Synthesis of hindered tertiary amines by a mild reductive amination procedure

Article abstract of DOI:10.1016/j.tetlet.2006.11.082

An efficient metal-free procedure for the synthesis of tertiary amines by the reductive amination of carbonyl compounds is reported, which allows a convergent access to sterically hindered amines of the general formulas NR(R′)₂ and NRR′R″. The mild and operationally simple protocol uses the Hantzsch ester for transfer hydrogenation and catalytic amounts of thiourea for imine activation.

Full text of DOI:10.1016/j.tetlet.2006.11.082

Tetrahedron Letters 48 (2007) 365–369
Synthesis of hindered tertiary amines by a mild
reductive amination procedure
*
Dirk Menche, Stefanie B o¨ hm, Jun Li, Sven Rudolph and Wiebke Zander
Helmholtz-Zentrum f u¨ r Infektionsforschung GmbH, Medizinische Chemie, Inhoffenstr. 7, 38124 Braunschweig, Germany
Received 27 October 2006; revised 10 November 2006; accepted 14 November 2006
Available online 1 December 2006
Abstract—An efficient metal-free procedure for the synthesis of tertiary amines by the reductive amination of carbonyl compounds
0
0 00
is reported, which allows a convergent access to sterically hindered amines of the general formulas NR(R ) and NRR R . The mild
2
and operationally simple protocol uses the Hantzsch ester for transfer hydrogenation and catalytic amounts of thiourea for imine
activation.
Ó 2006 Elsevier Ltd. All rights reserved.
Tertiary amines are key structural elements in synthetic
reagents (e.g., 1, Fig. 1) and numerous biologically ac-
and aldehydes for the synthesis of secondary aromatic
1
5,6
amines.
This method uses the Hantzsch ester for
tive natural products and pharmaceuticals like the clin-
ically used antibiotic ciproflaxin (2), which renders their
transfer hydrogenation and proceeds in the presence of
molecular sieves and catalytic amounts of thiourea for
imine activation. The efficiency and wide applicability
of this procedure to various substrates, including poly-
functional, as well as unreactive aldehydes and amines,
prompted us to investigate whether this approach could
also be extended to tertiary amines.
2
synthesis an objective of high priority from the perspec-
tive of organic and medicinal chemistry. The direct
reductive amination of carbonyls is widely recognized
as one of the most convergent and simple procedures
for the synthesis of amines and a number of procedures
have been developed to carry out such a process in a
3
–5
one-pot fashion
While many applications for the
As a first target we studied the access to aromatic amines
0
preparation of primary and secondary amines have been
reported, the synthesis of tertiary amines using such pro-
tocols is much less developed, due to increased steric
hindrance. This is particularly true for the amination
of alpha-branched carbonyls and preparation of aro-
matic amines.
of the general type NR(R ) by the reaction of a primary
2
amine (3) with two (or more) equivalents of a carbonyl
fragment (4, Table 1). For this purpose, the preparation
of tertiary amine 7a by the condensation of para-anisi-
dine (3a) with benzaldehyde (4a) in the presence of
˚
Hantzsch ester (5), 5 A molecular sieves and catalytic
amounts of thiourea (6) was evaluated. After developing
reaction conditions, the desired synthesis of tertiary
amine 7a proceeded in an essentially quantitative man-
ner. Optimum conditions included a slight excess of
the aldehyde (2.2 equiv) and the Hantzsch ester
Herein, we report an efficient direct reductive amination
procedure for the synthesis of sterically demanding ter-
tiary amines under mild and operationally simple
conditions.
Based on an innovative biomimetic approach, we have
recently developed an amination procedure of ketones
O
F
CO H
2
NR
N
Keywords: Organocatalysis; Synthetic methodology; Tertiary amines;
Reductive amination; Hantzsch ester.
HN
*
Corresponding author. Tel.: +49 531 9407; fax: +49 531 9499; e-mail:
dirk.menche@helmholtz-hzi.de
1
Ciproflaxin (2)
Recently renamed from Gesellschaft f u¨ r Biotechnologische For-
schung mbH.
Figure 1. Tertiary amines: key structural elements in synthetic reagents
such as 1 and bioactive structures (e.g., 2).
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.082

