Transfer hydrogenative reductive amination of aldehydes in aqueous sodium formate solution

Article abstract of DOI:10.1016/j.tetlet.2015.12.072

A practical direct reductive amination reaction of aldehydes in aqueous sodium formate solution which produces amines in good yields under mild conditions is described. The amount and strength of the acid additives were critical factors to affect the reaction selectivities. This reductive amination method has great application potential for the synthesis of amine products given the mild conditions, short reaction time, the use of water as a solvent, and the use of benign hydrogen sources.

Full text of DOI:10.1016/j.tetlet.2015.12.072

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Tetrahedron Letters 57 (2016) 509–511
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Transfer hydrogenative reductive amination of aldehydes in aqueous
sodium formate solution
Mengping Zhu
Department of Chemistry, Georgetown University, Washington, DC 20057, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical direct reductive amination reaction of aldehydes in aqueous sodium formate solution which
produces amines in good yields under mild conditions is described. The amount and strength of the acid
additives were critical factors to affect the reaction selectivities. This reductive amination method has
great application potential for the synthesis of amine products given the mild conditions, short reaction
time, the use of water as a solvent, and the use of benign hydrogen sources.
Received 30 November 2015
Revised 12 December 2015
Accepted 18 December 2015
Available online 18 December 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Aqueous
Reductive amination
Transfer hydrogenation
Ruthenium
Sodium formate
Nitrogen containing molecules have important uses in such
diverse areas as pharmaceuticals and manufacturing. Reductive
amination of carbonyls is one of the powerful convergent strate-
gies for synthesizing functionalized amine structures.1–4 Aqueous
reductive amination was not developed until the beginning of last
decade. In 2002, Beller group5 reported for the first time that direct
reductive amination of aldehydes with aqueous ammonia can be
performed using soluble transition metal catalysts. Afterward,
several groups have developed different methods of aqueous
reductive amination based on either hydride reagents or hydro-
genation using gaseous H2.6–11 However, these reactions usually
suffer some drawbacks, such as the requirement of high tempera-
tures and moderate to high pressures, or poor atom economy.
Xiao and co-workers12–16 have pioneered in the catalytic
transfer hydrogenation reactions in water. They have used
Noyori–Ikariya precatalyst RuCl(TsDPEN)(p-cymene) (1)17–19 to
hydrogenate ketones and quinolones in high yields. Other exam-
ples of catalytic transfer hydrogenation of ketones in aqueous
mixed media have also been reported.20–25 However, there is little
information on transfer hydrogenative aqueous reductive
amination in the literature.26–29 This paper reports a practical
and efficient catalytic transfer hydrogenative reductive amination
of aldehydes using the Noyori–Ikariya precatalyst RuCl(TsDPEN)
(p-cymene) (1) in aqueous sodium formate solution.
using transfer hydrogenation was finding the optimal reaction con-
ditions of temperature and acidity under which selective hydro-
genation of the intermediate imine was favored over the starting
aldehyde. Also under the optimal conditions, the formylation of
amine reagents as well as the reverse reaction of imine formation
should be minimized if possible. The results of screening experi-
ments for the reductive amination of benzaldehyde (2) with aniline
(3) using in situ formed 1 as a precatalyst and HCO2H as an acid
additive are shown in Table 1.
Clearly, product N-benzylaniline (5) selectivity is sensitive to
the amount of HCO2H and temperature. Preliminary experiments
on the reduction of N-benzylideneaniline (4) failed at room tem-
perature due to its melting point (52–54 °C) and the low solubility
in water, thus temperature screening began at 50 °C. Without the
addition of HCO2H (entry 1), no N-benzylaniline (5) but only 6%
benzyl alcohol (6) was detected, even though all the rest of ben-
zaldehyde was converted to the intermediate imine (4). This
clearly shows the essential role of acid additive in reductive amina-
tion. Addition of 0.5 equiv of HCO2H produced 40% of 5 and 19% of
6 (entry 2). Under these conditions, the selectivity toward the
desired amine product over benzyl alcohol was inferior, however,
delightful results were observed after adding additional HCO2H.
