Direct reductive amination of aldehydes and ketones mediated by a thiourea derivative as an organocatalyst

Article abstract of DOI:10.3184/030823409X12561332783406

The direct reductive arylamination of arylaldehydes and ketones has been achieved using a selective imine activation by a hydrogen bond of a thiourea derivative. This mild, acid- and metal-free process requires a catalytic amount of N N′-bis[3,5-bis(trifluoromethyl)phenyl]thiourea, the Hantzsch 1,4-dihydropydine diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate as hydride source and activated 5A-molecule sieve as dehydrant. The method is adaptable for the synthesis of various amines.

Full text of DOI:10.3184/030823409X12561332783406

686 RESEARCH PAPER
NOVEMBER, 686–688
JOURNAL OF CHEMICAL RESEARCH 2009
Direct reductive amination of aldehydes and ketones mediated by a
thiourea derivative as an organocatalyst
Yi-Bo Huang and Chun Cai*
School of Chemical Engineering, Nanjing University of Science & Technology, Nanjing 210094, P.R. China
The direct reductive arylamination of arylaldehydes and ketones has been achieved using a selective imine
activation by a hydrogen bond of a thiourea derivative. This mild, acid- and metal-free process requires a catalytic
amount of N,N'-bis[3,5-bis(trifluoromethyl)phenyl]thiourea, the Hantzsch 1,4-dihydropydine diethyl 1,4-dihydro-2,6-
dimethyl-3,5-pyridinedicarboxylate as hydride source and activated 5Å-molecule sieve as dehydrant. The method is
adaptable for the synthesis of various amines.
Keywords: thiourea derivative, reduction, organocatalyst, hydrogen bond, amination
Chiral amines are key structural units in many biologically
active natural products and pharmaceuticals.1,2 Reductive
amination is an effective method for the synthesis of various
amines in which the carbonyl component is treated with an
amine and reductant in a “one-pot” fashion. Thus, many
methods have been reported to accomplish this direct
process.3-6 Some classic methods such as the procedure of
Borch7,8 rely on a Brønsted acid or Lewis acid to facilitate
the formation of the intermediate imines and to activate the
C=N for preferential reduction in the presence of a carbonyl
compound.
Nevertheless, application of these methods to sensitive,
acid-labile or polyfunctional substrates is limited. Many of
these procedures seem not to be adaptable for asymmetric
variants.3 This leads to the development of novel catalysts for
a mild direct reductive amination.
We report here the direct reductive amination of aldehyde
and ketone based on a hydrogen bond for imine activation,
based on Menche's reports of thiourea-catalysis applied
to the direct reductive amination.9,10 In Menche's reports,
this acid-free reaction is mediated by thiourea as a simple
organocatalyst. Unfortunately the reaction time was long
and the catalyst loading was large. We considered that a
some modified thiourea derivative might catalyse these
reactions,11-14 and thought that an electron-deficient
thiourea derivative could accelerate this process effectively.
In addition, we examined the scope of the method for the
synthesis of various amines is described in our studies.
Biosynthetically, amines may be derived by the reductive
amination of carbonyl groups by NADH-transferases or by
the vitamin B6 pathway.15 During the biosynthetic process
NADH acts as reducing agent and some enzyme may activate
the imine by hydrogen bond. To mimic the key feature
of biosynthetic pathway, the combination of a Hantzsch
1,4-dihydropydine and thiourea derivative was selected as the
basis for our studies.
acid activation16 of the imine significantly improved this
result. The groups of Rueping17 and List18 have recently
reported on the organocatalytic, asymmetric hydrogenation
of imines by 3 in the presence of a chiral Brønsted acid.
Unfortunately, these methods have not been adaptable for
direct reductive amination.
