmetrical secondary amines

Article abstract of DOI:10.1016/j.tetlet.2003.12.037

A novel one-pot reductive amination of ketones using the combination Ti(OⁱPr)₄/H₂/Pd-C is reported. This practical procedure does not require any solvent, and affords C₂-symmetrical secondary amines in high yields and excellent diastereoselectivities.

Full text of DOI:10.1016/j.tetlet.2003.12.037

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1449–1451
A practical, solvent free, one-pot synthesis of C2-symmetrical
secondary amines
a
a
a
Alexandre Alexakis,a, Segolene Gille, Fabrice Prian, Stephane Rosset
*
ꢀ
ꢁ
ꢀ
and Klaus Ditrichb
aUniversity of Geneva, Department of Organic Chemistry, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland
bBASF Aktiengesellschaft GVF/E-A030, Ludwigshafen D-67056, Germany
Received 10 November 2003; revised 2 December 2003; accepted 9 December 2003
Abstract—A novel one-pot reductive amination of ketones using the combination Ti(OiPr)4/H2/Pd–C is reported. This practical
procedure does not require any solvent, and affords C2-symmetrical secondary amines in high yields and excellent diastereoselec-
tivities.
Ó 2003 Elsevier Ltd. All rights reserved.
In 1980 Whitesell and Felman described the first use
of the C2-symmetrical amine 1 in the enantioselective
Et
deprotonation of cyclohexene oxide.1 This chiral auxil-
iary had a tremendous influence on the later design of
chiral amines. There are numerous applications of 1 as a
chiral base,2 as a nucleophile, as a ligand or as a struc-
tural part of a ligand.3 The preparation of 1 is
straightforward, and corresponds to the general
approach toward the synthesis of secondary amines.4
In connection with our program on chiral ligands
for copper-catalyzed asymmetric transformations, we
needed a simple and efficient way to prepare amine 2,
the ethyl homologue of 1.
Ph
Ph
N
Ph
Ph
A
B
4
Ph
NH2
Ph
N
H
Ph
H
2
3
N
5
Scheme 1.
but the subsequent nucleophilic addition proceeded with
poor diastereoselectivity. This result was not surprising:
indeed, Yamada et al. showed that a bulky chiral aux-
iliary such as the a-naphthylethyl group was necessary
to induce high diastereoselectivity in this type of asym-
metric reaction.5
Ph
NH2
Ph
N
H
Ph
Ph
N
H
Ph
1
2
3
The unsatisfactory results obtained using path A
prompted us to investigate the alternative reductive
alkylation of amine 3. Path B has already been explored
by Yoshida and Harada for the preparation of amine 2,6
following the two-step procedure developed before for
amine 1.4 Good stereoselectivities have been obtained by
this procedure, but the synthesis of imine 5 starting from
propiophenone required harsh conditions: the use of
a catalytic amount of p-toluenesulfonic acid at reflux
with a Dean–Stark trap to remove water, for several
days.
Starting from commercially available 3, two synthetic
pathways were possible (Scheme 1).
Path A needed the preparation of chiral imine 4, starting
from benzaldehyde. This was an easy and fast reaction,
Keywords: Reductive amination; C2-symmetry; Chiral amines; Tita-
nium isopropoxide.
* Corresponding author. Tel.: +41-22-379-65-22; fax: +41-22-379-
32-15; e-mail: alexandre.alexakis@chiorg.unige.ch
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.037