The selectivity of 5 versus 6 was enhanced as more HCO2H was
added, however, the tradeoff was that the conversion of benzalde-
hyde was reduced (entry 4–11). This phenomenon indicates that
the hydrogenation of benzaldehyde was significantly suppressed
at lower pH, whereas the reverse reaction of imine formation
was accelerated under the same conditions. With 20 equiv HCO2H,
As shown in Scheme 1 where benzaldehyde and aniline are
used as representatives, the key to aqueous reductive amination
E-mail address: mz63@georgetown.edu
http://dx.doi.org/10.1016/j.tetlet.2015.12.072
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
510
M. Zhu / Tetrahedron Letters 57 (2016) 509–511
Table 2
Reductive amination of benzaldehydeà
Entry
Amine
Time (h)
Distribution (%)
2
4c
5c
6
15a
16a
17a
18
19
20
H2N–C6H4(p-OCH3)
H2N–C6H4(p-OC2H5)
H2N–C6H4(p-CH3)
H2N–C6H5
H2N–C6H4(p-F)
H2N–C6H4(p-Cl)
H2N–C6H4(p-CN)
H2N–C6H4(p-NO2)
H2N–CH2Ph
2.0
2.0
2.0
2.0
2.0
3.0
2.0
2.0
2.0
1.5
1.0
0
0
0
0
0
0
0
0
69
0
0
0
0
0
0
0
0
0
0
0
0
0
89
92
95
94
94
92
68
22
0
0
0
3
6
6
8
32
78
31
78
100
21
22
23
24b
25b
H2N–CH2Ph
H2N–(CH2)3CH3
22
0
à
Experimental conditions: 1:2:3:HCO2Na = 1:100:100:1000, 1 mmol 1, 20 equiv
HCO2H relative to 2, 5 mL H2O, 60 °C, 750 rpm stirrer speed.
a
Yield loss was due to N-formylation of 5.
2 equiv HCO2H relative to 2, 50 °C.
4 and 5 refer to the corresponding imine and amine product.
b
c
Scheme 1. Reaction scheme for 1-catalyzed reductive amination.
For the reaction of benzaldehyde with aniline derivatives (entry
15–22), complete conversion of benzaldehyde occured within 2 or
3 h, however, selectivities toward 5 versus 6 decreased as the sub-
stituents in the para position went from electron-donating to elec-
tron-withdrawing. N-formylated side products (7) were detected
at varying levels except for the reaction of p-nitroaniline. Notably,
N-formylation of 5 was also observed for entry 15–17. When same
reaction conditions were applied to the reaction between ben-
zaldehyde and aliphatic amines, such as benzyl amine, only 31%
of benzaldehyde was converted to 6 and neither 5 nor 4 was
observed (entry 23). After screening different amounts of HCO2H
at varying temperature, the best condition was found to be with
2 equiv HCO2H at 50 °C. However, the selectivity of 5 was still
low (22%). With these modified conditions, the reaction between
benzaldehyde and n-butylamine led to benzyl alcohol (6) exclu-
sively (entry 25), suggesting that the reaction conditions involving
aliphatic amines need to be further turned.
Valeraldehyde was chosen as the aliphatic aldehyde model to
react with amine reagents, and results are shown in Table 3. Given
the possible aldol condensation of aliphatic aldehydes under acidic
conditions, the amount of HCO2H used was screened and the tem-
perature was adjusted to 50 °C. In the absence of HCO2H, only
imine was formed after 1 h reaction. In the presence of 1 equiv of
HCO2H, valeraldehyde was subjected to the aldol condensation,
and the yield loss due to aldol condensation was 63% and only
27% of desired amine product was obtained (entry 27). Increasing
the amount of HCO2H further promoted the aldol condensation
(entry 28). Therefore, the challenge with aliphatic aldehydes relies
on suppressing acid-catalyzed self-condensation reactions. After
25% yield of 5 was obtained and no yield of 6 was observed at 1 h
reaction (entry 9). Under the same conditions, the extension of
reaction time to 4 h increased the yield of 5 to 51% and 2% of 6
was formed (entry 10). Increasing the HCO2H addition to 50 equiv
maintained the high selectivity toward 5, however, it further
reduced the reactivity because of the fast reverse reaction of imine
formation. Taking into account both selectivity and reactivity,
20 equiv of HCO2H was selected to be further optimized. The tem-
perature was then raised from 50 to 60 °C to enhance the reactiv-
ity. Delightedly, the reaction accomplished completion within two
hours with 94% yield to N-benzylaniline (5), with only 6% yield loss
due to the hydrogenation of benzaldehyde itself (entry 14). It was
noted that unreacted aniline was transformed to N-phenylfor-
mamide (7) at 60 °C. It was also observed that insufficient mixing
led to inferior results (entry 3). In short, complete conversion in
2 h for a reductive amination reaction performed in water at rela-
tively low temperatures is the most significant finding of this work.
Thus, 20 equiv of HCO2H and 60 °C were chosen as the optimal
reaction conditions.
Under the optimized conditions, aqueous direct reductive
amination between benzaldehyde and a series of para-substituted
aniline derivatives as well as aliphatic amines were carried out and
results are summarized in Table 2.