366
D. Menche et al. / Tetrahedron Letters 48 (2007) 365–369
0
a
2
Table 1. Synthesis of tertiary amines of the type: NR(R )
H H
EtO C
CO Et
2
2
R1
H N
R2
2
N
H
3
R1
5
R3
N
+
S
R2
R3
O
2
H N
6
NH2
(0.1 eq)
Å MS
2
R2
R3
7
4
5
c
Entry
1
Amine 3
Carbonyl 4
Product amine 7
Yield (%)
OMe
O
H
OMe
OMe
N
90
H N
2
3
a
a
4a
7a
OMe
O
2
3
H
N
73
82
H N
2
3
4b
7b
O
N
H
H N
2
3
b
b
4a
7
c
O
N
4
5
H
O
64
H N
2
3
4b
7d
OMe
OMe
OMe
N
N
b
<5
H N
2
3
a
a
4c
7e
OMe
O
O
H
6
63
H N
2
3
O
4d
O
7
f
a
b
c
6,10
Reaction conditions: 1 mmol amine, 2.2 mmol carbonyl compounds, 2.4 mmol Hantzsch ester, 0.1 mmol thiourea; toluene, 60 °C, 24–72 h.
Only monoalkylation was observed.
Isolated yield after column chromatography.
(
2.4 equiv) in toluene at 60 °C, which is slightly lower
branched substrates (4a,b, e.g., entries 2 and 4) as well
as electronically less rich amines (entries 3 and 4). In
all examples, the desired tertiary amines (i.e., 5b–d) were
obtained in high yields. The observation, that ketones
could not be converted to the tertiary products (entry 5)
under these conditions, leading only to monoalkylation,
opened the possibility to selectively react mixed sub-
strates, such as 4d incorporating both an aldehyde as
well as a ketone functionality (entry 6). This allowed ac-
cess to the desired polysubstituted amine 7f as the main
when compared to the previously devised conditions
for the synthesis of secondary amines.
conditions a complete conversion to the tertiary amine
was observed. In particular, no trace of the intermediate
secondary amine was detectable by NMR of the crude
product.
7
–9
Under these
1
0
Under these conditions a variety of amines and alde-
hydes may be converted, including aliphatic alpha-

D. Menche et al. / Tetrahedron Letters 48 (2007) 365–369
367
0
00
a
Table 2. Synthesis of tertiary amines of the type: NRR R
R1
R2
O
R1
R3
R2
5
N
H
8
N
+
R3
H
6
(0.1 eq)
5 Å MS
4
9
b
Entry
1
Amine 8
Aldehyde 4
Product amine 9
Yield (%)
OMe
OMe
O
H
N
N
77
H
4b
8
a
9
a
OMe
OMe
O
2
H
N
75
N
H
4b
8b
9
b
O
N
N
3
4
N
H
H
O
63
79
4
b
8c
9
c
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
N
H
4a
8d
9d
O
5
6
H
N
75
86
N
H
4
b
8d
9
e
OMe
OMe
OMe
O
N
H
N
H
O N
2
O N
4a
2
8e
9
f
OMe
OMe
O
7
8
9
H
N
N
82
84
56
N
H
4b
O N
2
O N
2
8e
9
g
g
OMe
O
H
N
H
O N
O N
2
2
4e
8f
9
OMe
OMe
O
N
N
H
H
4b
8g
9
h
a
10,11
Reaction conditions: 1 mmol amine, 1.2 mmol of carbonyl compound, 1.4 mmol Hantzsch ester, 0.1 mmol thiourea; toluene, 60 °C, 24–72 h.
Isolated yield after column chromatography.
b