We studied the direct reductive amination of aldehydes
and ketones mediated by N,N'-bis[3,5-bis(trifluoromethyl)
phenyl]thiourea 4 using the Hantzsch 1,4-dihydropyridine
3 as the reducing agent as shown in Scheme 1. We hoped to
obtain better results with a thiourea derivative rather than with
thiourea itself.
First, we began to explore the direct reduction
of benzaldehyde and p-anisidine using Hantzsch
1,4-dihydropydine as a model reaction. The comparative
catalytic activities of thiourea and its derivative were
examined (see Table 1). Obviously, the electron deficient
thiourea catalyst was more active than thiourea. As shown
from entries 3 to 5, the reaction yields were excellent. It
showed that thiourea derivative 4 was so efficient that the
catalyst loading could be decreased to 0.01equiv. In addition,
this direct reduction cannot happen in the absence of catalyst.
We then studied the scope of this procedure for the
synthesis of sterically, electronically and functionally diverse
amines (5a–m) (see Table 2). Electron-deficient (entry 3) and
electron-rich (entry 4) aromatic aldehydes were both easily
transformed into the products. Furthemore no reduction of
nitro group (entry 3) was observed and free hydroxyl was
tolerated (entry 5). In addition, an electron-deficient aromatic
aldehyde afforded higher yields than an electron-rich aromatic
aldehyde.
From entries 6 to 10, diverse aromatic amines were
easily reacted with aromatic aldehydes. This showed that
the approach can be applied to various aromatic amines.
Some yields of the products were good (entries 6–8), whilst
the yields of other products were moderate (entries 9–10).
Functional groups such as the nitro group and the hydroxyl
group in the amino substrate 2 were also tolerated during the
reaction process.
Only a few reports describe the reduction of imines by the
Hantzsch 1,4-dihydropydine 3, and these reactions proceeded
in low yield and required an extended reaction time. Lewis
EtOOC
COOEt
R3
NH
CF3
CF3
O
N
H
S
3
+
H2N-R3
C
R1
R2
R2
CF3
N
H
N
H
CF3
R1
Catalyst 4 (0.01eq)
5Å MS, CH2Cl2, r.t
5
4
2
1
Scheme 1 Direct reductive amination of aldehydes and ketones.
* Correspondent. E-mail: c.cai@mail.njust.edu.cn
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JOURNAL OF CHEMICAL RESEARCH 2009 687
Table 1 Direct amination of benzaldehyde and p-anisidine under different conditions
EtOOC
COOEt
OMe
OMe
CHO
N
H
N
H
+
Catalyst
NH
2
Entry
Catalyst/Equiv.
Conditionsa
Yield/%b
1
2
3
4
5
6
Thiourea (0.1)
Thiourea (1.0)
Thiourea derivative 4 (0.1)
Thiourea derivative 4 (0.01)
Thiourea derivative 4 (0.01)
None
R.t. CH2Cl2 24 h
R.t. CH2Cl2 24 h
R.t. CH2Cl2 15 h
R.t. CH2Cl2 15 h
35°C CH2Cl2 15 h
50°C, Toluene, 24 h
22%
58%
92%
90%
92%
trace
a2.0 mmol benzaldehyde, 2.2 mmol p-anisidine, 2.4 mmol Hantzsch 1,4-dihydropydine, 5Å-molecule sieve (activated)1.0 g, solvent
10 mL.
bIsolated yield using column chromatography.
Table 2 Direct reduction reaction of substitute benzaldehyde and diverse anilinea
Entry
R1
R2
R3
Product
M.p./°C
Yieldb/%
Observed
Reported
22
1
2
Ph
H
H
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
–
–
75
81
90
70
75
90
84
93
75
79
65
80c
85c
4-Cl–C6H4
4-O2N–C6H4
4-MeO–C6H4
2-HO–C6H4
Ph
Ph
50–52
67–69
63–65
110–112
48–50
88–90
97–99
92–94
140–142
–
51–5220
67–6920
3
H
Ph
4
H
Ph
63–6420
5
H
Ph
113–11420
48.6–48.96
89–9020
6
H
4-MeO–C6H4
4-HO–C6H4
4-MeO–C6H4
4-MeO–C6H4
4-O2N–C6H4
Ph
7
Ph
H
8
4-O2N–C6H4
4-MeO–C6H4
4-MeO–C6H4
PhCH=CH
Ph
H
97.7–97.96
91–9322
9
H
10
11
12
13
H
5j
5k
5l
140–14122
21
H
–
CH3
4-MeO–C6H4
4-MeO–C6H4
56–58
–
56.3–56.76
10
Cyclohexanone
5m
–
aAldehyde or ketone 2.0 mmol, amine 2.2 mmol, 2.4 mmol Hantzsch 1,4-dihydropydine, 5Å molecule sieve (activated)1.0 g,
CH2Cl210 mL, reaction time 15 h.
bisolated yield by column chromatography.
cReaction time extended to 24 h.
was removed on a rotary evaporator under reduced pressure.