Table 1
Screening results of catalytic reductive aminationà
Entry
HCO2Ha (equiv)
Time (h)
Temp (°C)
Distributionb (%)
2
4
5
6
1
0.0
0.5
0.5
0.7
1.0
3.0
5.0
10
20
20
50
20
0.3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
4.0
1.0
1.0
1.5
2.0
50
50
50
50
50
50
50
50
50
50
50
60
60
60
0
0
4
5
6
8
11
18
46
2
94
41
80
76
80
80
64
60
29
45
14
10
5
0
40
8
6
2
19
8
6
3
1
2
2
0
2
0
2
2
6
Table 3
3c
4
Reductive amination of valeraldehydeà
13
11
11
23
20
25
51
19
71
81
94
5
6
7
8
Entry Amine
Acid
equiv Time
(h)
Distribution (%)
2a 4a 5a 8b
26
27
28
29
30
31
32
H2N–C6H5
HCO2H
HCO2H
HCO2H
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
0
1
2
1
1
1
1
1.0
1.0
1.0
1.0
4.0
2.0
1.0
0
0
0
0
0
0
0
100
0
0
9
H2N–C6H5
H2N–C6H5
H2N–C6H5
H2N–C6H5
H2N–CH2Ph
H2N–
10 27 63
10 21 69
49 33 18
10
11
12
13
14
67
17
12
0
6
59 35
22 11 67
100
20
20
0
0
0
(CH2)3CH3
à
Experimental conditions: 1:2:3:HCO2Na = 1:100:100:1000, 1 mmol 1, 5 mL H2O,
à
750 rpm stirrer speed.
Experimental conditions: 1:2:3:HCO2Na = 1:100:100:1000, 1 mmol 1, 5 mL H2O,
60 °C, 750 rpm stirrer speed.
a
Relative to 2 and 3.
b
a
Determined from 1H NMR or GC–MS analysis.
2, 4, and 5 refer to valeraldehyde, the corresponding imine and amine product.
Aldol condensation products of valeraldehyde.
c
b
Stirrer speed at 350 rpm.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
M. Zhu / Tetrahedron Letters 57 (2016) 509–511
3. Tararov, V. I.; Börner, A. Synlett 2005, 203–211.
511
varying different acid additives, NaH2PO4 was found the best in
terms of minimizing the yield loss due to aldol condensation. Upon
addition of 1 equiv NaH2PO4, the yield was improved to 33% after
1 h reaction and 59% after 4 h reaction. This is a substantial
improvement over formic acid and a promising result that fine tun-
ing of the acid can result in a widening of the scope of this reaction.
Reactions between valeraldehyde and aliphatic amines were sub-
jected to more severe aldol condensation. Reaction with benzyl
amine only generated 11% of product after 2 h, and reaction with
n-butylamine resulted in no desired product formation. Therefore
the substrate scope of this method is limited to aromatic amines.
4. Gomez, S.; Peters, J. A.; Maschmeyer, T. J. Adv. Synth. Catal. 2002, 344, 1037–
1057.
5. Gross, T.; Seayad, A. M.; Ahmad, M.; Beller, M. Org. Lett. 2002, 4, 2055–2058.
6. Sato, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. Tetrahedron 2004, 60, 7899–
7906.
7. Bhor, M. D.; Bhanushali, M. J.; Nandurkar, N. S.; Bhanage, B. M. Tetrahedron Lett.
2008, 49, 965–969.
8. Lai, R. Y.; Lee, C. I.; Liu, S. T. Tetrahedron 2008, 64, 1213–1217.
9. Simion, C.; Simion, A. M.; Arimura, T.; Miyazawa, A.; Tashiro, M. Lett. Org. Chem.
2010, 7, 388–391.
10. Giovenzana, G. B.; Imperio, D.; Penoni, A.; Palmisano, G. Beilstein J. Org. Chem.
2011, 7, 1095–1099.
11. Bagal, D. B.; Watile, R. A.; Khedkar, M. V.; Dhake, K. P.; Bhanage, B. M. Sci.
Technol. 2012, 2, 354–358.
12. Li, X.; Wu, X.; Chen, W.; Hancock, F. E.; King, F.; Xiao, J. Org. Lett. 2004, 6, 3321–
3324.
13. Wang, C.; Li, C.; Wu, X.; Pettman, A.; Xiao, J. Angew. Chem., Int. Ed. 2009, 48,
6524–6528.
14. Wu, X.; Li, X.; Zanotti-Gerosa, A.; Pettman, A.; Liu, J.; Mills, A. J.; Xiao, J. Chem.
Eur. J. 2008, 14, 2209–2222.