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D. Menche et al. / Tetrahedron Letters 48 (2007) 365–369
product, which was obtained in preparatively useful
yields. This demonstrates the general functional group
tolerance of our method, which together with the mild
conditions adds to the overall efficiency of our
procedure.
C. O. Eur. J. Med. Chem. 2000, 35, 1043; de Vries, J. G.
Can. J. Chem. 2001, 79, 1086; Newman, D. J.; Cragg, G.
M.; Snader, K. M. J. Nat. Prod. 2003, 66, 1022.
. For reviews, see: (a) Martens, J. In Houben-Weyl, 4th ed.;
Thieme: Stuttgart, 1995; Vol. E21d, p 4199; (b) Baxter, E.
W.; Reitz, A. B. In Organic Reactions; Wiley: New York,
3
2
002; Vol. 59, p 1; (c) Gomez, S.; Peters, J. A.; Masch-
With this method in hand, we then proceeded to further
study and expand the applicability also for the synthesis
meyer, T. Adv. Synth. Catal. 2002, 344, 1037; (d) Tararov,
V. I.; Kadyrov, R.; Riermeier, T. H.; Fischer, C.; B o¨ rner,
A. Adv. Synth. Catal. 2004, 346, 561; (e) Ohkuma, T.;
Noyori, R. In Comprehensive Asymmetric Catalysis; Jac-
obsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
New York, 2004.
0
00
of trisubstituted amines of the general type NRR R by
1
1
the reaction of a secondary amine (8) with an addi-
tional aldehyde component under similar reductive con-
ditions as developed above (Table 2). To obtain full
conversion on a reasonable time scale, using 1.2 equiv
of the aldehyde and 1.5 equiv of the reducing agent
proved beneficial. In all cases, the desired trisubstituted
amines (9) were obtained in good (entries 1–8) to useful
4
. For selected more recent examples, see: (a) Gross, T.;
Seayad, A. M.; Ahmad, M.; Beller, M. Org. Lett. 2002, 4,
2
055; (b) Miriyala, B.; Bhattacharyya, S.; Williamson, J. S.
Tetrahedron 2004, 60, 1463; (c) Itoh, T.; Nagata, K.;
Miyazaki, M.; Ishikawa, H.; Kurihara, A.; Ohsawa, A.
Tetrahedron 2004, 60, 6649.
1
2
(
entry 9) yields. Both aliphatic and aromatic aldehydes
and amines are accepted as substrates (e.g., entries 1–3)
and variations in the electronic and steric properties are
tolerated (entries 4–8). The order of attaching the alde-
hyde component appears to have no influence on the
isolated yield (entries 7 and 8). Notably, also alpha-
branched amines such as 8g (entry 9), which may be
readily obtained by the reductive amination of the
5
. (a) Menche, D.; Arikan, F. Synlett 2006, 6, 841; (b)
Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.;
Rudolph, S. Org. Lett. 2006, 8, 741.
6. For recent work on the use of the Hantzsch ester for
reductive aminations in the presence of chiral phosphoric
acids, see: (a) Hoffmann, S.; Seayad, A.; List, B. Angew.
Chem., Int. Ed. 2005, 44, 7424; (b) Storer, R. I.; Carrera,
D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc.
5
b
respective ketones as previously described,
are
2
006, 128, 84; (c) Hoffmann, S.; Nicoletti, M.; List, B. J.
alkylated under these conditions to give the desired
products (9h). This demonstrates the usefulness of our
method also to particularly sterically demanding tertiary
amines.
Am. Chem. Soc. 2006, 128, 13368.
7
. General procedure: A solution of the amine (3a–b,
1
.00 mmol) and the carbonyl component (4a–d,
2.20 mmol) in toluene (5 mL) was treated with the
Hantzsch ester (3, 760 mg, 2.40 mmol), thiourea (4,
˚
In conclusion, we have developed an efficient procedure
for the synthesis of structurally diverse tertiary amines
7.6 mg, 0.100 mmol) and MS 5 A (1.0 g) and the mixture
was stirred under nitrogen at 60 °C until complete
conversion (24–72 h). After filtration over Celite, the
solvent is evaporated and the residue purified by flash
chromatography on silica gel using mixtures of petroleum
ether and ethyl acetate as eluants to give the product
amines (7a–f) in a pure form.
. The use of only 2 equiv of the carbonyl component leads
to a decrease in the isolated yields, in particular when
volatile aldehydes are used.
9. The second amination step is much slower due to steric
reasons, which allows a selective amination for the
synthesis of secondary amines, as previously reported:
see Ref. 5. For optimum conversion also in the second
amination step, thiourea is crucial.
0
0
00
of the general formulas NR(R ) and NRR R , includ-
2
ing aromatic and sterically demanding amines. The
operationally simple procedure uses the Hantzsch ester
for transfer hydrogenation and proceeds in the presence
of molecular sieves and thiourea. The mild conditions
and chemoselectivity of this protocol should enable
applications also to complex and/or acid-sensitive sub-
strates. It is expected, that this method opens the venue
for further exploring sterically hindered tertiary amines
as synthons for preparative and medicinal chemistry.
8
1
0. All new compounds had spectroscopic data in support of
Acknowledgments
1
the assigned structures. Examplary data: 7a: H NMR d
(
300 MHz, CDCl ): 7.28 (m, 10H), 6.76 (d, J = 9.2 Hz,
3
We thank the Fonds der Chemischen Industrie (‘Liebig-
Stipendium’ to D.M.) and the Deutsche Forschungs-
gemeinschaft (Grant: ME 2765/2-1) for financial
support. Furthermore, this work was supported by the
HZI. We thank Antje Ritter and Tatjana Arnold for
technical support and Fatih Arikan for fruitful discus-
sion. Thanks is also due to C. Kakoschke and B. Jas-
chok-Kentner for recording NMR spectra.
2
H), 6.69 (d, J = 9.2 Hz, 2H), 4.55 (s, 4H), 3.72 (s, 3H);
1
3
C NMR d (75 MHz, CDCl ): 151.9, 143.9, 139.1,
3
128.6, 127.0, 126.9, 114.8, 114.7, 55.8, 55.2; HRMS
(ESI): m/z: calcd for C21
3
7
J = 8.7 Hz, 2H), 4,61 (s, 4H), 2.22 (s, 3H); C NMR
d (75 MHz, CDCl ): 147.2, 139.0, 129.8, 128.6, 126.8,
1
C H21N [M] : 287.1674. Found: 287.1674. Compound
9
1H), 6.82 (m, 2H), 6.75 (d, J = 9.2 Hz, 2H), 6.54 (d,
J = 9.2 Hz, 2H), 4.50 (s, 2H), 3.86 (s, 3H), 3.71 (s, 3H),
3.15 (d, J = 8 Hz, 2H), 2.10 (dt, J = 7.0, 8.0 Hz, 1H),
+
H
21NO [M] : 303.1623. Found:
1
03.1626. Compound 7c: H NMR d (300 MHz, CDCl
3
):
.26 (m, 10H), 6.97 (d, J = 8.7 Hz, 2H), 6.66 (d,
13
3
26.1, 112.9, 54.5, 20.2; HRMS (ESI): m/z: calcd for
+
21
1
e: H NMR d (300 MHz, CDCl ): 7.16 (m, 1H), 7.0 (m,
3
References and notes
1
. (a) Hawkins, J. M.; Lewis, T. A. J. Org. Chem. 1994, 59,
49; (b) Ooi, T.; Uematsu, Y.; Maruoka, K. J. Am Chem.
1
3
6
0.96 (d, J = 7.0 Hz, 6H); C NMR d (75 MHz, CDCl ):
3
Soc. 2006, 128, 2548.
157.3, 150.9, 143.8, 127.6, 127.4, 126.7, 120.3, 114.8,
2
. (a) Wolfson, J. S.; Hooper, D. C. Clin. Microbiol. Rev.
113.5, 109.9, 60.4, 55.8, 55.2, 50.9, 27.6, 20.6; HRMS
+
1989, 2, 378; For some further examples, see: (b) Kappe,
(ESI): m/z: calcd for C19
H25NO
2
[M+H] : 300.1964.