1450
A. Alexakis et al. / Tetrahedron Letters 45 (2004) 1449–1451
Table 2. Effect of the solvent on the diastereoselectivity of formation
of amine 1
1) Ti(OiPr)4 (3 eq.),
no solvent
+
Ph
N
H
Ph
O
Ph
Ph NH2
1) Ti(OiPr)4 (4 eq.),
solvent
2) 10% Pd/C (0.5 mol%),
H2, 1 atm , rt
(S)-3
+
Ph
N
H
Ph
6
(S,S)-2
O
Ph
Ph NH2
2) 10% Pd/C (0.5 mol%),
H2, 1 atm, rt
(1 eq.)
(1 eq.)
yield 92%
d.r. 91/9
8
(S)-7
(S,S)-1
(1 eq.)
(1 eq.)
Scheme 2. Diastereoselective synthesis of (S,S)-2 using the combina-
tion Ti(OiPr)4/H2/Pd–C.
Entry
Solventa
Conversionb (%)
Drc (S,S)/(S,R)
1
2
3
4
EtOH
Toluene
AcOEt
THF
>99
>99
>99
>99
91:9
71:29
85:15
85:15
Recently, a high yielding, single-step reductive amina-
tion of carbonyl compounds has been reported, using
polymethylhydrosiloxane (PMHS) as reductant and
titanium(IV) isopropoxide (Ti(OiPr)4) as activator.7
This latter reagent was already known as a mild and
efficient Lewis acid catalyst for imine (or a titanium
complex intermediate) formation,8 but it has also been
identified as a good activator for PMHS.
a [7] ¼ 4 M.
b Determined by GC/MS analysis.
c Determined by GC/MS analysis and 1H NMR spectroscopy.
Thus, in preliminary reactions, the synthesis of 2 was
carried out following this one-step procedure, but the
results were not satisfactory. Other reducing reagents
were then tested and we were pleased to find that (S,S)-2
could be obtained from amine (S)-3 and propiophenone
6 with a high level of stereoselectivity (91:9 dr) using the
combination Ti(OiPr)4/H2/Pd–C [Ti(OEt)4 works
equally well] (Scheme 2). It should be pointed out that
this reaction was performed without additional solvent.
According to the experiments shown in Table 2, a polar
and protic solvent such as ethanol was required to
maintain the diastereoisomeric ratio at its highest level
(entry 1 vs entries 2–4). However, from a practical point
of view, addition of ethanol to the reaction medium
made the process very sluggish, which renders any large-
scale synthesis impractical by this method. A good
compromise was the use of ethyl acetate, which is the
extraction solvent and which does not significantly
decrease the stereoselectivity (entry 3).
Optimization studies were carried out in order to
determine the effect of the amount of Ti(OiPr)4, and the
results are outlined in Table 1. Having stated that
Ti(OiPr)4 is absolutely necessary for the reaction to
occur (entry 1), it was noticed that the diastereoisomeric
ratio was not dramatically influenced by the amount of
Ti(OiPr)4 employed (entries 2–7). However, a problem
of solidification of the reaction mixture arose as the
quantity decreased, since Ti(OiPr)4 may play the role of
solvent.
As a consequence of these preliminary studies, the syn-
thesis of several chiral C2-symmetrical secondary amines
was undertaken (Table 3).9;10 Good yields and good
diastereoisomeric ratios were obtained, probing the
efficiency of this one-pot reductive amination. It should
be noted that the preparation of (1S,10S)-bis[1-(2-
naphthyl)ethyl]amine 11 was performed in the presence
of ethyl acetate as the corresponding substrates formed
an insoluble intermediate.
To overcome this solidification problem encountered in
substoichiometric reactions, we decided to add a sol-
vent, studying first its effect on the diastereoselectivity.
These amines could be purified by recrystallization of
their hydrobromide or hydrochloride salts in ethyl
acetate/methanol [85/15 to 75/25 (v/v)] to afford dia-
stereomerically pure C2-symmetrical secondary amines.
Thus, amines (S,S)-2 (99.5:0.5 dr) and (S,S)-11 (99.5:0.5
dr) were obtained, respectively, in 51% and 63% yields.
Table 1. Effect of the amount of Ti(OiPr)4 on the diastereoselectivity
of formation of amine 1
1) Ti(OiPr)4, no solvent
In conclusion, a high yielding, simple and diastereo-
selective synthesis of various C2-symmetrical secondary
amines was developed via one-pot reductive amination
using the combination Ti(OiPr)4/H2/Pd–C. This proce-
dure is not only economical, but also environment-
friendly since it does not require any solvent.11
+
Ph
N
H
Ph
O
Ph
Ph NH2
2) 10% Pd/C (0.5 mol%),
H2, 1 atm, rt
(S)-7
(1 eq.)
8
(S,S)-1
(1 eq.)
Ti(OiPr)4 (equiv) Conversiona (%) Drb (S,S)/(S,R)
Entry
1
2
3
4
5
6
7
0
0
>99
>99
>99
>99
>99
>99
––
6
85:15
88:12
89:11
83:17
84:16
85:15
4
3
2
Acknowledgements
1
0.5
We thank BASF for its generous gift of chiral amines.
We also thank the Swiss National Science Foundation
(grant no 20-61891-00) for financial support.
a Determined by GC/MS analysis.
b Determined by GC/MS analysis and 1H NMR spectroscopy.