We found that a C=C double bond in the substrate was not
The concentrated brown-coloured residue was added to water
reduced during the reaction (entry 11). Aliphatic ketone and
(200 mL), and the aqueous layer was extracted with diethyl ether
aromatic ketone were reduced directly to amine with good
(2 × 80 mL). The combined organic layers were washed with brine
yields (entries 12 and 13). But the reaction time was extended
to 24 h.
(1 × 80 mL) and dried over sodium sulfate. After filtration and
evaporation of the solvent, the red-brown solid crude product was
purified by recrystallisation from chloroform twice. Then pure
thiourea derivative catalyst was dried in vacuo at 70°C.
In summary, we have developed a method for the direct
reductive amination of aldehydes and ketones based on the
imine activation of hydrogen bond of thiourea derivative.
The protocol is mild and acid-free, together with the high
chemoselctivity.
General procedure for the direct reductive amination of aldehyde and
ketone
In a typical experiment, the aldehyde or ketone 1 (2.0 mmol) and
the amine 2 (2.2 mmol) in CH2Cl2 (10 mL) was treated with the
Hantzsch 1,4-dihydropydine 3 (2.4 mmol), thiourea derivative
catalyst 4 (0.02 mmol) and MS 5Å (1.0 g). The mixture was stirred
at room temperature under nitrogen atmosphere. After 15 h, the crude
product was filtered. Then the solvent was evaporated, the residue
was purified by column chromatography on silica gel using mixtures
of PE and EtOAc as elutant to give the product amines 5a–m in
pure form.
Experimental
Reagents were obtained from commercial sources. 1H NMR and
13C NMR spectra were recorded on a Bruker AM 400 spectrometer
using TMS as an internal standard, chemical shift values were given
in ppm. Mass spectra were obtained on a Sectorfield-MS. Elemental
analyses were conducted using a Yanaco MT-3CHN elemental
analyser. Melting points were uncorrected. All products were known
compounds and were identified by comparing their physical and
spectra data with those reported in the literatures.6,10,19-22
N,N'-bis[3,5-bis(trifluoromethyl)phenyl]thiourea (4):19 M.p. 172–
173°C, 1H NMR(d4-methanol) d: 7.27–7.33 (6H, m), 7.68(2H, s),
13C NMR(d4-methanol) d: 120.47, 123.17, 125.87, 132.67, 142.51,
182.20. HRMS Calcd C17H8N2SF12: 500.0216. Found: 498.6. Anal
Calcd for C17H8N2SF12: C, 40.81; H, 1.61; N, 5.60. Found: C, 40.69;
H, 1.65; N 5.68%.
General procedure of synthesis of 4
N-benzyl-p-anisidine (5f)6: M.p. 48–50°C, 1H NMR(CDCl3) d:
3.73(3H, s), 4.28(2H, s), 6.60(2H, dt, J = 9.0, 3.0 Hz), 6.77(2H, dt,
J 9.0, 2.9 Hz), 7.25(1H, tt, J 6.9, 2.1 Hz), 7.30–7.37(4H, m); 13C
NMR(CDCl3) d: 49.2, 55.8, 114.0, 114.8, 127.0, 127.4, 128.4, 139.5,
142.2, 152.0. Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57.
Found: C, 78.87; H, 7.21; N, 6.58%.
A
mixture of 3,5-bis(trifluoromethyl)aniline (50 mmol) and
triethylamine (60 mmol) in THF (300 mL) was added to a 500 mL
three-necked flask. A mixture of thiophosgene (22 mmol) in THF
(50 mL) was added dropwise to the stirred solution at –5–0°C.
After addition, the yellow suspension (a white solid precipitated)
was stirred at room temperature. After 24 h the bulk of the solvent
PAPER: JC090732

688 JOURNAL OF CHEMICAL RESEARCH 2009
N-(1-phenylethyl)-p-anisidine (5l):6 M.p. 56–58°C, 1H NMR
(CDCl3) d: 1.49 (3H, d, J = 6.6 Hz), 3.69 (3H, s), 4.40 (1H, q,
J = 6.8 Hz), 5.40 (1H, brs), 6.47 (2H, d, J = 8.8 Hz), 6.69 (2H, d,
J = 8.8 Hz), 7.21 (1H, tt, J = 7.1, 1.7 Hz), 7.29–7.37 (4H, m); 13C
NMR(CDCl3) d: 25.1, 54.2, 55.7, 114.5, 114.7, 125.9, 126.8, 128.6,
141.5, 145.5, 151.9. Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N,
6.16. Found: C, 79.01; H, 7.78; N, 6.12%.
6
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Received 11 August 2009; accepted 16 October 2009
Paper 09/0732 doi: 10.3184/030823409X12561332783406
Published online: 16 November 2009
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