15. Wu, X.; Liu, J.; Tommaso, D. D.; Iggo, J. A.; Catlow, C. R. A.; Bacsa, J.; Xiao, J.
Chem. Eur. J. 2008, 14, 7699–7715.
16. Wu, X.; Xiao, J. Chem. Commun. 2007, 2449–2466.
17. Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed.
1997, 36, 285–288.
18. Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. 1997, 36, 288–290.
19. Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393–406.
20. Liu, Z. S.; Rempel, G. L. J. Mol. Catal. A: Chem. 2007, 278, 228–236.
21. Romain, C.; Gaillard, S.; Elmkaddem, M. K.; Toupet, L.; Fischmeister, C.;
Thomas, C. M.; Renaud, J.-L. Organometallics 2010, 29, 1992–1995.
22. Wang, F.; Liu, H.; Cun, L.; Zhu, J.; Deng, J.; Jiang, Y. J. Org. Chem. 2005, 70, 9424–
9429.
23. Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun, L.; Zhu, J.; Deng, J.; Yu, B. Chem. Commun.
2006, 1766–1768.
24. Zhu, M. Appl. Catal., A: Gen. 2014, 479, 45–48.
For (g
6-arene)Ru(II) piano stool complexes Ts-DPEN is consid-
ered the benchmark ligand for assessing the catalytic performance
of bifunctional hydrogenation reactions, whether they are
asymmetric transformations or not. For this reason the chiral
(S,S)-Ts-DPEN ligand was employed in this study although none
of the substrates included enantiomerically pure or racemic
a-branched aldehydes. However, using the parent N-tosylethylene-
diamine ligand, lacking any substitution in the backbone, gave 79%
of 5 which was inferior to the 94% yield when Ts-DPEN was used
under the same conditions. Notedly, compared with the previously
reported reductive amination using Noyori–Ikariya catalyst in
HCOOH/NEt3 mixture,30 the aqueous catalytic method is limited
to aromatic amines.
In conclusion, the optimal conditions for reductive amination of
anilines with sodium formate in aqueous formic acid catalyzed by
RuCl(TsDPEN)(p-cymene) (1) were found. The merits of this reduc-
tive amination are short reaction times, mild conditions, and the
use of water as solvent.31 The reactions are carried out under nitro-
gen but do not require degassing or high pressure gas handling.
This reaction can be conducted on the bench top without
specialized equipment. The active catalyst is used in 1 mol % and
is generated in situ from commercially available reagents. This
reaction is particularly suitable for rapid library synthesis, for mod-
ification of biological molecules, or for synthesis on a large scale.
25. Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621–6686.
26. McFarland, J. M.; Francis, M. B. J. Am. Chem. Soc. 2005, 127, 13490–13491.
27. Ogo, S.; Uehara, K.; Abura, T.; Fukuzumi, S. J. Am. Chem. Soc. 2004, 126, 3020–
3021.
28. Lei, Q.; Wei, Y.; Talwar, D.; Wang, C.; Xue, D.; Xiao, J. Chem. Eur. J. 2013, 19,
4021–4029.
29. Wei, Y.; Wu, X.; Wang, C.; Xiao, J. Catal. Today 2015, 247, 104–116.
30. Zhu, M. Catal. Lett. 2014, 144, 1568–1572.
31. A typical catalytic reaction was carried out in the following manner: [RuCl2(p-
cymene)]2 (3.1 mg, 0.005 mmol) and (1S,2S)-TsDPEN (4.4 mg, 0.012 mmol)
were stirred in 3 mL distilled water at 50 °C under N2 for 15 min. Meanwhile,
Acknowledgement
aniline (91
lL, 1 mmol) was slowly added to 1 mL water solution containing
benzaldehyde (102
lL, 1 mmol) at room temperature to immediately form a
cloudy white mixture. After 5 min, the substrate mixture was combined with a
1 mL aqueous solution containing HCO2Na (680 mg, 10 mmol) and HCO2H
(760 lL, 20 mmol). Under N2, the yellowish catalyst solution was transferred to
The author would like to thank Dr. Bahram Moasser for the
assistance, support, and comments.
the substrate/formate/formic acid mixture via syringe and the mixture stirred
(750 rpm) at 50 or 60 °C. After a given time interval, catalysis was quenched by
cooling the reaction vial to room temperature. Around 3 mL of methylene
chloride was added to the reaction vial and mixed thoroughly. Approximately
10 drops of the organic layer were removed and diluted in CDCl3 to make NMR
samples. The conversion was determined by NMR spectroscopy and/or GC–MS.
References and notes
1. Robichaud, A.; Ajjou, A. N. Tetrahedron Lett. 2006, 47, 3633–3636.
2. Ohkuma, T.; Noyori, R. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 2004; Suppl. 1.