A. Alexakis et al. / Tetrahedron Letters 45 (2004) 1449–1451
Table 3. Diastereoselective synthesis of some C2-symmetrical secondary amines 2, 9–11
1451
1) Ti(OiPr)4 (3 eq.)
no solvent
R
R
R
R
+
Ar
N
H
Ar
O
Ar
Ar NH2
2) 10% Pd/C (0.5 mol%),
H2, 1 atm , rt
(S)-amine
(S,S)-2, 9-11
ketone
(1 eq.)
conv >99%
(1 eq.)
Entry
Ar
Ph
R
Solventa
Product10
Yield (%)
Drb
N
H
1
Et
––
92
91:9
2
OMe
OMe
N
H
9
2
3
o-MeOC6H4
Me
Me
––
––
88
90
87:13
94:6
1-Naphthyl
N
H
10
N
H
4
2-Naphthyl
Me
EtOAc
90
85:15
11
a [(S)-Amine] ¼ 4 M.
b Determined by GC/MS analysis and 1H NMR spectroscopy.
20 min. The mixture was then hydrogenated at 1 atm with
10% palladium-on-charcoal (500 mg, 0.5 mol %) under
vigorous stirring at room temperature. The reaction
course was monitored by GC/MS. At complete conver-
sion, the reaction mixture was treated with an aqueous
solution of 1 M sodium hydroxide (150 mL). After stirring
for 10 min, the solution was extracted five times with ethyl
acetate. The combined organic layers were filtered over
Celite, dried over Na2SO4, and finally evaporated under
References and notes
1. Whitesell, J. K.; Felman, S. W. J. Org. Chem. 1980, 45, 755.
2. (a) OÕBrien, P. Tetrahedron 2002, 58(23), Symposium-in-
Print, Recent Developments in Chiral Lithium Amide
Base Chemistry, pp 4567–4733; (b) OÕBrien, P. J. Chem.
Soc., Perkin Trans. 1 1998, 1439; (c) OÕBrien, P. J. Chem.
Soc., Perkin Trans. 1 2001, 95.
3. (a) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M.
J. Am. Chem. Soc. 2002, 124, 5262; (b) Alexakis, A.;
Rosset, S.; Allamand, J.; March, S.; Guillen, F.; Benhaim,
C. Synlett 2001, 1375.
reduced pressure.
20
D
10. Compound 2: colorless oil; ½aꢀ +159° (c 13.5, CHCl3); 1H
NMR (400 MHz, CDCl3) d 0.75 (6H, t, J ¼ 7:4 Hz), 1.55–
1.68 (5H, m), 3.21 (2H, t, J ¼ 7:0 Hz), 7.18–7.37 (10H, m)
ppm; 13C NMR (100 MHz, CDCl3) d 10.9, 31.5, 61.4,
4. Overberger, C. G.; Marullo, N. P.; Hiskey, R. G. J. Am.
Chem. Soc. 1961, 83, 1374.
126.7, 127.4, 128.2, 144.6 ppm. Compound 11: colorless
5. Yamada, H.; Kawate, T.; Nishida, A.; Nakagawa, M.
J. Org. Chem. 1999, 64, 8821.
6. Yoshida, T.; Harada, K. Bull. Chem. Soc. Jpn. 1972, 45,
3706.
7. Chandrasekhar, S.; Reddy, C. R.; Ahmed, M. Synlett
2000, 1655.
8. Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A.
J. Org. Chem. 1990, 55, 2552.
9. Synthesis of (1S,10S)-bis(1-phenylpropyl)amine [(S,S)-2].
Typical procedure (Table 3, entry 1). A mixture of
propiophenone (14.9 g, 0.11 mol), (S)-a-phenylpropyl-
amine (15.1 g, 0.11 mol) and titanium(IV) isopropoxide
(100 mL, 0.33 mol) was stirred at room temperature for
20
D
oil; ½aꢀ )335° (c 16.5, CHCl3); 1H NMR (400 MHz,
CDCl3) d 1.44 (6H, d, J ¼ 6:7 Hz), 1.83 (1H, br s), 3.77
(2H, q, J ¼ 6:7 Hz), 7.49–7.55 (6H, m), 7.65 (2H, br s),
7.85–7.93 (6H, m) ppm; 13C NMR (100 MHz, CDCl3) d
24.8, 55.2, 124.7, 125.4, 125.9, 127.6, 127.7, 128.2, 132.7,
133.4, 143.0 ppm; Amines 10 and 11 were characterized by
comparison of their spectral data with those reported. For
amine 10, see: Saudan, L. Ph.D. Dissertation 3013,
University of Geneva, Geneva, 1998. For amine 11, see:
Yamada, H.; Kawate, T.; Nishida, A.; Nakagawa, M.
J. Org. Chem. 1999, 64, 8821.
11. Ti(OR)4 is considered as nontoxic waste.