D. Menche et al. / Tetrahedron Letters 48 (2007) 365–369
369
1
Found: 300.1962. Compound 9g: H NMR d (300 MHz,
CDCl ): 8.12 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 9.2 Hz,
H), 6.76 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H),
.54 (s, 2H), 3.72 (s, 3H), 3.11 (d, J = 7.1 Hz, 2H), 2.04
12. General procedure: A solution of the secondary amine (8a–
e, 1 mmol) and the aldehyde (4a/b/e 1.2 mmol) in toluene
(5 mL) was treated under nitrogen with the Hantzsch ester
(3, 390 mg, 1.50 mmol), thiourea (4, 7.6 mg, 0.100 mmol)
3
2
4
1
3
˚
(
m, 1H), 0.94 (d, J = 6.61 Hz, 6H); C NMR d (75
MHz, CDCl ): 152.1, 147.6, 147.1, 142.9, 127.7, 123.8,
15.3, 114.8, 61.1, 56.4, 55.7, 27.5, 20.8; HRMS (ESI):
and MS 5 A (1.0 g) and the mixture was stirred at 60 °C
3
until completion of the reaction (24–72 h). After filtration
over Celite, the solvent is evaporated and the residue
purified by flash chromatography on silica gel using
mixtures of petroleum ether and ethyl acetate as eluents
to give product amines (9a–h) in a pure form.
1
+
m/z: calcd for C18
14.1634.
1. For the synthesis of the secondary amines, see Ref. 5.
22 2 3
H N O [M] : 314.1630. Found:
3
1